Hiney, Jill K; Srivastava, Vinod K; Vaden Anderson, Danielle N; Hartzoge, Nicole L; Dees, William L
Alcohol (ALC) causes suppressed secretion of prepubertal luteinizing hormone-releasing hormone (LHRH). Insulin-like growth factor-1 (IGF-1) and kisspeptin (Kp) are major regulators of LHRH and are critical for puberty. IGF-1 may be an upstream mediator of Kp in the preoptic area and rostral hypothalamic area (POA/RHA) of the rat brain, a region containing both Kp and LHRH neurons. We investigated the ability of IGF-1 to stimulate prepubertal Kp synthesis and release in POA/RHA, and the potential inhibitory effects of ALC. Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 0730 hours. At 0900 hours, both groups were subdivided where half received either saline or IGF-1 into the brain third ventricle. A second dose of ALC (2 g/kg) or water was administered at 1130 hours. Rats were killed 6 hours after injection and POA/RHA region collected. IGF-1 stimulated Kp, an action blocked by ALC. Upstream to Kp, IGF-1 receptor (IGF-1R) activation, as demonstrated by the increase in insulin receptor substrate 1, resulted in activation of Akt, tuberous sclerosis 2, ras homologue enriched in brain, and mammalian target of rapamycin (mTOR). ALC blocked the central action of IGF-1 to induce their respective phosphorylation. IGF-1 specificity and ALC specificity for the Akt-activated mTOR pathway were demonstrated by the absence of effects on PRAS40. Furthermore, IGF-1 stimulated Kp release from POA/RHA incubated in vitro. IGF-1 stimulates prepubertal Kp synthesis and release following activation of a mTOR signaling pathway, and ALC blocks this pathway at the level of IGF-1R. Copyright © 2017 by the Research Society on Alcoholism.
Full Text Available Abstract Background The hypothalamus is a brain region with essential functions for homeostasis and energy metabolism, and alterations of its development can contribute to pathological conditions in the adult, like hypertension, diabetes or obesity. However, due to the anatomical complexity of the hypothalamus, its development is not well understood. Sonic hedgehog (Shh is a key developmental regulator gene expressed in a dynamic pattern in hypothalamic progenitor cells. To obtain insight into hypothalamic organization, we used genetic inducible fate mapping (GIFM to map the lineages derived from Shh-expressing progenitor domains onto the four rostrocaudally arranged hypothalamic regions: preoptic, anterior, tuberal and mammillary. Results Shh-expressing progenitors labeled at an early stage (before embryonic day (E9.5 contribute neurons and astrocytes to a large caudal area including the mammillary and posterior tuberal regions as well as tanycytes (specialized median eminence glia. Progenitors labeled at later stages (after E9.5 give rise to neurons and astrocytes of the entire tuberal region and in particular the ventromedial nucleus, but not to cells in the mammillary region and median eminence. At this stage, an additional Shh-expressing domain appears in the preoptic area and contributes mostly astrocytes to the hypothalamus. Shh-expressing progenitors do not contribute to the anterior region at any stage. Finally, we show a gradual shift from neurogenesis to gliogenesis, so that progenitors expressing Shh after E12.5 generate almost exclusively hypothalamic astrocytes. Conclusions We define a fate map of the hypothalamus, based on the dynamic expression of Shh in the hypothalamic progenitor zones. We provide evidence that the large neurogenic Shh-expressing progenitor domains of the ventral diencephalon are continuous with those of the midbrain. We demonstrate that the four classical transverse zones of the hypothalamus have clearly
Dong, Jun; Xie, Xin-Hua; Lu, Da-Xiang; Fu, Yong-Mei
Although there is considerable evidence supporting that fever evolved as a host defense response, it is important that the rise in body temperature would not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified. Endogenous antipyretics attenuate fever by influencing the thermoregulatory neurons in the preoptic anterior hypothalamus (POAH) and in adjacent septal areas including ventral septal area (VSA). Our previous study showed that intracerebroventricular (I.C.V.) injection of interleukin-1beta (IL-1beta) affected electrophysiological activities of thermosensitive neurons in VSA regions, and electrical stimulation of POAH reversed the effect of IL-1beta. To further investigate the functional electrophysiological connection between POAH and VSA and its mechanisms in thermoregulation, the firing rates of thermosensitive neurons in POAH of forty-seven unit discharge were recorded by using extracellular microelectrode technique in New Zealand white rabbits. Our results show that the firing rates of the warm-sensitive neurons decreased significantly and those of the cold-sensitive neurons increased in POAH when the pyrogen (IL-1beta) was injected I.C.V. The effects of IL-1beta on firing rates in thermosensitive neurons of POAH were reversed by electrical stimulation of VSA. An arginine vasopressin (AVP) V1 antagonist abolished the regulatory effects of VSA on the firing rates in thermosensitive neurons of POAH evoked by IL-1beta. However, an AVP V2 antagonist had no effects. These data indicated that VSA regulates the activities of the thermosensitive neurons of POAH through AVP V1 but not AVP V2 receptor.
Larsen, P J; Hay-Schmidt, Anders; Mikkelsen, J D
, iontophoretic injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin were delivered into distinct areas of the lateral hypothalamic region. Neurons of the intermediate hypothalamic area projected mainly to the PVN subnuclei, which contained parvicellular neuroendocrine cells. In contrast...
Fahlbusch, R.; Schrell, U.
On one hand pituitary microadenomas with autonomous character and those, which had been influenced by hypothalamic disorders, are summarized and discussed. On the other hand, the neurosurgical management of tumours, adjacent to our involved with the hypothalamus, are described. Endocrinologically active pituitary adenomas are characterized by their hormone excess of ACTH, GH, and prolactin. In Cushing's disease endocrine and clinical remission occurred in 74%. 3 patients out of this group showed a reincrease of ACTH after a period of remission, indicating a possible hypothalamic influence. In acromegaly the hypothalamic influence is also discussed. One patient with an ectopic GRF-producing tumour showing a reincrease of GH levels after successful transsphenoidal adenomectomy has been described. In microprolactinomas, 7 patients out of 45 showed a reincrease of prolactin-levels after a period of normalization, we also discussed hypothalamic disorders. Tumours with suprasellar extension such as macroadenomas without endocrine activity and meningiomas are removed nowadays with minimal risk for the life of the patients. In craniopharyngiomas radical excision is accompanied by a high risk of hypothalamic defects caused by mechanical lesions and possible secondary vasospasm. Finally the excision of a hamartoma growing from the floor of the third ventricle into the interpeduncular cistern is discussed. Up to now the successful excision could be documented by endocrinological data, which give no sign of further growth of the hamartoma. (Author)
Fahlbusch, R.; Schrell, U. (Erlangen-Nuernberg Univ., Erlangen (Germany, F.R.))
On one hand pituitary microadenomas with autonomous character and those, which had been influenced by hypothalamic disorders, are summarized and discussed. On the other hand, the neurosurgical management of tumours, adjacent to or involved with the hypothalamus, are described. Endocrinologically active pituitary adenomas are characterized by their hormone excess of ACTH, GH, and prolactin. In Cushing's disease endocrine and clinical remission occurred in 74%. 3 patients out of this group showed a reincrease of ACTH after a period of remission, indicating a possible hypothalamic influence. In acromegaly the hypothalamic influence is also discussed. One patient with an ectopic GRF-producing tumour showing a reincrease of GH levels after successful transsphenoidal adenomectomy has been described. In microprolactinomas, 7 patients out of 45 showed a reincrease of prolactin-levels after a period of normalization, we also discussed hypothalamic disorders. Tumours with suprasellar extension such as macroadenomas without endocrine activity and meningiomas are removed nowadays with minimal risk for the life of the patients. In craniopharyngiomas radical excision is accompanied by a high risk of hypothalamic defects caused by mechanical lesions and possible secondary vasospasm. Finally the excision of a hamartoma growing from the floor of the third ventricle into the interpeduncular cistern is discussed. Up to now the successful excision could be documented by endocrinological data, which give no sign of further growth of the hamartoma.
Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C.; Ali, Almas; Tamarina, Natalia; Philipson, Louis H.; Enquist, Lynn W.; Myers, Martin G.
The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. PMID:27207534
Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud; Patterson, Christa; Flak, Jonathan; Becker, Thomas C; Ali, Almas; Tamarina, Natalia; Philipson, Louis H; Enquist, Lynn W; Myers, Martin G; Rhodes, Christopher J
The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia. © 2016 by the American Diabetes Association.
Full Text Available Most studies in mammals and birds have demonstrated common patterns of hypothalamic development highlighted by the combination of developmental regulatory genes (genoarchitecture, supporting the notion of the hypothalamus as a component of the secondary prosencephalon, topologically rostral to the diencephalon. In our comparative analysis we have summarized the data on the expression patterns of different transcription factors and neuroactive substances, used as anatomical markers, in the developing hypothalamus of the amphibian Xenopus laevis and the juvenile turtle Pseudemys scripta. This analysis served to highlight the organization of the hypothalamus in the anamniote/amniotic transition. We have identified supraoptoparaventricular and the suprachiasmatic regions in the alar part of the hypothalamus, and tuberal and mammillary regions in the basal hypothalamus. Shared features in the two species are: 1 The supraoptoparaventricular region is defined by the expression of Otp and the lack of Nkx2.1/Isl1. It is subdivided into rostral, rich in Otp and Nkx2.2, and caudal, only Otp-positive, portions. 2 The suprachiasmatic area contains catecholaminergic cell groups and lacks Otp, and can be further divided into rostral (rich in Nkx2.1 and Nkx2.2 and a caudal (rich in Isl1 and devoid of Nkx2.1 portions. 3 Expression of Nkx2.1 and Isl1 define the tuberal hypothalamus and only the rostral portion expresses Otp. 4 Its caudal boundary is evident by the lack of Isl1 in the adjacent mammillary region, which expresses Nkx2.1 and Otp. Differences in the anamnio-amniote transition were noted since in the turtle, like in other amniotes, the boundary between the alar hypothalamus and the telencephalic preoptic area shows distinct Nkx2.2 and Otp expressions but not in the amphibian (anamniote, and the alar supraoptoparaventricular region is defined by the expression of Otp/Pax6, whereas in Xenopus only Otp is expressed.
Full Text Available Hypothalamic glioma account for 10-15% of supratentorial tumors in children. They usually present earlier (first 5 years of age than craniopharyngioma. Hypothalamic glioma poses a diagnostic dilemma with craniopharyngioma and other hypothalamic region tumors, when they present with atypical clinical or imaging patterns. Neuroimaging modalities especially MRI plays a very important role in scrutinizing the lesions in the hypothalamic region. We report a case of a hypothalamic glioma masquerading as a craniopharyngioma on imaging along with brief review of both the tumors.
Mori, Koreaki; Takeuchi, Juji; Hanakita, Junya; Handa, Hajime; Nakano, Yoshihisa.
Two cases of hypothalamic hamartoma were reported. Hypothalamic hamartoma is a rate tumor. The onset of symptoms is in infancy and early childhood. Clinical symptoms are composed of convulsive seizures, laughing spells and precocious puberty. CT finding of hypothalamic hamartoma is a mass in the suprasellar and interpeduncular cisterns which has the same density as the surrounding normal brain. The mass is not enhanced by injection of the contrast material and is easily differentiated from other masses in the suprasellar region. (author)
Zhong, Ying-Jun; Feng, Zhen; Wang, Liang; Wei, Tian-Qi
A coma is a serious complication, which can occur following traumatic brain injury (TBI), for which no effective treatment has been established. Previous studies have suggested that neural electrical stimulation, including median nerve stimulation (MNS), may be an effective method for treating patients in a coma, and orexin‑A, an excitatory hypothalamic neuropeptide, may be involved in wakefulness. However, the exact mechanisms underlying this involvement remain to be elucidated. The present study aimed to examine the arousal‑promoting role of MNS in rats in a TBI‑induced coma and to investigate the potential mechanisms involved. A total of 90 rats were divided into three groups, comprising a control group, sham‑stimulated (TBI) group and a stimulated (TBI + MNS) group. MNS was performed on the animals, which were in a TBI‑induced comatose state. Changes in the behavior of the rats were observed following MNS. Subsequently, hypothalamic tissues were extracted from the rats 6, 12 and 24 h following TBI or MNS, respectively. The expression levels of orexin‑A and orexin receptor‑1 (OX1R) in the hypothalamus were examined using immunohistochemistry, western blotting and an enzyme‑linked immunosorbent assay. The results demonstrated that 21 rats subjected to TBI‑induced coma exhibited a restored righting reflex and response to pain stimuli following MNS. In addition, ignificant differences in the expression levels of orexin‑A and OXIR were observed among the three groups and among the time‑points. Orexin‑A and OX1R were upregulated following MNS. The rats in the stimulated group reacted to the MNS and exhibited a re‑awakening response. The results of the present study indicated that MNS may be a therapeutic option for TBI‑induced coma. The mechanism may be associated with increasing expression levels of the excitatory hypothalamic neuropeptide, orexin-A, and its receptor, OX1R, in the hypothalamic region.
Dixon-Douglas, Julia; Burgess, John; Dreyer, Michael
Hypothalamic involvement in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is rare and endocrinopathies involving the hypothalamic-pituitary axis in patients with demyelinating conditions have rarely been reported. We present two cases of MS/NMOSD with associated hypothalamic-pituitary involvement and subsequent hypopituitarism, including the first report of a patient with hypothalamic demyelination causing panhypopituitarism. Differential diagnoses, including alemtuzumab-related and primary pituitary pathology are discussed. © 2018 Royal Australasian College of Physicians.
López-González, M V; Díaz-Casares, A; Peinado-Aragonés, C A; Lara, J P; Barbancho, M A; Dawid-Milner, M S
In order to assess the possible interactions between the pontine A5 region and the hypothalamic defence area (HDA), we have examined the pattern of double staining for c-Fos protein immunoreactivity (c-Fos-ir) and tyrosine hydroxylase, throughout the rostrocaudal extent of the A5 region in spontaneously breathing anaesthetized male Sprague-Dawley rats during electrical stimulation of the HDA. Activation of the HDA elicited a selective increase in c-Fos-ir with an ipsilateral predominance in catecholaminergic and non-catecholaminergic A5 somata (P HDA. Cardiorespiratory changes were analysed in response to electrical stimulation of the HDA before and after ipsilateral microinjection of muscimol within the A5 region. Stimulation of the HDA evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (P HDA stimulation were reduced (P HDA and the A5 region, extracellular recordings of putative A5 neurones were obtained during HDA stimulation. Seventy-five A5 cells were recorded, 35 of which were affected by the HDA (47%). These results indicate that neurones of the A5 region participate in the cardiovascular response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.
Baldino, F; Davis, L G; Wolfson, B
The purpose of this study was to determine the structural requirements for the activity of neurotensin (NT1-13) on preoptic/anterior hypothalamic (POAH) neurons in vitro. Standard explant culture electrophysiological techniques were employed. NT was administered to POAH cultures through the superfusion fluid, or, to the vicinity of individual neurons by pressure ejection (0.5-10 psi) from micropipettes. Computer-generated, peri-event histograms were used to quantitate neuronal responses. Pressure ejection of NT1-13 (50 pM to 1 microM) consistently produced an excitatory effect on 30 of 42 neurons. The remaining cells were either inhibited or unaffected. Application of the C-terminal hexapeptide, NT8-13, but not the N-terminal octapeptide, NT1-8 (less than or equal to 1 mM), produced an excitatory response in 21 of 30 neurons, but was less potent than NT1-13. Application of an N-acetylated NT8-13 fragment (NTAC8-13) produced a response that was similar to that produced by NT8-13. The excitatory effects of NT1-13 and NT8-13 were maintained in medium which effectively blocked synaptic transmission (0 mM Ca2+/12 mM Mg2+ 1 mM EGTA). These data indicate that the C-terminal hexapeptide, but not the N-terminal octapeptide, produces a dose-related, excitatory effect on single neurons in the POAH in vitro. The persistence of these effects in Ca2+-free medium supports a postsynaptic site of action for these peptides.
Kalina, Maria A; Kalina-Faska, Barbara; Gruszczyńska, Katarzyna; Baron, Jan; Małecka-Tendera, Ewa
The purpose of this study is to assess the relationship between magnetic resonance images (MRI) of the hypothalamic-pituitary (H-P) region and response to recombinant human growth hormone (rhGH) treatment in short children with growth hormone deficiency, basing on changes of auxologic parameters, as well as to answer the question if MRI may serve for selecting and monitoring the rhGH responders. The study group comprised 85 children treated with rhGH, aged 7.3-18.7 years, followed for the mean period of 3.2 years (range, 2.1-9.5 years). Auxologic parameters (height deficit hSDS, deviation from the mid-parental height hSDS-mpSDS, bone delay index bone age/chronological age ratio (BA/CA)) were assessed before, during and at the end of rhGH treatment; growth velocity was calculated before and during rhGH therapy. Parameters were correlated with the MRI of the H-P region. Structural anomalies of the H-P region were found in 22 (25.9%) children: empty sella syndrome (ESS) in 12 (14.1%) patients, ectopic posterior pituitary (EPP) in ten (11.8%). Patients' height deficit and their deviation from parental height before rhGH therapy was significantly greater in the EPP group (median hSDS = -3.8; hSDS-mpSDS = -2.5), bone age delay was the greatest in the ESS group (median BA/CA = 0.69), after therapy - in the EPP group (median BA/CA = 0.82). Growth velocity improved in the first year of the rhGH therapy in all groups; however, the most significant acceleration was observed in the EPP group (median delta hSDS = 0.9), then stabilised and was comparable in all groups. MRI may be helpful in predicting response to the rhGH treatment, providing midline abnormalities are taken into account.
Bataduwaarachchi, Vipula R.; Tissera, Nirmali
Paraneoplastic limbic encephalitis is an uncommon association of common malignancies such as small cell lung carcinoma, testicular teratoma, and breast carcinoma. The nonspecific nature of the clinical presentation, lack of freely available diagnostic markers, and requirement for advanced imaging techniques pose a great challenge in the diagnosis of this disease in resource-poor settings. A 64-year-old previously healthy Sri Lankan man was admitted to the general medical unit with subacute memory impairment regarding recent events that had occurred during the previous 3 weeks. Initial noncontrast computed tomography of the brain revealed a hyperdensity in the hypothalamic region surrounded by hypodensities extending toward the bilateral temporal lobes; these findings were consistent with a possible hypothalamic tumor with perilesional edema. The patient later developed cranial diabetes insipidus, which was further suggestive of hypothalamic disease. Interestingly, gadolinium-enhanced magnetic resonance imaging of the brain showed no such lesions; instead, it showed prominent T2-weighted signals in the inner mesial region, characteristic of encephalitis. The possibility of tuberculosis and viral encephalitis was excluded based on cerebrospinal fluid analysis results. Limbic encephalitis with predominant hypothalamitis was suspected based on the radiological pattern. Subsequent screening for underlying malignancy revealed a mass lesion in the right hilum on chest radiographs. Histological examination of the lesion showed small cell lung cancer of the “oat cell” variety. We suggest that the initial appearance of a hyperdensity in the hypothalamus region on noncontrast computed tomography is probably due to hyperemia caused by hypothalamitis. If hypothalamitis is predominant in a patient with paraneoplastic limbic encephalitis, magnetic resonance imaging will help to differentiate it from a hypothalamic secondary deposit. Limbic encephalitis should be considered in
Stelmachowska, M.; Bolko, P.; Wasko, R.; Sowinski, J.; Kosinski, D.; Towpik, I.
Lymphocytic hypophysitis is an unusual disorder that nearly exclusively affects women. We present a case of 69 year-old female patient who developed the symptoms of diabetes insipidus and partial insufficiency of the anterior pituitary gland. Magnetic resonance imaging of the brain revealed a mass involving the sella and suprasellar region. After exclusion of other causes of infiltrate in this region and due to evident reaction to glucocorticoid treatment the diagnosis of lymphocytic hypophisitis and hypothalamitis was established. (author)
Cai, Dongsheng; Liu, Tiewen
The hypothalamus is one of the master regulators of various physiological processes, including energy balance and nutrient metabolism. These regulatory functions are mediated by discrete hypothalamic regions that integrate metabolic sensing with neuroendocrine and neural controls of systemic physiology. Neurons and non-neuronal cells in these hypothalamic regions act supportively to execute metabolic regulations. Under conditions of brain and hypothalamic inflammation, which may result from overnutrition-induced intracellular stresses or disease-associated systemic inflammatory factors, extracellular and intracellular environments of hypothalamic cells are disrupted, leading to central metabolic dysregulations and various diseases. Recent research has begun to elucidate the effects of hypothalamic inflammation in causing diverse components of metabolic syndrome leading to diabetes and cardiovascular disease. These new understandings have provocatively expanded previous knowledge on the cachectic roles of brain inflammatory response in diseases, such as infections and cancers. This review describes the molecular and cellular characteristics of hypothalamic inflammation in metabolic syndrome and related diseases as opposed to cachectic diseases, and also discusses concepts and potential applications of inhibiting central/hypothalamic inflammation to treat nutritional diseases. PMID:22417140
Full Text Available The hypothalamus is a brain region which regulates homeostasis by mediating endocrine, autonomic and behavioral functions. It is comprised of several nuclei containing distinct neuronal populations producing neuropeptides and neurotransmitters that regulate fundamental body functions including temperature and metabolic rate, thirst and hunger, sexual behavior and reproduction, circadian rhythm, and emotional responses. The identity, number and connectivity of these neuronal populations are established during the organism’s development and are of crucial importance for normal hypothalamic function. Studies have suggested that developmental abnormalities in specific hypothalamic circuits can lead to obesity, sleep disorders, anxiety, depression and autism. At the molecular level, the development of the hypothalamus is regulated by transcription factors, secreted growth factors, neuropeptides and their receptors. Recent studies in zebrafish and mouse have demonstrated that some of these molecules maintain their expression in the adult brain and subsequently play a role in the physiological functions that are regulated by hypothalamic neurons. Here, we summarize the involvement of some of the key developmental factors in hypothalamic development and function by focusing on the mouse and zebrafish genetic model organisms.
Hahn, F.J.; Leibrock, L.G.; Huseman, C.A.; Makos, M.M.
Hypothalamic hamartoma is the most common detectable cerebral lesion causing precocious puberty. Two histologically confirmed cases were studied by computerized tomography (CT) and magnetic resonance (MR) imaging. T2 weighted, sagittal MR images were superior to CT in delineating the tumor from surrounding grey matter. The lesion was isointense to grey matter on T1 weighted images allowing exclusion of other hypothalamic tumors. MR will undoubtedly become the imaging modality of choice in the detection of hypothalamic hamartoma.
Full Text Available One of the most striking examples of dysfunctional hypothalamic signaling of energy homeostasis is observed in patients with hypothalamic lesions leading to hypothalamic obesity (HO. This drastic condition is frequently seen in patients with craniopharyngioma (CP, an embryological tumor located in the hypothalamic and/or pituitary region, frequently causing not only hypopituitarism, but also leading to damage of medial hypothalamic nuclei due to the tumor and its treatment. HO syndrome in CP patients is characterized by fatigue, decreased physical activity, uncontrolled appetite, and morbid obesity, and is associated with insulin and leptin resistance. Mechanisms leading to the profoundly disturbed energy homeostasis are complex. This review summarizes different aspects of important clinical studies as well as data obtained in rodent studies. In addition a model is provided describing how medial hypothalamic lesion can interact simultaneously with several weight regulating circuitries.
Werder, K. von; Mueller, O.A.
Hormonal disturbances caused by hypothalamic pathology can be treated effectively by target hormone replacement in the case of failure of glandotropic hormone secretion. Hyposomatotropism in children has to be substituted by parenteral administration of growth hormone. In addition gonadotropins respectively gonadotropin releasing factor have to be given in order to restore fertility in hypothalamic hypogonadism. Posterior pituitary failure can be adequately replaced by administration of analogues of antidiuretic hormone. Hypothalamic pathology causing hypersecretion of anterior pituitary hormones may also be accessable to medical treatment. This pertains particularly to hyperprolactinemia and precocious puberty. However, there is no medical therapy so far for hypothalamic disturbances leading to veterative dysfunction like disturbances of temperature regulation and control of thirst and polyphagia. In this situation symptomatic correction of the abnormality represents the only possibility to keep these patients alive. (Author)
Autophagy is a conserved cellular turnover process that degrades unwanted cytoplasmic material within lysosomes. Through ?in bulk? degradation of cytoplasmic proteins and organelles, including lipid droplets, autophagy helps provide an alternative fuel source, in particular, when nutrients are scarce. Recent work demonstrates a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in regulation of food intake and energy balance. The induction of autophagy in hypothalamic ne...
Stárka, Luboslav; Dušková, Michaela
Functional hypothalamic amenorrhea (FHA) besides pregnancy and syndrome of polycystic ovary is one of the most common causes of secondary amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). FHA is a form of the defence of organism in situations where life functions are more important than reproductive function. FHA is reversible; it can be normalized after ceasing the stress situation. There are three types of FHA: weight loss related, stress-related, and exercise-related amenorrhea. The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. Women health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects.
Cota, Daniela; Proulx, Karine; Smith, Kathi A Blake; Kozma, Sara C; Thomas, George; Woods, Stephen C; Seeley, Randy J
The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.
Christian L. Roth
Full Text Available Hypothalamic obesity (HO occurs in patients with tumors and lesions in the medial hypothalamic region. Hypothalamic dysfunction can lead to hyperinsulinemia and leptin resistance. This review is focused on HO caused by craniopharyngiomas (CP, which are the most common childhood brain tumors of nonglial origin. Despite excellent overall survival rates, CP patients have substantially reduced quality of life because of significant long-term sequelae, notably severe obesity in about 50% of patients, leading to a high rate of cardiovascular mortality. Recent studies reported that both hyperphagia and decreased energy expenditure can contribute to severe obesity in HO patients. Recognized risk factors for severe obesity include large hypothalamic tumors or lesions affecting several medial and posterior hypothalamic nuclei that impact satiety signaling pathways. Structural damage in these nuclei often lead to hyperphagia, rapid weight gain, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue. To date, most efforts to treat HO have shown disappointing long-term success rates. However, treatments based on the distinct pathophysiology of disturbed energy homeostasis related to CP may offer options for successful interventions in the future.
Littley, M.D.; Shalet, S.M.; Beardwell, C.G.
This paper reports on radiation therapy which is an essential treatment in the management of many conditions. It is important to appreciate the high incidence of subsequent endocrine morbidity, however, if the hypothalamic pituitary region is within the radiation fields. This is very much more common with external radiation therapy than with other forms of radiation treatment. The dose and fractional of administered radiation are important determinants of the endocrine deficits, their time on onset, and severity. Irradiation of large volumes of brain and hypothalamus may increase the risk of hormonal abnormalities as may preceding surgery in the treatment of pituitary disease. The phenomena observed in children and adults illustrate that there may be damage to pituitary, hypothalamus, and higher centers. In patients who have received a significant radiation dose to the hypothalamic-pituitary region, regular follow-up is mandatory. In adults, surveillance will include pituitary function testing on an annual basis for at least 10 years. In children careful monitoring of growth and pubertal development and early treatment of radiation-induced GH deficiency are vital
Ranke, M B; Bierich, J R
In five cases of Sotos Syndrome serum somatomedin activities were measured. In two of these cases elevated levels and an increased secretion of growth hormone was observed. In one case (index case) a suspected hypothalamic tumor mass could be excluded, but hydrocephalus with increased intracranial pressure was present. The pathogenesis of gigantism in this syndrome is discussed.
Projection from the prefrontal cortex to histaminergic cell groups in the posterior hypothalamic region of the rat. Anterograde tracing with Phaseolus vulgaris leucoagglutinin combined with immunocytochemistry of histidine decarboxylase
Wouterlood, F.G.; Steinbusch, H.W.M.; Luiten, P.G.M.; Bol, J.G.J.M.
We investigated the projection from the infralimbic division of the prefrontal cortex (area 25) to histaminergic neurons in the posterior hypothalamic area. Phaseolus vulgaris-leucoagglutinin (PHA-L) was injected in the prefrontal cortex of rats. Frozen brain sections were subjected to combined
Full Text Available Some pathological conditions with feeding pattern alterations, including obesity and Huntington disease (HD are associated with hypothalamic dysfunction and neuronal cell death. Additionally, the hypothalamus is a neurogenic region with the constitutive capacity to generate new cells of neuronal lineage, in adult rodents. The aim of the present work was to evaluate the expression of feeding-related neuropeptides in hypothalamic progenitor cells and their capacity to differentiate to functional neurons which have been described to be affected by hypothalamic dysfunction. Our study shows that hypothalamic progenitor cells from rat embryos grow as floating neurospheres and express the feeding-related neuropeptides Neuropeptide Y (NPY, Agouti-related Protein (AGRP, Pro-OpioMelanocortin (POMC, Cocaine-and-Amphetamine Responsive Transcript (CART and Orexin-A/Hypocretin-1. Moreover the relative mRNA expression of NPY and POMC increases during the expansion of hypothalamic neurospheres in proliferative conditions.Mature neurons were obtained from the differentiation of hypothalamic progenitor cells including NPY, AGRP, POMC, CART and Orexin-A positive neurons. Furthermore the relative mRNA expression of NPY, CART and Orexin-A increases after the differentiation of hypothalamic neurospheres. Similarly to the adult hypothalamic neurons the neurospheres-derived neurons express the glutamate transporter EAAT3. The orexigenic and anorexigenic phenotype of these neurons was identified by functional response to ghrelin and leptin hormones, respectively. This work demonstrates the presence of appetite-related neuropeptides in hypothalamic progenitor cells and neurons obtained from the differentiation of hypothalamic neurospheres, including the neuronal phenotypes that have been described by others as being affected by hypothalamic neurodegeneration. These in vitro models can be used to study hypothalamic progenitor cells aiming a therapeutic intervention to
Bingham, Nathan C.; Rose, Susan R.; Inge, Thomas H.
Craniopharyngiomas (CP) are epithelial neoplasms generally found in the area of the pituitary and hypothalamus. Despite benign histology, these tumors and/or their treatment often result in significant, debilitating disorders of endocrine, neurological, behavioral, and metabolic systems. Severe obesity is observed in a high percentage of patients with CP resulting in significant comorbidities and negatively impacting quality of life. Obesity occurs as a result of hypothalamic damage and disru...
Full Text Available Craniopharyngiomas (CP are epithelial neoplasms generally found in the area of the pituitary and hypothalamus. Despite benign histology, these tumors and/or their treatment often result in significant, debilitating disorders of endocrine, neurological, behavioral, and metabolic systems. Severe obesity is observed in a high percentage of patients with CP resulting in significant comorbidities and negatively impacting quality of life. Obesity occurs as a result of hypothalamic damage and disruption of normal homeostatic mechanisms regulating energy balance. Such pathological weight gain, termed hypothalamic obesity (HyOb, is often severe and refractory to therapy.Unfortunately, neither lifestyle intervention nor pharmacotherapy has proven truly effective in the treatment of CP-HyOb. Given the limited choices and poor results of these treatments, several groups have examined bariatric surgery as a treatment alternative for patients with CP-HyOb. While a large body of evidence exists supporting the use of bariatric surgery in the treatment of exogenous obesity and its comorbidities, its role in the treatment of HyOb has yet to be well defined. To date, the existing literature on bariatric surgery in CP-HyOb is largely limited to case reports and series with short term follow-up. Here we review the current reports on the use of bariatric surgery in the treatment of CP-HyOb. We also compare these results to those reported for other populations of HyOb, including Prader-Willi Syndrome and patients with melanocortin signaling defects. While initial reports of bariatric surgery in CP-HyOb are promising, their limited scope makes it difficult to draw any substantial conclusions as to the long term safety and efficacy of bariatric surgery in CP-HyOb. There continues to be a need for more robust, controlled, prospective trials with long term follow-up in order to better define the role of bariatric surgery in the treatment of all types of hypothalamic
This case report describes a patient who presented with panhypopituitarism secondary to hypothalamic metastasis. A primary hypothalamic abnormality was suggested by computed tomographic (CT) demonstration of a small enhancing circular mass centered within the hypothalamus. Sellar radiographs and cerebral angiography were normal. (orig.)
This case report describes a patient who presented with panhypopituitarism secondary to hypothalamic metastasis. A primary hypothalamic abnormality was suggested by computed tomographic (CT) demonstration of a small enhancing circular mass centered within the hypothalamus. Sellar radiographs and cerebral angiography were normal.
Conclusions: Combined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.
Samaan, N.A.; Bakdash, M.M.; Caderao, J.B.; Cangir, A.; Jesse, R.H. Jr.; Ballantyne, A.J.
Endocrine complications after radiotherapy for tumors of the head and neck are thought to be relatively rare. The availability of synthetic hypothalamic hormones for clinical investigations and the radioimmunoassay of hormones have enabled us to study function of the hypothalamic pituitary axis in 15 patients who had radiotherapy for nasopharyngeal cancer. Fourteen had evidence of endocrine deficiency. Twelve patients had evidence of hypothalamic dysfunction, 7 developed primary pituitary hormone deficiencies, and 3 developed primary hypothyroidism. These results indicate that (1) secondary hypopituitarism due to a hypothalamic lesion after radiotherapy for nasopharyngeal cancer may be more common than suspected in the past; (2) primary hypopituitarism after irradiation of extracranial tumors can occur; and (3) primary hypothyroidism may result from irradiation of regional neck nodes
Koshiyama, Hiroyuki; Hamamoto, Yoshiyuki; Honjo, Sachiko; Wada, Yoshiharu; Lkeda, Hiroki
There have recently been increasing experimental and clinical evidences suggesting that hypothalamic dysregulation may be one of the underlying mechanisms of abnormal glucose metabolism. First, increased hypothalamic-pituitary-adrenal axis activity induced by uncontrollable excess stress may cause diabetes mellitus as well as dyslipidemia, visceral obesity, and osteoporosis with some resemblance to Cushing's disease. Second, several molecules are known to be expressed both in pancreas and hypothalamus; adenosine triphosphate-sensitive potassium channels, malonyl-CoA, glucokinase, and AMP-activated protein kinase. Those molecules appear to form an integrated hypothalamic system, which may sense hypothalamic fuel status, especially glucose level, and inhibit action of insulin on hepatic gluconeogenesis, thereby forming a brain-liver circuit. Third, hypothalamic resistance to insulin as an adiposity signal may be involved in pathogenesis of peripheral insulin resistance. The results with mice with a neuron-specific disruption of the insulin receptor gene or those lacking insulin receptor substrate 2 in hypothalamus supported this possibility. Finally, it has very recently been suggested that dysregulation of clock genes in hypothalamus may cause abnormal glucose metabolism. Taken together, it is plausible that some hypothalamic abnormality may underlie at least some portion of type 2 diabetes or insulin resistance in humans, and this viewpoint of hypothalamic pathogenesis of type 2 diabetes may lead to the development of new drugs for type 2 diabetes.
Gao, Yuanqing; Bielohuby, Maximilian; Fleming, Thomas; Grabner, Gernot F.; Foppen, Ewout; Bernhard, Wagner; Guzm?n-Ruiz, Mara; Layritz, Clarita; Legutko, Beata; Zinser, Erwin; Garc?a-C?ceres, Cristina; Buijs, Ruud M.; Woods, Stephen C.; Kalsbeek, Andries; Seeley, Randy J.
Objective: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. Methods: We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-car...
Caronia, L.M.; Martin, C.; Welt, C.K.; Sykiotis, G.P.; Quinton, R.; Thambundit, A.; Avbelj, M.; Dhruvakumar, S.; Plummer, L.; Hughes, V.A.; Seminara, S.B.; Boepple, P.A.; Sidis, Y.; Crowley, W.F.; Martin, K.A.
Background: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogon...
Allan L Reiss
Full Text Available Cataplexy is observed in a subset of patients with narcolepsy and affects approximately 1 in 2,000 persons. Cataplexy is most often triggered by strong emotions such as laughter, which can result in transient, yet debilitating, muscle atonia. The objective of this study was to examine the neural systems underlying humor processing in individuals with cataplexy.While undergoing functional Magnetic Resonance Imaging (fMRI, we showed ten narcolepsy-cataplexy patients and ten healthy controls humorous cartoons. In addition, we examined the brain activity of one subject while in a full-blown cataplectic attack. Behavioral results showed that participants with cataplexy rated significantly fewer humorous cartoons as funny compared to controls. Concurrent fMRI showed that patients, when compared to controls and in the absence of overt cataplexy symptoms, showed pronounced activity in the emotional network including the ventral striatum and hypothalamus while viewing humorous versus non-humorous cartoons. Increased activity was also observed in the right inferior frontal gyri--a core component of the inhibitory circuitry. In comparison, the one subject who experienced a cataplectic attack showed dramatic reductions in hypothalamic activity.These findings suggest an overdrive of the emotional circuitry and possible compensatory suppression by cortical inhibitory regions in cataplexy. Moreover, during cataplectic attacks, the hypothalamus is characterized by a marked decrease in activity similar to that observed during sleep. One possible explanation for these findings is an initial overdrive and compensatory shutdown of the hypothalamus resulting in full cataplectic symptoms.
Caronia, Lisa M.; Martin, Cecilia; Welt, Corrine K.; Sykiotis, Gerasimos P.; Quinton, Richard; Thambundit, Apisadaporn; Avbelj, Magdalena; Dhruvakumar, Sadhana; Plummer, Lacey; Hughes, Virginia A.; Seminara, Stephanie B.; Boepple, Paul A.; Sidis, Yisrael; Crowley, William F.; Martin, Kathryn A.; Hall, Janet E.; Pitteloud, Nelly
BACKGROUND Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. METHODS We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. RESULTS Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kall-mann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. CONCLUSIONS Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.) PMID:21247312
Caronia, Lisa M; Martin, Cecilia; Welt, Corrine K; Sykiotis, Gerasimos P; Quinton, Richard; Thambundit, Apisadaporn; Avbelj, Magdalena; Dhruvakumar, Sadhana; Plummer, Lacey; Hughes, Virginia A; Seminara, Stephanie B; Boepple, Paul A; Sidis, Yisrael; Crowley, William F; Martin, Kathryn A; Hall, Janet E; Pitteloud, Nelly
Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.).
Mechanick, J.I.; Hochberg, F.H.; LaRocque, A.
The authors describe 15 cases with evidence of hypothalamic dysfunction 2 to 9 years following megavoltage whole-brain x-irradiation for primary glial neoplasm. The patients received 4000 to 5000 rads in 180- to 200-rad fractions. Dysfunction occurred in the absence of computerized tomography-delineated radiation necrosis or hypothalamic invasion by tumor, and antedated the onset of dementia. Fourteen patients displayed symptoms reflecting disturbances of personality, libido, thirst, appetite, or sleep. Hyperprolactinemia (with prolactin levels up to 70 ng/ml) was present in all of the nine patients so tested. Of seven patients tested with thyrotropin-releasing hormone, one demonstrated an abnormal pituitary gland response consistent with a hypothalamic disorder. Seven patients developed cognitive abnormalities. Computerized tomography scans performed a median of 4 years after tumor diagnosis revealed no hypothalamic tumor or diminished density of the hypothalamus. Cortical atrophy was present in 50% of cases and third ventricular dilatation in 58%. Hypothalamic dysfunction, heralded by endocrine, behavioral, and cognitive impairment, represents a common, subtle form of radiation damage
Mori, Y.; Takeuchi, Y.; Shimada, M.; Hayashi, S.; Hoshino, K.
Practical method was devised for precise approach to hypothalamic nuclei in the Shiba goat. A stereotaxic instrument and a brain atlas with stereotaxic coordinates were developed. For an accurate placement of probes into specific hypothalamic regions a radiographic method was employed in which radio-opaque material was injected into the lateral ventricle and the ventricular outline was depicted. A sagittal diagram showing the arrangement of hypothalamic nuclei in relation to the brain ventricular system was constructed from the transverse stereotaxic atlas. This diagram was revealed extremely useful in pinpointing the target on the radiographs of lateral view. Precision of this method was evaluated in female Shiba goats (n = 4) by comparing radiographically estimated positions of hypothalamic nuclei with those histologically determined. Despite of cranial variability among individual animals these two parameters matched well each other in all the nuclei examined. Furthermore, chronic cannulae were implanted into different hypothalamic structures of one goat and the accuracy of their placement was confirmed histologically. Thus, it was revealed that the stereotaxy by aid of radiography herein described was accurate enough to apply to various neuroendocrinological studies in the Shiba goat
Gottschalk, S.; Tavakolian, R.; Lehmann, R.; Buske, A.; Tinschert, S.
We report two children with neurofibromatosis type 1 showing enhancing masses on MRI suggesting neoplasms in the chiasm and hypothalamic region. In both patients no visual or endocrinal dysfunction was present. On serial MRI spontaneous partial remission was found, implying that a cautious approach to therapeutic management of similar cases should be taken. (orig.) (orig.)
Ammy M. Santiago
Full Text Available Objective: Brain regulation of glucose homeostasis is sexually dimorphic; however, the impact sex hormones have on specific neuronal populations within the ventromedial hypothalamic nucleus (VMN, a metabolically sensitive brain region, has yet to be fully characterized. Glucose-excited (GE and -inhibited (GI neurons are located throughout the VMN and may play a critical role in glucose and energy homeostasis. Within the ventrolateral portion of the VMN (VL-VMN, glucose sensing neurons and estrogen receptor (ER distributions overlap. We therefore tested the hypothesis that VL-VMN glucose sensing neurons were sexually dimorphic and regulated by 17β-estradiol (17βE. Methods: Electrophysiological recordings of VL-VMN glucose sensing neurons in brain slices isolated from age- and weight-matched female and male mice were performed in the presence and absence of 17βE. Results: We found a new class of VL-VMN GI neurons whose response to low glucose was transient despite continued exposure to low glucose. Heretofore, we refer to these newly identified VL-VMN GI neurons as ‘adapting’ or AdGI neurons. We found a sexual dimorphic response to low glucose, with male nonadapting GI neurons, but not AdGI neurons, responding more robustly to low glucose than those from females. 17βE blunted the response of both nonadapting GI and AdGI neurons to low glucose in both males and females, which was mediated by activation of estrogen receptor β and inhibition of AMP-activated kinase. In contrast, 17βE had no impact on GE or non-glucose sensing neurons in either sex. Conclusion: These data suggest sex differences and estrogenic regulation of VMN hypothalamic glucose sensing may contribute to the sexual dimorphism in glucose homeostasis. Author Video: Author Video Watch what authors say about their articles Keywords: 17β-estradiol, AMP-activated kinase, Glucose excited neurons, Glucose inhibited neurons, Ventromedial hypothalamic nucleus, Sexual dimorphism
Fernandez-Guasti, Alonso; Swaab, Dick; Rodríguez-Manzo, Gabriela
Male sexual behavior is regulated by limbic areas like the medial preoptic nucleus (MPN), the bed nucleus of the stria terminalis (BST), the nucleus accumbens (nAcc) and the ventromedial hypothalamic nucleus (VMN). Neurons in these brain areas are rich in androgen receptors (AR) and express
The main objective of this thesis is to increase our understanding of hypothalamic (dys)function in patients with pituitary insufficiency. This goal is driven by the clinical experience of persisting symptoms in patients adequately treated for pituitary insufficiency. We focus primarily on patients
J Gordon Millichap
Full Text Available The patterns of clinical presentation, evolution of the epilepsy, and electoclinical diagnostic features of hypothalamic hamartoma (HH in 19 patients (8 children and 11 adults, seen between 1991 and 2001, were evaluated at Kings College Hospital and the Institute of Epileptology, London, UK.
Gao, Yuanqing; Bielohuby, Maximilian; Fleming, Thomas; Grabner, Gernot F; Foppen, Ewout; Bernhard, Wagner; Guzmán-Ruiz, Mara; Layritz, Clarita; Legutko, Beata; Zinser, Erwin; García-Cáceres, Cristina; Buijs, Ruud M; Woods, Stephen C; Kalsbeek, A.; Seeley, Randy J; Nawroth, Peter P; Bidlingmaier, Martin; Tschöp, Matthias H; Yi, Chun-Xia
OBJECTIVE: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory
Gao, Yuanqing; Bielohuby, Maximilian; Fleming, Thomas; Grabner, Gernot F.; Foppen, Ewout; Bernhard, Wagner; Guzmán-Ruiz, Mara; Layritz, Clarita; Legutko, Beata; Zinser, Erwin; García-Cáceres, Cristina; Buijs, Ruud M.; Woods, Stephen C.; Kalsbeek, Andries; Seeley, Randy J.; Nawroth, Peter P.; Bidlingmaier, Martin; Tschöp, Matthias H.; Yi, Chun-Xia
Objective: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory
Campinho, Marco A; Silva, Nadia; Roman-Padilla, Javier; Ponce, Marian; Manchado, Manuel; Power, Deborah M
Anuran and flatfish metamorphosis are tightly regulated by thyroid hormones that are the necessary and sufficient factors that drive this developmental event. In the present study whole mount in situ hybridization (WISH) and quantitative PCR in sole are used to explore the central regulation of flatfish metamorphosis. Central regulation of the thyroid in vertebrates is mediated by the hypothalamus-pituitary-thyroid (HPT) axis. Teleosts diverge from other vertebrates as hypothalamic regulation in the HPT axis is proposed to be through hypothalamic inhibition although the regulatory factor remains enigmatic. The dynamics of the HPT axis during sole metamorphosis revealed integration between the activity of the thyrotrophes in the pituitary and the thyroid follicles. No evidence was found supporting a role for thyroid releasing hormone (trh) or corticotrophin releasing hormone (crh) in hypothalamic control of TH production during sole metamorphosis. Intriguingly the results of the present study suggest that neither hypothalamic trh nor crh expression changes during sole metamorphosis and raises questions about the role of these factors and the hypothalamus in regulation of thyrotrophs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Corkill, G.; Hanson, F.W.; Gold, E.M.; White, V.A.
In 1975 Samaan et al., described the effects of radiation damage of the hypothalamus in 15 patients with head and neck cancer. Shalet et al., in 1977 described endocrine morbidity in adults who as children had been irradiated for brain tumors. This report describes instances of hyperprolactinemia and associated hypothalamic, pituitary, and thyroid dysfunction following irradiation of a young adult female for brain neoplasia
Taïb, Bouchra; Bouyakdan, Khalil; Hryhorczuk, Cécile; Rodaros, Demetra; Fulton, Stephanie; Alquier, Thierry
Hypothalamic controls of energy balance rely on the detection of circulating nutrients such as glucose and long-chain fatty acids (LCFA) by the mediobasal hypothalamus (MBH). LCFA metabolism in the MBH plays a key role in the control of food intake and glucose homeostasis, yet it is not known if glucose regulates LCFA oxidation and esterification in the MBH and, if so, which hypothalamic cell type(s) and intracellular signaling mechanisms are involved. The aim of this study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), and to establish if changes in LCFA metabolism and its regulation by glucose vary as a function of the kind of LCFA, cell type, and brain region. We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures, and MBH slices ex vivo but not in cortical astrocytes and slice preparations. In contrast, oleate oxidation was not affected by glucose or AMPK inhibition in MBH slices. In addition, our results show that glucose increases palmitate, but not oleate, esterification into neutral lipids in neurons and MBH slices but not in hypothalamic astrocytes. These findings reveal for the first time the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons, and establish metabolic coupling of glucose and LCFA as a distinguishing feature of hypothalamic nuclei critical for the control of energy balance. PMID:24240094
Taïb, Bouchra; Bouyakdan, Khalil; Hryhorczuk, Cécile; Rodaros, Demetra; Fulton, Stephanie; Alquier, Thierry
Hypothalamic controls of energy balance rely on the detection of circulating nutrients such as glucose and long-chain fatty acids (LCFA) by the mediobasal hypothalamus (MBH). LCFA metabolism in the MBH plays a key role in the control of food intake and glucose homeostasis, yet it is not known if glucose regulates LCFA oxidation and esterification in the MBH and, if so, which hypothalamic cell type(s) and intracellular signaling mechanisms are involved. The aim of this study was to determine the impact of glucose on LCFA metabolism, assess the role of AMP-activated Kinase (AMPK), and to establish if changes in LCFA metabolism and its regulation by glucose vary as a function of the kind of LCFA, cell type, and brain region. We show that glucose inhibits palmitate oxidation via AMPK in hypothalamic neuronal cell lines, primary hypothalamic astrocyte cultures, and MBH slices ex vivo but not in cortical astrocytes and slice preparations. In contrast, oleate oxidation was not affected by glucose or AMPK inhibition in MBH slices. In addition, our results show that glucose increases palmitate, but not oleate, esterification into neutral lipids in neurons and MBH slices but not in hypothalamic astrocytes. These findings reveal for the first time the metabolic fate of different LCFA in the MBH, demonstrate AMPK-dependent glucose regulation of LCFA oxidation in both astrocytes and neurons, and establish metabolic coupling of glucose and LCFA as a distinguishing feature of hypothalamic nuclei critical for the control of energy balance.
Full Text Available Brain glucosensing is essential for normal body glucose homeostasis and neuronal function. However, the exact signaling mechanisms involved in the neuronal sensing of extracellular glucose levels remain poorly understood. Of particular interest is the identification of candidate membrane molecular sensors allowing neurons to change firing rates independently of intracellular glucose metabolism. Here we describe for the first time the expression of the taste receptor genes Tas1r1, Tas1r2 and Tas1r3, and their associated G-protein genes, in the mammalian brain. Neuronal expression of taste genes was detected in different nutrient-sensing forebrain regions, including the paraventricular and arcuate nuclei of the hypothalamus, the CA fields and dentate gyrus of the hippocampus, the habenula, and cortex. Expression was also observed in the intra-ventricular epithelial cells of the choroid plexus. These same regions were found to express the corresponding gene products that form the heterodimeric T1R2/T1R3 and T1R1/T1R3 sweet and L-amino acid taste G-protein coupled receptors, respectively. These regions were also found to express the taste G-protein α-Gustducin. Moreover, in vivo studies in mice demonstrate that the hypothalamic expression of taste-related genes is regulated by the nutritional state of the animal, with food deprivation significantly increasing expression levels of Tas1r1 and Tas1r2 in hypothalamus, but not in cortex. Furthermore, exposing mouse hypothalamic cells to a low-glucose medium, while maintaining normal L-amino acid concentrations, specifically resulted in higher expression levels of the sweet-associated gene Tas1r2. This latter effect was reversed by adding the non-metabolizable artificial sweetener sucralose to the low-glucose medium, indicating that taste-like signaling in hypothalamic neurons does not require intracellular glucose oxidation. Our findings suggest that the G-protein coupled sweet receptor T1R2/T1R3 is a
Won, S J; Lin, M T
The effects of intracerebral administration of interferon (IFN) or its inducer polyriboinosinic acid-polyribocytidylic acid (poly I:C) on thermoregulatory responses were assessed in conscious rabbits. Administration of IFN (10(2)-10(6) IU) or poly I:C (0.012-12 micrograms) into the preoptic anterior hypothalamus or the third cerebral ventricle caused a dose-dependent fever in rabbits at three ambient temperatures (Ta) tested. In the cold (Ta = 8 degrees C), the fever was due to increased metabolism, whereas in the heat (Ta = 32 degrees C) the fever was due to a reduction in respiratory evaporative heat loss and ear skin blood flow. At the moderate environmental temperature (Ta = 22 degrees C), the fever was due to increased metabolism and cutaneous vasoconstriction. Compared with the febrile responses induced by cerebroventricular route injection of IFN or poly I:C, the hypothalamic route of injection required a much lower dose of IFN or poly I:C to produce a similar fever. Furthermore, the fever induced by intrahypothalamic injection of IFN or poly I:C was reduced by pretreatment of animals with a systemic dose of indomethacin (an inhibitor of all prostaglandins formation) or cycloheximide (an inhibitor of protein synthesis). The data indicate that IFN or its inducer may act through the endogenous release of a prostaglandin or a protein factor of an unknown chemical nature in the preoptic anterior hypothalamic region to induce fever in rabbits. The fever induced by IFN or its inducer is brought about by a decrease in heat loss and/or an increase in heat production in rabbits.
Kanazawa, Junichi; Uozumi, Tohru; Sakoda, Katsuaki; Yamanaka, Masami; Kihara, Mikio; Nishi, Yoshikazu; Kagawa, Yoshihiro; Kajima, Toshio.
Magnetic resonance (MR) findings of two patients with a hypothalamic hamartoma are discussed. The two girls showed clinical symptoms and endocrinological signs of precocious puberty. MR imaging was of diagnostic value superior to that of CT in the demonstration of the characteristic location of this tumor and relationships to the neighboring structures because of its multi-dimensional utility. Although it has been reported that CT showed this lesion as isodense to the grey matter with and without injection of contrast medium, MR imaging depicted the lesion as a high signal intensity area on T2-weighted images in both patients. MR imaging is a useful method for the evaluation of the hypothalamic hamartoma.
van Norren, Klaske; Dwarkasing, Jvalini T; Witkamp, Renger F
In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1β-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.
Iwasa, Takeshi; Matsuzaki, Toshiya; Tungalagsuvd, Altankhuu; Munkhzaya, Munkhsaikhan; Kawami, Takako; Yamasaki, Mikio; Murakami, Masahiro; Kato, Takeshi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru
Prokineticin (PK2) and its receptors (PKRs) are expressed in several regions of the central nervous system, including the hypothalamus. It has been reported that PK2 inhibits food intake via PKR1 and that the hypothalamic PK2 mRNA levels of adult rodents were reduced by food deprivation. However, some hypothalamic factors do not exhibit sensitivity to undernutrition in the early neonatal period, but subsequently become sensitive to it during the neonatal to pre-pubertal period. In this study, we investigated the changes in the sensitivity of hypothalamic PK2 and PKR1 mRNA expression to fasting during the developmental period in male rats. Under the fed conditions, the rats' hypothalamic PK2 and/or PKR1 mRNA levels were higher on postnatal day (PND) 10 than on PND20 or PND30. In addition, the hypothalamic PK2 and/or PKR1 mRNA levels of the male rats were higher than those of the females at all examined ages (PND10, 20, and 30). Hypothalamic PK2 mRNA expression was decreased by 24h fasting at PND10 and 30, but not at PND20. In addition, hypothalamic PKR1 mRNA expression was decreased by 24h fasting at PND10, but not at PND20 or 30. These results indicate that both PK2 and PKR1 are sensitive to nutritional status in male rats and that this sensitivity has already been established by the early neonatal period. It can be speculated that the PK2 system might compensate for the immaturity of other appetite regulatory factors in the early neonatal period. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.
Full Text Available The neuroendocrine system governs essential survival and homeostatic functions. For example, growth is needed for development. Thermoregulation maintains optimal core temperature in a changing environment. Reproduction ensures species survival. Stress and immune responses enable an organism to overcome external and internal threats. The circadian system regulates arousal and sleep such that vegetative and active functions do not overlap. All of these functions require a significant portion of the body’s energy. As the integrator of the neuroendocrine system, the hypothalamus carefully assesses the energy status of the body in order to appropriately partition resources to provide for each system without compromising the others. While doing so the hypothalamus must ensure that adequate glucose levels are preserved for brain function since glucose is the primary fuel of the brain. To this end, the hypothalamus contains specialized glucose sensing neurons which are scattered throughout the nuclei controlling distinct neuroendocrine functions. We hypothesize that these neurons play a key role in enabling the hypothalamus to partition energy to meet these peripheral survival needs without endangering the brain’s glucose supply. The goal of this review is to describe the varied mechanisms underlying glucose sensing in neurons within discrete hypothalamic nuclei. We will then evaluate the way in which peripheral energy status regulates glucose sensitivity. For example, during energy deficit such as fasting specific hypothalamic glucose sensing neurons become sensitized to decreased glucose. This increases the gain of the information relay when glucose availability is a greater concern for the brain. Finally, changes in glucose sensitivity under pathological conditions (e.g., recurrent insulin-hypoglycemia, diabetes will be addressed. The overall goal of this review is to place glucose sensing neurons within the context of hypothalamic control of
Sisley, Stephanie; Sandoval, Darleen
The central nervous system (CNS), generally accepted to regulate energy homeostasis, has been implicated in the metabolic perturbations that either cause or are associated with obesity. Normally, the CNS receives hormonal, metabolic, and neuronal input to assure adequate energy levels and maintain stable energy homeostasis. Recent evidence also supports that the CNS uses these same inputs to regulate glucose homeostasis and this aspect of CNS regulation also becomes impaired in the face of dietary-induced obesity. This review focuses on the literature surrounding hypothalamic regulation of energy and glucose homeostasis and discusses how dysregulation of this system may contribute to obesity and T2DM.
Benoit, Stephen C.; Kemp, Christopher J.; Elias, Carol F.; Abplanalp, William; Herman, James P.; Migrenne, Stephanie; Lefevre, Anne-Laure; Cruciani-Guglielmacci, Céline; Magnan, Christophe; Yu, Fang; Niswender, Kevin; Irani, Boman G.; Holland, William L.; Clegg, Deborah J.
Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of ...
Chaker, Zayna; George, Caroline; Petrovska, Marija; Caron, Jean-Baptiste; Lacube, Philippe; Caillé, Isabelle; Holzenberger, Martin
Hypothalamic tanycytes are specialized glial cells lining the third ventricle. They are recently identified as adult stem and/or progenitor cells, able to self-renew and give rise to new neurons postnatally. However, the long-term neurogenic potential of tanycytes and the pathways regulating lifelong cell replacement in the adult hypothalamus are largely unexplored. Using inducible nestin-CreER(T2) for conditional mutagenesis, we performed lineage tracing of adult hypothalamic stem and/or progenitor cells (HySC) and demonstrated that new neurons continue to be born throughout adult life. This neurogenesis was targeted to numerous hypothalamic nuclei and produced different types of neurons in the dorsal periventricular regions. Some adult-born neurons integrated the median eminence and arcuate nucleus during aging and produced growth hormone releasing hormone. We showed that adult hypothalamic neurogenesis was tightly controlled by insulin-like growth factors (IGF). Knockout of IGF-1 receptor from hypothalamic stem and/or progenitor cells increased neuronal production and enhanced α-tanycyte self-renewal, preserving this stem cell-like population from age-related attrition. Our data indicate that adult hypothalamus retains the capacity of cell renewal, and thus, a substantial degree of structural plasticity throughout lifespan. Copyright © 2016 Elsevier Inc. All rights reserved.
Merkle, Florian T.; Maroof, Asif; Wataya, Takafumi; Sasai, Yoshiki; Studer, Lorenz; Eggan, Kevin; Schier, Alexander F.
Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin...
Menéndez, A; Alvarez-Uría, M
Light and electron microscopy of the hypothalamic ventricle in neonatal rats demonstrate morphological specializations of the ventricular wall at the level of the premammillary region of the third ventricle. The morphological features are: (1) A ventricular recess that we have called the "hypothalamic dorso-lateral recess" (HDR). (2) The presence of intraventricular capillaries near the dorso-lateral recess. (3) The HDR possessing a specialized ependymal lining; this consists of non-ciliated cells with short microvilli and bleb-like processes. (4) The existence of cerebrospinal fluid-contacting neurons within the HDR. (5) The presence of numerous phagocytic supraependymal cells. The HDR is not found in adult rats. This indicates that the dorso-lateral recess may play a physiological role during development.
Sefton, Charlotte; Harno, Erika; Davies, Alison; Small, Helen; Allen, Tiffany-Jayne; Wray, Jonathan R; Lawrence, Catherine B; Coll, Anthony P; White, Anne
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.
Dwarkasing, J T; Witkamp, R F; Boekschoten, M V; Ter Laak, M C; Heins, M S; van Norren, K
Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice. Overall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.
Scholly, Julia; Valenti, Maria-Paola; Staack, Anke M; Strobl, Karl; Bast, Thomas; Kehrli, Pierre; Steinhoff, Bernhard J; Hirsch, Edouard
Gelastic seizures associated with hypothalamic hamartomas (HHs) are a clinicoradiologic syndrome presenting with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, electroencephalography (EEG) abnormalities, precocious puberty, behavioral disturbances, and progressive cognitive deterioration. Surgery in adults provides seizure freedom in only one third of patients. The poor results of epilepsy surgery could be explained by an extrahypothalamic epileptogenic zone. The existence of an independent, secondary epileptogenic area with persistent seizures after resection of the presumably primary lesion supports the concept of a "hypothalamic plus" epilepsy. "Hypothalamic plus" epilepsy could be related to either an extrahypothalamic structural lesion (visible on magnetic resonance imaging [MRI] or on neuropathology) or if the former is absent, to a functional alteration with enhanced epileptogenic properties due to a process termed secondary epileptogenesis. We report two patients with gelastic seizures with HH (gelastic seizures isolated or associated with dyscognitive seizures of temporal origin). Both patients underwent two-step surgery: first an endoscopic resection of the HH, followed at a later time by temporal lobectomy. Both patients became seizure-free only after the temporal lobectomy. In both cases, neuropathology failed to demonstrate a significant structural lesion in the temporal lobe. To our knowledge, for the first time, these two cases suggest the existence of independent secondary epileptogenesis in humans. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.
Haliloglu, B; Atay, Z; Guran, T; Abalı, S; Bas, S; Turan, S; Bereket, A
Hypothalamic obesity (HyOb) is a common complication of childhood hypothalamic tumours. Patients with HyOb probably have a higher mortality rate than those with other types of obesity due in many cases to obstructive sleep apnoea/hypoventilation. To identify predictive factors for mortality caused by HyOb in children. Twenty children with HyOb secondary to hypothalamic tumours that were followed-up for ≥3 years and aged 6 years at diagnosis (3.71 ± 1.96 vs. 0.83 ± 0.73, P 1 SDS after 6 months of therapy (RR: 8.4, P obesity-related mortality rates were higher in the patients aged 0.05). The mortality rate was also 3.7-fold higher in the patients with a maximum BMI SDS ≥ 3 at any time during the first 3 years after therapy(P > 0.05). An increase in BMI SDS after 6 months of therapy was observed to be a risk factor for mortality caused by HyOb. In addition, age obesity is required. © 2015 World Obesity.
Tschugguel, Walter; Berga, Sarah L
To determine the effects of hypnotherapy on resumption of menstruation in patients with functional hypothalamic amenorrhea (FHA). Uncontrolled clinical study. Academic clinical care center. Twelve consecutive women with FHA were selected. A single 45- to 70-minute session of hypnotherapy was administered, and patients were observed for 12 weeks. Patients were asked whether or not menstruation resumed and whether or not well-being and self-confidence changed. Within 12 weeks, 9 out of 12 patients (75%) resumed menstruation. All of the patients, including those who did not menstruate, reported several beneficial side effects such as increased general well-being and increased self-confidence. Hypnotherapy could be an efficacious and time-saving treatment option that also avoids the pitfalls of pharmacological modalities for women with FHA.
Berga, Sarah L; Loucks, Tammy L
Behaviors that chronically activate the hypothalamic-pituitary-adrenal (HPA) axis and/or suppress the hypothalamic-pituitary-thyroidal (HPT) axis disrupt the hypothalamic-pituitary-gonadal axis in women and men. Individuals with functional hypothalamic hypogonadism typically engage in a combination of behaviors that concomitantly heighten psychogenic stress and increase energy demand. Although it is not widely recognized clinically, functional forms of hypothalamic hypogonadism are more than an isolated disruption of gonadotropin-releasing hormone (GnRH) drive and reproductive compromise. Indeed, women with functional hypothalamic amenorrhea display a constellation of neuroendocrine aberrations that reflect allostatic adjustments to chronic stress. Given these considerations, we have suggested that complete neuroendocrine recovery would involve more than reproductive recovery. Hormone replacement strategies have limited benefit because they do not ameliorate allostatic endocrine adjustments, particularly the activation of the adrenal and the suppression of the thyroidal axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only or primarily an alteration in the hypothalamic-pituitary-gonadal axis. Potential health consequences of functional hypothalamic amenorrhea, often termed stress-induced anovulation, may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the adrenal and thyroidal axes. Initiating pregnancy with exogenous means without reversing the hormonal milieu induced by chronic stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that
Bae, Won Kyong; Kim, Pyo Nuyn; Kim, Il Young; Lee, Byoung Ho; Lee, Kyeong Seok; Bae, Hack Gun; Yun, Il Gyu
Hamartoma of the hypothalamic area is a well recognized cause of central precocious puberty. We report a case of histologically proven hypothalamic hamartoma in a 8 year old girl with precocious puberty. The CT showed an isodense, nonenhancing mass in suprasellar area, measuring 4.2 X 3.1 cm, which, to our knowledge, seems to be the largest one of the published cases. On MR imaging, the signal intensity of the mass was homogeneous and isointense relative to gray matter on T1-, and hyperintense on T2-weighted images. The clinical and radiologic findings of the published cases of hypothalamic hamartoma are reviewed
Bae, Won Kyong; Kim, Pyo Nuyn; Kim, Il Young; Lee, Byoung Ho; Lee, Kyeong Seok; Bae, Hack Gun; Yun, Il Gyu [Soonchunhyang University, Chonan Hospital, Chonan (Korea, Republic of)
Hamartoma of the hypothalamic area is a well recognized cause of central precocious puberty. We report a case of histologically proven hypothalamic hamartoma in a 8 year old girl with precocious puberty. The CT showed an isodense, nonenhancing mass in suprasellar area, measuring 4.2 X 3.1 cm, which, to our knowledge, seems to be the largest one of the published cases. On MR imaging, the signal intensity of the mass was homogeneous and isointense relative to gray matter on T1-, and hyperintense on T2-weighted images. The clinical and radiologic findings of the published cases of hypothalamic hamartoma are reviewed.
Støving, R K; Andersen, M; Flyvbjerg, A
in the central feeding mechanism in anorexia nervosa (AN). Peripheral administration of pyridostigmine (PD) minimizes the release of hypothalamic SRIH. DESIGN: To study the influence of hypothalamic somatostatinergic inhibition on the exaggerated somatotroph responsiveness to GHRH in patients with severe AN, two...... indirectly to greater SRIH withdrawal and greater GHRH release in anorexia nervosa. Moreover, hypothalamic SRIH activity seems to be inversely related to cortisol levels, indirectly supporting the hypothesis that SRIH and CRH neuronal activity are inversely related in anorexia nervosa. Leptin, which...... is believed to act on hypothalamic feeding mechanisms, seems to be positively related to SRIH activity. Finally, the present data demonstrate that the potentiating effect of pyridostigmine in anorexia nervosa is related to body mass index and increases upon weight gain, suggesting that the low...
Merkle, Florian T; Maroof, Asif; Wataya, Takafumi; Sasai, Yoshiki; Studer, Lorenz; Eggan, Kevin; Schier, Alexander F
Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agouti-related peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases. © 2015. Published by The Company of Biologists Ltd.
Wellhauser, Leigh; Gojska, Nicole M; Belsham, Denise D
Attesting to its intimate peripheral connections, hypothalamic neurons integrate nutritional and hormonal cues to effectively manage energy homeostasis according to the overall status of the system. Extensive progress in the identification of essential transcriptional and post-translational mechanisms regulating the controlled expression and actions of hypothalamic neuropeptides has been identified through the use of animal and cell models. This review will introduce the basic techniques of hypothalamic investigation both in vivo and in vitro and will briefly highlight the key advantages and challenges of their use. Further emphasis will be place on the use of immortalized models of hypothalamic neurons for in vitro study of feeding regulation, with a particular focus on cell lines proving themselves most fruitful in deciphering fundamental basics of NPY/AgRP, Proglucagon, and POMC neuropeptide function. Copyright © 2014 Elsevier Inc. All rights reserved.
A total of 223 patients with the hypothalamic pubertal syndrome (HPS) were followed up for 1 to 22 years. The course of HPS was regressive, stable , recurrent or progressive and dependent on the initial depth and spread of hypothalamic lesion, repeated unfavourable hypothalamic exposures, and timely and regular treatment. HPS outcomes were followed up in 190 cases. The recovery was complete in 21.05%, obesity alone persisted in 10.53%, vegetovascular dystonia was persistent in 7.36%, and polycystic ovaries in 5.79%. Neuroendocrine hypothalamic syndrome was the most common (50.53%) HPS outcome. Hormone levels in blood were investigated using radioimmunoassay in patients with neuroendocrine form of HPS
Eachus, Helen; Bright, Charlotte; Cunliffe, Vincent T; Placzek, Marysia; Wood, Jonathan D; Watt, Penelope J
Psychiatric disorders arise due to an interplay of genetic and environmental factors, including stress. Studies in rodents have shown that mutants for Disrupted-In-Schizophrenia-1 (DISC1), a well-accepted genetic risk factor for mental illness, display abnormal behaviours in response to stress, but the mechanisms through which DISC1 affects stress responses remain poorly understood. Using two lines of zebrafish homozygous mutant for disc1, we investigated behaviour and functioning of the hypothalamic-pituitary-interrenal (HPI) axis, the fish equivalent of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that the role of DISC1 in stress responses is evolutionarily conserved and that DISC1 is essential for normal functioning of the HPI axis. Adult zebrafish homozygous mutant for disc1 show aberrant behavioural responses to stress. Our studies reveal that in the embryo, disc1 is expressed in neural progenitor cells of the hypothalamus, a conserved region of the vertebrate brain that centrally controls responses to environmental stressors. In disc1 mutant embryos, proliferating rx3+ hypothalamic progenitors are not maintained normally and neuronal differentiation is compromised: rx3-derived ff1b+ neurons, implicated in anxiety-related behaviours, and corticotrophin releasing hormone (crh) neurons, key regulators of the stress axis, develop abnormally, and rx3-derived pomc+ neurons are disorganised. Abnormal hypothalamic development is associated with dysfunctional behavioural and neuroendocrine stress responses. In contrast to wild type siblings, disc1 mutant larvae show altered crh levels, fail to upregulate cortisol levels when under stress and do not modulate shoal cohesion, indicative of abnormal social behaviour. These data indicate that disc1 is essential for normal development of the hypothalamus and for the correct functioning of the HPA/HPI axis. © The Author 2017. Published by Oxford University Press.
Chou, Sharon H.; Chamberland, John P.; Liu, Xiaowen; Matarese, Giuseppe; Gao, Chuanyun; Stefanakis, Rianna; Brinkoetter, Mary T.; Gong, Huizhi; Arampatzi, Kalliopi; Mantzoros, Christos S.
Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove d...
Warren, M P; Voussoughian, F; Geer, E B; Hyle, E P; Adberg, C L; Ramos, R H
Because the exact etiology of functional, or idiopathic, hypothalamic amenorrhea (FHA) is still unknown, FHA remains a diagnosis of exclusion. The disorder may be stress induced. However, mounting evidence points to a metabolic/nutritional insult that may be the primary causal factor. We explored the thyroid, hormonal, dietary, behavior, and leptin changes that occur in FHA, as they provide a clue to the etiology of this disorder. Fourteen cycling control and amenorrheic nonathletic subjects were matched for age, weight, and height. The amenorrheic subjects denied eating disorders; only after further, detailed questioning did we uncover a higher incidence of anorexia and bulimia in this group. The amenorrheic subjects demonstrated scores of abnormal eating twice those found in normal subjects (P < 0.05), particularly bulimic type behavior (P < 0.01). They also expended more calories in aerobic activity per day and had higher fiber intakes (P < 0.05); lower body fat percentage (P < 0.05); and reduced levels of free T4 (P < 0.05), free T3 (P < 0.05), and total T4 (P < 0.05), without a significant change in rT3 or TSH. Cortisol averaged higher in the amenorrheics, but not significantly, whereas leptin values were significantly lower (P < 0.05). Bone mineral density was significantly lower in the wrist (P < 0.05), with a trend to lower BMD in the spine (P < 0.08). Scores of emotional distress and depression did not differ between groups. The alterations in eating patterns, leptin levels, and thyroid function present in subjects with FHA suggest altered nutritional status and the suppression of the hypothalamic-pituitary-thyroid axis or the alteration of feedback set-points in women with FHA. Both lower leptin and thyroid levels parallel changes seen with caloric restriction. Nutritional issues, particularly dysfunctional eating patterns and changes in thyroid metabolism, and/or leptin effects may also have a role in the metabolic signals suppressing GnRH secretion and
Fulder, S J
There are a group of so-called tonic remedies in Far Eastern medicine which are traditionally viewed as harmonizing or adjustive. Ginseng and eleutherococcus are the best known, and there is evidence that they increase arousal, stamina and stress resistance. We have attempted to explore the relationship between the behavioral and the stress effects, and to relate this to traditional concepts. In one series of experiments mice were given ginseng throughout their lifespan. At intervals their behavior response to mild stress was examined and found to be exaggerated compared to controls without ginseng. However, normal ambulatory behavior in the absence of stress was unaffected. A second series of experiments indicated that the binding of corticosteroid to certain brain regions was increased in adrenalectomized rats given ginseng saponin, compared to saline treated controls. This can be interpreted as a result of an increase in hypothalamic-pituitary-adrenal sensitivity caused by ginseng saponin. This is in accord with traditional concepts of the use of these remedies.
Cassone, V M; Speh, J C; Card, J P; Moore, R Y
A detailed analysis of the cytoarchitecture, retinohypothalamic tract (RHT) projections, and immunohistochemical localization of major cell and fiber types within the hypothalamic suprachiasmatic nuclei (SCN) was conducted in five mammalian species: two species of opossum, the domestic cat, the guinea pig, and the house mouse. Cytoarchitectural and immunohistochemical studies were conducted in three additional species of marsupial mammals and in the domestic pig. The SCN in this diverse transect of mammalian taxonomy bear striking similarities. First, the SCN are similar in location, lying close to the third ventricle (3V) dorsal to the optic chiasm (OC), with a cytoarchitecture characterized by small, tightly packed neurons. Second, in all groups studied, the SCN receive bilateral retinal input. Third, the SCN contain immunohistochemically similar elements. These similarities suggest that the SCN developed characteristic features early in mammalian phylogeny. Some details of SCN organization vary among the species studied. In marsupials, vasopressin-like immunoreactive (VP-LI) and vasoactive intestinal polypeptide-like immunoreactive (VIP-LI) cells codistribute primarily in the dorsomedial aspects of the SCN, while in eutherians, VP-LI and VIP-LI cells are separated into SCN subnuclei. Furthermore, the marsupial RHT projects to the periventricular dorsomedial region, whereas the eutherian RHT projects more ventrally in the SCN into the zone that typically contains VIP-LI perikarya.
Li, Yi; Zeng, Jiawei; Zhang, Juen; Yue, Chenyu; Zhong, Weixin; Liu, Zhixiang; Feng, Qiru; Luo, Minmin
The interactions between predator and prey represent some of the most dramatic events in nature and constitute a matter of life and death for both sides. The hypothalamus has been implicated in driving predation and evasion; however, the exact hypothalamic neural circuits underlying these behaviors remain poorly defined. Here, we demonstrate that inhibitory and excitatory projections from the mouse lateral hypothalamus (LH) to the periaqueductal gray (PAG) in the midbrain drive, respectively, predation and evasion. LH GABA neurons were activated during predation. Optogenetically stimulating PAG-projecting LH GABA neurons drove strong predatory attack, and inhibiting these cells reversibly blocked predation. In contrast, LH glutamate neurons were activated during evasion. Stimulating PAG-projecting LH glutamate neurons drove evasion and inhibiting them impeded predictive evasion. Therefore, the seemingly opposite behaviors of predation and evasion are tightly regulated by two dissociable modular command systems within a single neural projection from the LH to the PAG. VIDEO ABSTRACT. Copyright © 2018 Elsevier Inc. All rights reserved.
Kurup, Ravi Kumar; Kurup, Parameswara Achutha
The human hypothalamus produces an endogenous membrane Na(+)-K+ ATPase inhibitor, digoxin, which regulates neuronal transmission. The digoxin status and neurotransmitter patterns were studied in creative and non-creative individuals, as well as in individuals with differing hemispheric dominance, in order to find out the role of cerebral dominance in this respect. The activity of HMG CoA reductase and serum levels of digoxin, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in creative/non-creative individuals, and in individuals with differing hemispheric dominance. In creative individuals there was increased digoxin synthesis, decreased membrane Na(+)-K+ ATPase activity, increased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and decreased tyrosine catabolites (dopamine, noradrenaline, and morphine). The pattern in creative individuals correlated with right hemispheric dominance. In non-creative individuals there was decreased digoxin synthesis, increased membrane Na(+)-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern in non-creative individuals correlated with that obtained in left hemispheric chemical dominance. Hemispheric chemical dominance and hypothalamic digoxin could regulate the predisposition to creative tendency.
Kurup, Ravi Kumar; Kurup, Parameswara Achutha
The isoprenoid path way produces endogenous digoxin, a substance that can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in individuals with chronic insomnia. The patterns were compared in those with right hemispheric and left hemispheric dominance. The activity of HMG GoA reductase and serum levels of digoxin, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in individuals with chronic insomnia and in individuals with differing hemispheric dominance. Digoxin synthesis was increased with upregulated tryptophan catabolism (increased levels of serotonin, strychnine, and nicotine), and downregulated tyrosine catabolism (decreased levels of dopamine, noradrenaline, and morphine) in those with chronic insomnia and right hemispheric chemical dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism (decreased levels of serotonin, strychnine, and nicotine) and upregulated tyrosine catabolism (increased levels of dopamine, noradrenaline, and morphine) in those with normal sleep patterns and left hemispheric chemical dominance. Hypothalamic digoxin plays a central role in the regulation of sleep behavior. Hemispheric chemical dominance in relation to digoxin status is also crucial.
Genazzani, Alessandro D; Ricchieri, Federica; Lanzoni, Chiara; Strucchi, Claudia; Jasonni, Valerio M
Hypothalamic amenorrhea (HA) is a secondary amenorrhea with no evidence of endocrine/systemic causal factors, mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stress conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be exclude any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stress situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This article tries to give insights into diagnosis and putative therapeutic strategies.
Marcus, M D; Loucks, T L; Berga, S L
To determine whether mood, attitudes, or symptoms of disordered eating discriminated women with functional hypothalamic amenorrhea (FHA) from those with organic causes of amenorrhea and eumenorrhea. Cross-sectional comparison of women with FHA, women with organic amenorrhea, and eumenorrheic control women. Clinical research center in an academic medical institution. Seventy-seven women > or =18 years old with time since menarche > or =5 and < or =25 years were recruited by advertisement. Ovulation was confirmed in eumenorrheic control women. Causes of anovulation were carefully documented in amenorrheic participants and LH pulse profiles were obtained to document the diagnosis of FHA. All participants were interviewed and completed questionnaires. Self-report measures of dysfunctional attitudes, coping styles, and symptoms of depression and eating disorders. Women with FHA reported more depressive symptoms and dysfunctional attitudes than did eumenorrheic women, but not significantly more than women with organic amenorrhea. However, women with FHA reported significantly more symptoms of disordered eating than did either anovulatory or ovulatory women. The findings are consistent with the hypothesis that FHA is precipitated by a combination of psychosocial stressors and metabolic challenge.
Genazzani, A D; Chierchia, E; Santagni, S; Rattighieri, E; Farinetti, A; Lanzoni, C
Among secondary amenorrheas, hypothalamic amenorrhea (HA) is the one with no evidence of endocrine/systemic causal factors. HA is mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressed conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be excluded any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stressed situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This chapter aims to give insights into diagnosis and putative therapeutic strategies. Copyright 2010 Elsevier Masson SAS. All rights reserved.
Kurup, Ravi Kumar; Kurup, Parameswara Achutha
The isoprenoid pathway was assessed in atheistic and spiritually inclined individuals. The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has a correlation with spiritual and atheistic tendency. HMG CoA reductase activity, serum digoxin, RBC membrane Na(+)-K+ ATPase activity, serum magnesium, and tyrosine/tryptophan catabolic patterns were assessed in spiritual/atheistic individuals and in those differing hemispheric dominance. In spiritually-inclined individuals, there was increased digoxin synthesis, decreased membrane Na(+)-K+ ATPase activity, increased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and decreased tyrosine catabolites (dopamine, noradrenaline, and morphine). The pattern in spiritually-inclined individuals correlated with right hemispheric chemical dominance. In atheistic individuals there was decreased digoxin synthesis, increased membrane Na(+)-K+ ATPase activity, decreased tryptophan catabolities (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern in atheistic individuals correlated with that obtained in left hemispheric chemical dominance. Hemispheric chemical dominance and hypothalamic digoxin could regulate the predisposition to spirituality or atheism.
Audhya, T.; Manzione, M.M.; Nakane, T.; Kanie, N.; Passarelli, J.; Russo, M.; Hollander, C.S.
Polyclonal antibodies to synthetic human pancreatic growth hormone-releasing factor [hpGRF(1-44)NH 2 ] and rat hypothalamic growth hormone-releasing factor [rhGRF(1-43)OH] were produced in rabbits. A subsequent booster injection by the conventional intramuscular route resulted in high-titer antibodies, which at a 1:20,000 dilution were used to develop highly sensitive and specific radioimmunoassays for these peptides. The antibody to hpGRF(1-44)NH 2 is directed against the COOH-terminal region of the molecule, as shown by its cross reactivity with various hpGRF analogues. Serial dilutions of human and rat hypothalamic extracts demonstrated parallelism with the corresponding species-specific standard and 125 I-labeled tracer. There was no cross reactivity with other neuropeptides, gastrointestinal peptides, or hypothalamic extracts of other species. Age-related changes in hypothalamic GRF content were present in rats, with a gradual increase from 2 to 16 weeks and a correlation between increasing body weight and GRF content. These radioimmunoassays will serve as important tools for understanding the regulation of growth hormone secretion in both human and rat
Stevens, Adam; Begum, Ghazala; Cook, Alice; Connor, Kristin; Rumball, Christopher; Oliver, Mark; Challis, John; Bloomfield, Frank; White, Anne
Maternal food restriction is associated with the development of obesity in offspring. This study examined how maternal undernutrition in sheep affects the fetal hypothalamic glucocorticoid receptor (GR) and the appetite-regulating neuropeptides, proopiomelanocortin (POMC) and neuropeptide Y, which it regulates. In fetuses from ewes undernourished from -60 to +30 d around conception, there was increased histone H3K9 acetylation (1.63-fold) and marked hypomethylation (62% decrease) of the POMC gene promoter but no change in POMC expression. In the same group, acetylation of histone H3K9 associated with the hypothalamic GR gene was increased 1.60-fold and the GR promoter region was hypomethylated (53% decrease). In addition, there was a 4.7-fold increase in hypothalamic GR expression but no change in methylation of GR gene expression in the anterior pituitary or hippocampus. Interestingly, hypomethylation of both POMC and GR promoter markers in fetal hypothalami was also identified after maternal undernutrition from -60 to 0 d and -2 to +30 d. In comparison, the Oct4 gene, was hypermethylated in both control and underfed groups. Periconceptional undernutrition is therefore associated with marked epigenetic changes in hypothalamic genes. Increase in GR expression in the undernourished group may contribute to fetal programming of a predisposition to obesity, via altered GR regulation of POMC and neuropeptide Y. These epigenetic changes in GR and POMC in the hypothalamus may also predispose the offspring to altered regulation of food intake, energy expenditure, and glucose homeostasis later in life.
Chen, Hui; Hansen, Michelle J; Jones, Jessica E; Vlahos, Ross; Bozinovski, Steve; Anderson, Gary P; Morris, Margaret J
Appetite is regulated by a number of hypothalamic neuropeptides including neuropeptide Y (NPY), a powerful feeding stimulator that responds to feeding status, and drugs such as nicotine and cannabis. There is debate regarding the extent of the influence of obesity on hypothalamic NPY. We measured hypothalamic NPY in male Sprague-Dawley rats after short or long term exposure to cafeteria-style high fat diet (32% energy as fat) or laboratory chow (12% fat). Caloric intake and body weight were increased in the high fat diet group, and brown fat and white fat masses were significantly increased after 2 weeks. Hypothalamic NPY concentration was only significantly decreased after long term consumption of the high fat diet. Nicotine decreases food intake and body weight, with conflicting effects on hypothalamic NPY reported. Body weight, plasma hormones and brain NPY were investigated in male Balb/c mice exposed to cigarette smoke for 4 days, 4 and 12 weeks. Food intake was significantly decreased by smoke exposure (2.32+/-0.03g/24h versus 2.71+/-0.04g/24h in control mice (non-smoke exposed) at 12 weeks). Relative to control mice, smoke exposure led to greater weight loss, while pair-feeding the equivalent amount of chow caused an intermediate weight loss. Chronic smoke exposure, but not pair-feeding, was associated with decreased hypothalamic NPY concentration, suggesting an inhibitory effect of cigarette smoking on brain NPY levels. Thus, consumption of a high fat diet and smoke exposure reprogram hypothalamic NPY. Reduced NPY may contribute to the anorexic effect of smoke exposure.
Anna M Van Opstal
Full Text Available Background. Inconsistent findings about the neurobiology of Anorexia Nervosa (AN hinder the development of effective treatments for this severe mental disorder. Therefore the need arises for elucidation of neurobiological factors involved in the pathophysiology of AN. The hypothalamus plays a key role in the neurobiological processes that govern food intake and energy homeostasis, processes that are disturbed in anorexia nervosa (AN. The present study will assess the hypothalamic response to energy intake and the hypothalamic structure in patients with AN and healthy controls. Methods. 10 women aged 18-30 years diagnosed with AN and 11 healthy, lean (BMI <23 kg/m2 women in the same age range were recruited. We used functional magnetic resonance imaging (MRI to determine function of the hypothalamus in response to glucose. Structural MRI was used to determine differences in hypothalamic volume and local grey volume using manual segmentation and voxel-based morphometry.Results. No differences were found in hypothalamic volume and neuronal activity in response to a glucose load between the patients and controls. Whole brain structural analysis showed a significant decrease in grey matter volume in the cingulate cortex in the AN patients, bilaterally.Conclusions. We argue that in spite of various known changes in the hypothalamus the direct hypothalamic response to glucose intake is similar in AN patients and healthy controls.
Şiraz, Ülkü Gül; Okdemir, Deniz; Direk, Gül; Akın, Leyla; Hatipoğlu, Nihal; Kendırcı, Mustafa; Kurtoğlu, Selim
Rapid-onset obesity with hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) syndrome is a rare disease that is difficult to diagnosis and distinguish from genetic obesity syndromes. The underlying causes of the disease has not been fully explained. Hypothalamic dysfunction causes endocrine problems, respiratory dysfunction and autonomic alterations. There are around 80 reported patients due to lack of recognition. We present two female patient suspected of ROHHAD due to weight gain since early childhood. The presented symptoms, respiratory and circulatory dysfunction, hypothalamic hypernatremia, hypothalamo-pituitary hormonal disorders such as santral hypothyrodism, hyperprolactinemia and santral early puberty are completely matched the criteria of ROHHAD syndrome. ROHHAD syndrome should be considered in differential diagnosis since it is difficult to distinguish from causes of monogenic obesity. Early identification of the disease reduces morbidity of the syndrome and patients require regular follow-up by a multidisciplinary approach.
Chou, Sharon H; Mantzoros, Christos
Anorexia nervosa (AN) and hypothalamic amenorrhea (HA) are states of chronic energy deprivation associated with severely compromised bone health. Poor bone accrual during adolescence followed by increased bone loss results in lifelong low bone density, degraded bone architecture, and higher risk of fractures, despite recovery from AN/HA. Amenorrhea is only one of several compensatory responses to the negative energy balance. Other hypothalamic-pituitary hormones are affected and contribute to bone deficits, including activation of hypothalamic-pituitary-adrenal axis and growth hormone resistance. Adipokines, particularly leptin, provide information on fat/energy stores, and gut hormones play a role in the regulation of appetite and food intake. Alterations in all these hormones influence bone metabolism. Restricted in scope, current pharmacologic approaches to improve bone health have had overall limited success. Copyright © 2017 Elsevier Inc. All rights reserved.
Conclusions: Myeloid cell leptin receptor deficient mice partially replicate the db/db phenotype. Leptin signaling in hypothalamic microglia is important for microglial function and a correct formation of the hypothalamic neuronal circuit regulating metabolism.
Tanaka, Susumu; Takizawa, Nae; Honda, Yoshiko; Koike, Taro; Oe, Souichi; Toyoda, Hiromi; Kodama, Tohru; Yamada, Hisao
Hypocretin, also known as orexin, maintains the vigilance state and regulates various physiological processes, such as arousal, sleep, food intake, energy expenditure, and reward. Previously, we found that when wild-type mice and hypocretin/ataxin-3 littermates (which are depleted of hypothalamic hypocretin-expressing neurons postnatally) were administered lipopolysaccharide (LPS), the two genotypes exhibited significant differences in their sleep/wake cycle, including differences in the degree of increase in sleep periods and in recovery from sickness behaviour. In the present study, we examined changes in the hypothalamic vigilance system and in the hypothalamic expression of inflammatory factors in response to LPS in hypocretin/ataxin-3 mice. Peripheral immune challenge with LPS affected the hypothalamic immune response and vigilance states. This response was altered by the loss of hypocretin. Hypocretin expression was inhibited after LPS injection in both hypocretin/ataxin-3 mice and their wild-type littermates, but expression was completely abolished only in hypocretin/ataxin-3 mice. Increases in the number of histidine decarboxylase (HDC)-positive cells and in Hdc mRNA expression were found in hypocretin/ataxin-3 mice, and this increase was suppressed by LPS. Hypocretin loss did not impact the change in expression of hypothalamic inflammatory factors in response to LPS, except for interferon gamma and colony stimulating factor 3. The number of c-Fos-positive/HDC-positive cells in hypocretin/ataxin-3 mice administered LPS injections was elevated, even during the rest period, in all areas, suggesting that there is an increase in the activity of histaminergic neurons in hypocretin/ataxin-3 mice following LPS injection. Taken together, our results suggest a novel role for hypocretin in the hypothalamic response to peripheral immune challenge. Our findings contribute to the understanding of the pathophysiology of narcolepsy. Copyright © 2016 Elsevier Inc. All
Aou, S; Ma, J; Hori, T
Although hormonal regulation of blood calcium homeostasis has been intensively investigated in the peripheral organs, the involvement of the central nervous system in calcium regulation is still poorly understood. In the present study, we found that (1) bilateral lesions of the ventromedial nucleus of the hypothalamus (VMH), but not those of the paraventricular hypothalamic nucleus or the lateral hypothalamic area, eliminated immobilization (IMB)-induced hypocalcemia, and (2) electrical stimulation of the VMH decreased the blood calcium level. The results suggest that the VMH has a hypocalcemic function and plays a role in IMB-induced hypocalcemia.
Meijneke, Ruud W. H.; Schouten-van Meeteren, Antoinette Y. N.; de Boer, Nienke Y.; van Zundert, Suzanne; van Trotsenburg, Paul A. S.; Stoelinga, Femke; van Santen, Hanneke M.
Abstract Hypothalamic obesity after treatment for craniopharyngioma is a well-recognized, severe problem. Treatment of hypothalamic obesity is difficult and often frustrating for the patient, the parents and the professional care-giver. Because hypothalamic obesity is caused by an underlying medical
Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A
A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593
Lam, K.S.; Ho, J.H.; Lee, A.W.; Tse, V.K.; Chan, P.K.; Wang, C.; Ma, J.T.; Yeung, R.T.
Endocrine assessment was performed in 32 relapse-free southern Chinese patients 5-17 years following radiation therapy (RT) alone for early nasopharyngeal carcinoma (NPC). Initial screening was done using questionnaires emphasizing impaired sexual function and menstrual disturbance plus measurement of serum levels of thyroxine, free thyroxine index, thyrotropic hormone, prolactin, and additionally testosterone for males only. Those showing abnormalities were subjected to detailed pituitary function tests. Hypothalamic-pituitary dysfunction was found in 7 female patients and only 1 male patient. A delayed TSH response to thyrotropin releasing hormone suggesting a hypothalamic disorder was seen in 6 of the affected female patients, and hyperprolactinaemia in also 6. None of the patients had evidence of diabetes insipidus. Hypopituitarism became symptomatic 2-5 years after RT with a mean latent interval of 3.8 years. A practical protocol for regular endocrine assessment for NPC patients after RT has been proposed. Multiple linear regression analysis of the radiotherapeutic data from the 11 female patients indicates that the likelihood of late occurrence of symptomatic hypothalamic-pituitary dysfunction following RT is dependent on the TDF of the target dose to the nasopharyngeal region and the height of the upper margin of the opposed lateral facial fields above the diaphragma sellae (coefficient of multiple correlation = 0.9025). Except when the sphenoid sinus or the middle cranial fossa is involved, it is advisable to set the height of the upper margin of the lateral facial field at a level no higher than the diaphragma sellae. The hypothalamus and possibly the pituitary stalk as well may sustain permanent damage by doses of radiation within the conventional radiotherapeutic range for carcinomas
Palmini, Andre; Van Paesschen, Wim; Dupont, Patrick; Van Laere, Koen; Van Driel, Guido
To present the first ictal fluorodeoxyglucose-positron emission tomography (FDG-PET) evidence of the hypothalamic origin of gelastic seizures in a patient with a hypothalamic hamartoma (HH) and to raise the issue of true dual pathology related to this entity. Ictal FDG-PET was acquired during an episode of status gelasticus with preserved consciousness, in a patient previously operated on for complex partial seizures (CPSs) due to a temporal lobe epileptogenic cyst. Ictal hypermetabolism was localized to the region of the HH during the status gelasticus. CPSs had been completely eliminated after temporal lobe surgery. Ictal FDG-PET independently confirmed that gelastic seizures in patients with HH do originate in the diencephalic lesion. An HH may coexist with another epileptogenic lesion, in a context of dual pathology.
Dwarkasing, J.T.; Witkamp, R.F.; Boekschoten, M.V.; Laak, ter M.C.; Heins, M.S.; Norren, van K.
Background: Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections
Kabra, Dhiraj G; Pfuhlmann, Katrin; García-Cáceres, Cristina
Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and...
Dec 21, 2016 ... membrane-filtered purified water were available ad libi- tum. Animals were cared for according ... Care and Use of Laboratory Animals, revised 1996. All .... section was blind-counted by hand, and STAT3 auto- counted, after ..... the hypothalamic 5-HT concentration and increases plasma lep- tin in rats. Eur.
Smeets, P.A.M.; Graaf, C. de; Stafleu, A.; Osch, M.J.P. van; Grond, J. van der
The hypothalamus is intimately involved in the regulation of food intake, integrating multiple neural and hormonal signals. Several hypothalamic nuclei contain glucose-sensitive neurons, which play a crucial role in energy homeostasis. Although a few functional magnetic resonance imaging (fMRI)
Kalsbeek, A.; Bruinstroop, E.; Yi, C. X.; Klieverik, L. P.; La Fleur, S. E.; Fliers, E.
The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the
Müller, Hermann L.
Purpose of review Hypothalamic alterations, pathological or treatment induced, have major impact on prognosis in craniopharyngioma patients mainly because of consequent hypothalamic obesity. Recent insight in molecular genetics, treatment strategies, risk factors and outcomes associated with hypothalamic obesity provide novel therapeutic perspectives. This review includes relevant publications since 2013. Recent findings Recent findings confirm that alterations in posterior hypothalamic areas because of tumour location and/or treatment-related injuries are associated with severe hypothalamic obesity, reduced overall survival and impaired quality of life in long-term survivors of childhood-onset craniopharyngioma. However, eating disorders are observed because of hypothalamic obesity without clear disease-specific patterns. Treatment options for hypothalamic obesity are very limited. Treatment with invasive, nonreversible bariatric methods such as Roux-en-Y gastric bypass is most efficient in weight reduction, but controversial in the paediatric population because of medical, ethical, and legal considerations. Accordingly, treatment in craniopharyngioma should focus on prevention of (further) hypothalamic injury. Presurgical imaging for grading of hypothalamic involvement should be the basis for hypothalamus-sparing strategies conducted by experienced multidisciplinary teams. Summary Until a nonsurgical therapeutic option for hypothalamic obesity for paediatric patients is found, prevention of hypothalamic injury should be the preferred treatment strategy, conducted exclusively by experienced multidisciplinary teams. PMID:26574645
Benoit, Stephen C.; Kemp, Christopher J.; Elias, Carol F.; Abplanalp, William; Herman, James P.; Migrenne, Stephanie; Lefevre, Anne-Laure; Cruciani-Guglielmacci, Céline; Magnan, Christophe; Yu, Fang; Niswender, Kevin; Irani, Boman G.; Holland, William L.; Clegg, Deborah J.
Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-θ to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-θ nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-θ attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-θ activation, resulting in reduced insulin activity. PMID:19726875
Benoit, Stephen C; Kemp, Christopher J; Elias, Carol F; Abplanalp, William; Herman, James P; Migrenne, Stephanie; Lefevre, Anne-Laure; Cruciani-Guglielmacci, Céline; Magnan, Christophe; Yu, Fang; Niswender, Kevin; Irani, Boman G; Holland, William L; Clegg, Deborah J
Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-theta, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-theta was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-theta to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-theta nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-theta attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-theta activation, resulting in reduced insulin activity.
Kiss David S
Full Text Available Abstract Background Based on its distribution in the brain, ecto-nucleoside triphosphate diphosphohydrolase 3 (NTPDase3 may play a role in the hypothalamic regulation of homeostatic systems, including feeding, sleep-wake behavior and reproduction. To further characterize the morphological attributes of NTPDase3-immunoreactive (IR hypothalamic structures in the rat brain, here we investigated: 1. The cellular and subcellular localization of NTPDase3; 2. The effects of 17β-estradiol on the expression level of hypothalamic NTPDase3; and 3. The effects of NTPDase inhibition in hypothalamic synaptosomal preparations. Methods Combined light- and electron microscopic analyses were carried out to characterize the cellular and subcellular localization of NTPDase3-immunoreactivity. The effects of estrogen on hypothalamic NTPDase3 expression was studied by western blot technique. Finally, the effects of NTPDase inhibition on mitochondrial respiration were investigated using a Clark-type oxygen electrode. Results Combined light- and electron microscopic analysis of immunostained hypothalamic slices revealed that NTPDase3-IR is linked to ribosomes and mitochondria, is predominantly present in excitatory axon terminals and in distinct segments of the perikaryal plasma membrane. Immunohistochemical labeling of NTPDase3 and glutamic acid decarboxylase (GAD indicated that γ-amino-butyric-acid- (GABA ergic hypothalamic neurons do not express NTPDase3, further suggesting that in the hypothalamus, NTPDase3 is predominantly present in excitatory neurons. We also investigated whether estrogen influences the expression level of NTPDase3 in the ventrobasal and lateral hypothalamus. A single subcutaneous injection of estrogen differentially increased NTPDase3 expression in the medial and lateral parts of the hypothalamus, indicating that this enzyme likely plays region-specific roles in estrogen-dependent hypothalamic regulatory mechanisms. Determination of
Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.
Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363
Kawakami, Akio; Okada, Nobukazu; Rokkaku, Kumiko; Honda, Kazufumi; Ishibashi, Shun; Onaka, Tatsushi
Metabolic conditions affect hypothalamo-pituitary-adrenal responses to stressful stimuli. Here we examined effects of food deprivation, leptin and ghrelin upon noradrenaline release in the hypothalamic paraventricular nucleus (PVN) and plasma adrenocorticotropic hormone (ACTH) concentrations after stressful stimuli. Food deprivation augmented both noradrenaline release in the PVN and the increase in plasma ACTH concentration following electrical footshocks (FSs). An intracerebroventricular injection of leptin attenuated the increases in hypothalamic noradrenaline release and plasma ACTH concentrations after FSs, while ghrelin augmented these responses. These data suggest that leptin inhibits and ghrelin facilitates neuroendocrine stress responses via noradrenaline release and indicate that a decrease in leptin and an increase in ghrelin release after food deprivation might contribute to augmentation of stress-induced ACTH release in a fasting state.
Full Text Available Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1 cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy. Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.
Camproux, A C; Thalabard, J C; Thomas, G
Luteinizing hormone (LH) is released by the pituitary in discrete pulses. In the monkey, the appearance of LH pulses in the plasma is invariably associated with sharp increases (i.e, volleys) in the frequency of the hypothalamic pulse generator electrical activity, so that continuous monitoring of this activity by telemetry provides a unique means to study the temporal structure of the mechanism generating the pulses. To assess whether the times of occurrence and durations of previous volleys exert significant influence on the timing of the next volley, we used a class of periodic counting process models that specify the stochastic intensity of the process as the product of two factors: 1) a periodic baseline intensity and 2) a stochastic regression function with covariates representing the influence of the past. This approach allows the characterization of circadian modulation and memory range of the process underlying hypothalamic pulse generator activity, as illustrated by fitting the model to experimental data from two ovariectomized rhesus monkeys.
Zha, Xi; Xu, Xiaohong
Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissect the physiological mechanisms governing complex behaviors. Since the last century, converging evidence has implicated the hypothalamus as the central brain area that controls innate behaviors. Recent studies using cutting-edge tools have revealed that genetically-defined populations of neurons residing in distinct hypothalamic nuclei and their associated neural pathways regulate the initiation and maintenance of diverse behaviors including feeding, sleep, aggression, and parental care. Here, we review the newly-defined hypothalamic pathways that regulate each innate behavior. In addition, emerging general principles of the neural control of complex behaviors are discussed.
Mikkelsen, J D; Jacobsen, Julie; Kiss, Adrian Emil
The magnocellular neurons in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) either contain vasopressin or oxytocin. Even though both hormones are released after systemic administration of nicotine, the mechanism through which the two populations of neurons are activated...... is not known. This study was carried out in the rat to investigate the effect of increasing doses of nicotine on subsets of magnocellular neurons containing either oxytocin or vasopressin....
Liu, James H; Bill, Arthur H
Stress-associated amenorrhea in the adolescent is likely similar to the disorder found in young reproductive-aged adults and is termed hypothalamic amenorrhea. The key defect is an abnormality in the secretion of gonadotropin-releasing hormone. This review examines the current studies that characterize the disorder and the plausible factor(s) that may account for the disturbances in gonadotropin-releasing hormone, and identifies directions for future research in this group of disorders.
Okuda, C; Miyazaki, M; Kuriyama, K
In order to investigate neuroendocrinological mechanisms of hypothermia, we determined the changes in plasma concentrations of corticosterone (CS), prolactin (PRL), and thyrotropin (TSH), and their correlations with alterations in hypothalamic dopamine (DA) and thyrotropin releasing hormone (TRH), in rats restrained and immersed in a water bath at various temperatures. A graded decrease of body temperature induced a progressive increase in the plasma level of CS, whereas that of PRL showed a drastic decrease. The plasma level of TSH also showed an increase during mild hypothermia (about 35 degrees C), but this increase was not evident during profound hypothermia (below 24 degrees C). The changes in these hormones were readily reversed by rewarming animals. Although DA content in the hypothalamus was not affected, its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), showed an increase following the decrease of body temperature. Pretreatment of the animals with sulpiride, a D2-antagonist, prevented the hypothermia-induced inhibition of PRL release. Hypothalamic TRH was significantly decreased during mild hypothermia, and it returned to control levels after rewarming. These results suggest that the decrease in plasma PRL induced by hypothermia may be associated with the activation of hypothalamic DA neurons, whereas the increase in plasma TSH during mild hypothermia seems to be caused by the increased release of TRH in the hypothalamus.
Crowne, Elizabeth; Gleeson, Helena; Benghiat, Helen; Sanghera, Paul; Toogood, Andrew
The past 30 years have seen a great improvement in survival of children and young adults treated for cancer. Cancer treatment can put patients at risk of health problems that can develop many years later, most commonly affecting the endocrine system. Patients treated with cranial radiotherapy often develop dysfunction of the hypothalamic-pituitary axis. A characteristic pattern of hormone deficiencies develops over several years. Growth hormone is disrupted most often, followed by gonadal, adrenal, and thyroid hormones, leading to abnormal growth and puberty in children, and affecting general wellbeing and fertility in adults. The severity and rate of development of hypopituitarism is determined by the dose of radiotherapy delivered to the hypothalamic-pituitary axis. Individual growth hormone deficiencies can develop after a dose as low as 10 Gy, whereas multiple hormone deficiencies are common after 60 Gy. New techniques in radiotherapy aim to reduce the effect on the hypothalamic-pituitary axis by minimising the dose received. Patients taking cytotoxic drugs do not often develop overt hypopituitarism, although the effect of radiotherapy might be enhanced. The exception is adrenal insufficiency caused by glucocorticosteroids which, although transient, can be life-threatening. New biological drugs to treat cancer can cause autoimmune hypophysitis and hypopituitarism; therefore, oncologists and endocrinologists should be vigilant and work together to optimise patient outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.
Heap, Lucy A.; Vanwalleghem, Gilles C.; Thompson, Andrew W.; Favre-Bulle, Itia; Rubinsztein-Dunlop, Halina; Scott, Ethan K.
The optic tectum of larval zebrafish is an important model for understanding visual processing in vertebrates. The tectum has been traditionally viewed as dominantly visual, with a majority of studies focusing on the processes by which tectal circuits receive and process retinally-derived visual information. Recently, a handful of studies have shown a much more complex role for the optic tectum in larval zebrafish, and anatomical and functional data from these studies suggest that this role extends beyond the visual system, and beyond the processing of exclusively retinal inputs. Consistent with this evolving view of the tectum, we have used a Gal4 enhancer trap line to identify direct projections from rostral hypothalamus (RH) to the tectal neuropil of larval zebrafish. These projections ramify within the deepest laminae of the tectal neuropil, the stratum album centrale (SAC)/stratum griseum periventriculare (SPV), and also innervate strata distinct from those innervated by retinal projections. Using optogenetic stimulation of the hypothalamic projection neurons paired with calcium imaging in the tectum, we find rebound firing in tectal neurons consistent with hypothalamic inhibitory input. Our results suggest that tectal processing in larval zebrafish is modulated by hypothalamic inhibitory inputs to the deep tectal neuropil. PMID:29403362
Colley, Danielle L; Castonguay, Thomas W
Several hypotheses for the causes of the obesity epidemic in the US have been proposed. One such hypothesis is that dietary intake patterns have significantly shifted to include unprecedented amounts of refined sugar. We set out to determine if different sugars might promote changes in the hypothalamic mechanisms controlling food intake by measuring several hypothalamic peptides subsequent to overnight access to dilute glucose, sucrose, high fructose corn syrup, or fructose solutions. Rats were given access to food, water and a sugar solution for 24h, after which blood and tissues were collected. Fructose access (as opposed to other sugars that were tested) resulted in a doubling of circulating triglycerides. Glucose consumption resulted in upregulation of 7 satiety-related hypothalamic peptides whereas changes in gene expression were mixed for remaining sugars. Also, following multiple verification assays, 6 satiety related peptides were verified as being affected by sugar intake. These data provide evidence that not all sugars are equally effective in affecting the control of intake. Copyright © 2014. Published by Elsevier Inc.
Lucy A. Heap
Full Text Available The optic tectum of larval zebrafish is an important model for understanding visual processing in vertebrates. The tectum has been traditionally viewed as dominantly visual, with a majority of studies focusing on the processes by which tectal circuits receive and process retinally-derived visual information. Recently, a handful of studies have shown a much more complex role for the optic tectum in larval zebrafish, and anatomical and functional data from these studies suggest that this role extends beyond the visual system, and beyond the processing of exclusively retinal inputs. Consistent with this evolving view of the tectum, we have used a Gal4 enhancer trap line to identify direct projections from rostral hypothalamus (RH to the tectal neuropil of larval zebrafish. These projections ramify within the deepest laminae of the tectal neuropil, the stratum album centrale (SAC/stratum griseum periventriculare (SPV, and also innervate strata distinct from those innervated by retinal projections. Using optogenetic stimulation of the hypothalamic projection neurons paired with calcium imaging in the tectum, we find rebound firing in tectal neurons consistent with hypothalamic inhibitory input. Our results suggest that tectal processing in larval zebrafish is modulated by hypothalamic inhibitory inputs to the deep tectal neuropil.
Full Text Available Gangliogliomas (GG are mixed glioneuronal tumors of the central nervous system (CNS, occurring mostly in the pediatric population, with common sites being temporal lobes and less commonly in the frontal and parietal lobes. We report a case of a 7-year-old child who presented with bilateral visual defects for 6 months. Magnetic resonance imaging (MRI of the brain revealed an intensely enhancing mass lesion with calcification in the sellar and suprasellar region involving the optic chiasm and the left optic nerve. The mass showed almost bilaterally symmetrical diffuse spread along the optic tracts posteriorly and hypothalamus, temporal lobes, thalami and the basal ganglia. The lesion was radiologically indistinguishable from chiasmatic astrocytoma or a germ cell tumor but histopathological features were of a ganglioglioma. While a few optic apparatus gangliogliomas have been reported in the literature, such widespread diffuse involvement of the entire optico-chiasmal hypothalamic pathway is unusual.
Chieng, P.U.; Huang, T.S.; Chang, C.C.; Chong, P.N.; Tien, R.D.; Su, C.T.
To determine the effect of cranial irradiation on hypothalamic blood flow, the authors performed 44 regional cerebral blood flow studies with 99mTc hexamethyl propyleneamine oxime (HMPAO) single-photon emission CT (SPECT) on four normal volunteers and 34 patients with pathologically proved nasopharyngeal cancer. Twenty-three men and 15 women, 30-65 years old, were divided into four study groups: group 1 served as a control and consisted of four normal volunteers and six patients studied prior to cranial irradiation; group 2 patients had cranial irradiation half a year before the SPECT study (n = 12, one from group 1); group 3 patients were irradiated 1 year before the study (n = 13, three from group 1 and two from group 2); and group 4 patients were irradiated at least 5 years before SPECT imaging (n = 9). Six patients were studied twice. Quantification of the 99mTc-HMPAO brain SPECT studies was done separately by three radiologists to obtain the hypothalamus/occipital (H/O) and hypothalamus/parasagittal (H/P) ratios. Endocrinologic studies were performed in all cases and the hypothalamus-thyrotroph-thyroid, hypothalamus-gonadotroph-testis (ovary), hypothalamus-lactotroph, hypothalamus-somatotroph, and hypothalamus-corticotroph-adrenal axes were evaluated separately. They determined that regional hypothalamic blood flow was reduced after cranial irradiation in patients with nasopharyngeal cancer. The H/O ratio of groups 3 and 4 did not differ from that of group 2 (one-half year after cranial irradiation). The H/O ratio was significantly reduced 6 months and 1 year after cranial irradiation; mean ± SD = 0.5801 ± 0.0829 (p less than .025), 0.5725 ± 0.0791 (p less than .01) versus 0.6477 ± 0.0458 before cranial irradiation, respectively
Vercruysse, Pauline; Sinniger, Jérôme; El Oussini, Hajer; Scekic-Zahirovic, Jelena; Dieterlé, Stéphane; Dengler, Reinhard; Meyer, Thomas; Zierz, Stephan; Kassubek, Jan; Fischer, Wilhelm; Dreyhaupt, Jens; Grehl, Torsten; Hermann, Andreas; Grosskreutz, Julian; Witting, Anke; Van Den Bosch, Ludo; Spreux-Varoquaux, Odile; Ludolph, Albert C; Dupuis, Luc
Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic
Sum, Melissa; Warren, Michelle P
The purpose of this study was to compare the hormonal/clinical profiles and markers of bone health of women with hypothalamic amenorrhea (HA) to women with suspected HA and underlying polycystic ovary syndrome (PCOS). The results indicate that compared to women with HA, women with HA and underlying PCOS exhibit higher body mass index (BMI), bone mineral densities, and incidence of hyperandrogenism, that they may exhibit increased hyperandrogenism and irregular menses with weight gain, and that they remain at similar risk for osteopenia and osteoporosis.
la Fleur, Susanne E.; Manalo, Sotara L.; Roy, Monica; Houshyar, Hani; Dallman, Mary F.
Hypothalamic anorexigenic [corticotropin-releasing factor (CRF) and proopiomelanocortin] peptides decrease and the orexigen, neuropeptide Y, increases with diabetic hyperphagia. However, when diabetic rats are allowed to eat lard (saturated fat) as well as chow, both caloric intake and hypothalamic
Full Text Available Background/Objective: The mechanistic target of rapamycin (mTOR is a serine–threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2 that regulate energy homeostasis. DEP-domain containing mTOR-interacting protein (DEPTOR is part of these complexes and is known to dampen mTORC1 function, consequently reducing mTORC1 negative feedbacks and promoting insulin signaling and Akt/PKB activation in several models. Recently, we observed that DEPTOR is expressed in several structures of the brain including the mediobasal hypothalamus (MBH, a region that regulates energy balance. Whether DEPTOR in the MBH plays a functional role in regulating energy balance and hypothalamic insulin signaling has never been tested. Methods: We have generated a novel conditional transgenic mouse model based on the Cre-LoxP system allowing targeted overexpression of DEPTOR. Mice overexpressing DEPTOR in the MBH were subjected to a metabolic phenotyping and MBH insulin signaling was evaluated. Results: We first report that systemic (brain and periphery overexpression of DEPTOR prevents high-fat diet-induced obesity, improves glucose metabolism and protects against hepatic steatosis. These phenotypes were associated with a reduction in food intake and feed efficiency and an elevation in oxygen consumption. Strikingly, specific overexpression of DEPTOR in the MBH completely recapitulated these phenotypes. DEPTOR overexpression was associated with an increase in hypothalamic insulin signaling, as illustrated by elevated Akt/PKB activation. Conclusion: Altogether, these results support a role for MBH DEPTOR in the regulation of energy balance and metabolism. Keywords: mTOR, DEPTOR, Hypothalamus, Energy balance, Glucose metabolism
the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis. Keywords: CART, Energy homeostasis, AAV-FLEX, Arcuate nucleus, Lateral hypothalamic area
Smeets, P.A.M.; Vidarsdottir, S.; Graaf, de C.; Stafleu, A.; Osch, M.J.P.; Viergever, M.A.; Pijl, H.; Grond, van der J.
Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion. Am J Physiol Endocrinol Metab 293: E754-E758, 2007. First published June 12, 2007; doi:10.1152/ajpendo.00231.2007. - We previously showed that hypothalamic neuronal activity, as measured by the blood
Smeets, P.A.M.; Vidarsdottir, S.; Graaf, C. de; Stafleu, A.; Osch, M.J.P. van; Viergever, M.A.; Pijl, H.; Grond, J. van der
We previously showed that hypothalamic neuronal activity, as measured by the blood oxygen level-dependent (BOLD) functional MRI signal, declines in response to oral glucose intake. To further explore the mechanism driving changes in hypothalamic neuronal activity in response to an oral glucose load,
Polledo, L; Oliveira, M; Adamany, J; Graham, P; Baiker, K
A 6-year old male neutered Scottish Terrier was referred with a 1 week history of progressive lethargy and anorexia. Neurological examination localized a lesion to the forebrain and hormonal testing showed panhypopituitarism. Magnetic resonance imaging (MRI) of the brain revealed a rounded, well-defined, suprasellar central mass. The mass was slightly hyperintense to the cortical grey matter on T2-weighted (T2W), hypointense on T1-weighted (T1W) images and without T2* signal void. There was a central fusiform enhancement of the mass after contrast administration which raised the suspicion of a pituitary neoplasm. Rapid deterioration of the dog prevented further clinical investigations. Histopathologic examination revealed a lymphocytic panhypophysitis of unknown origin suspected autoimmune involving the hypothalamus (hypothalamitis). This is a unique case report of a dog presenting with inflammatory hypophysitis and hypothalamitis of suspected autoimmune origin with detailed clinical, MRI, histology and immunohistochemistry findings. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
Ahmed, S.R.; Shalet, S.M.
The effect of synthetic human pancreatic tumour GH releasing factor (hp GRF1-44) on GH release has been studied in 10 patients with radiation-induced GH deficiency and four normal subjects. All 10 patients showed subnormal GH responses to both an ITT (median peak GH 3.2 mU/1) and to arginine stimulation (median peak GH 2.9 mU/1), although the remainder of pituitary function was intact. Following an acute intravenous bolus (100 μg) of hp GRF1-44, there was no GH response in two patients and a subnormal but definite GH response in a further four. The remaining four patients showed a significant GH response (median peak GH level 29 mU/1; range 22-57 mU/1) to hp GRF1-44, similar in magnitude and timing to that seen in th four normals. This strongly suggests that in these four subjects, the discrepancy in GH responses to hp GRF1-44, ITT and to arginine was a result of radiation-induced hypothalamic damage leading to a deficiency of endogenous GRF. The availability of synthetic hp GRF capable of stimulating GH secretion means that the distinction between hypothalamic and pituitary causes of GH deficiency will be of considerable therapeutic importance in the future. (author)
Shin, Mi-Seon; Chang, Hyukki; Namkoong, Churl; Kang, Gil Myoung; Kim, Hyun-Kyong; Gil, So Young; Yu, Ji Hee; Park, Kyeong Han; Kim, Min-Seon
Clusterin is a sulfated glycoprotein abundantly expressed in the pituitary gland and hypothalamus of mammals. However, its physiological role in neuroendocrine function is largely unknown. In the present study, we investigated the effects of intracerebroventricular (ICV) administration of clusterin on plasma pituitary hormone levels in normal rats. Single ICV injection of clusterin provoked neurohormonal changes seen under acute stress condition: increased plasma adrenocorticotropic hormone (ACTH), corticosterone, GH and prolactin levels and decreased LH and FSH levels. Consistently, hypothalamic and pituitary clusterin expression levels were upregulated following a restraint stress, suggesting an involvement of endogenous clusterin in stress-induced neurohormonal changes. In the pituitary intermediate lobe, clusterin was coexpressed with proopiomelanocortin (POMC), a precursor of ACTH. Treatment of clusterin in POMC expressing AtT-20 pituitary cells increased basal and corticotropin-releasing hormone (CRH)-stimulated POMC promoter activities and intracellular cAMP levels. Furthermore, clusterin treatment triggered ACTH secretion from AtT-20 cells in a CRH-dependent manner, indicating that increased clusterin under stressful conditions may augment CRH-stimulated ACTH production and release. In summary, hypothalamic and pituitary clusterin may function as a modulator of neurohormonal responses under stressful conditions. © 2013 S. Karger AG, Basel.
Lam, K.S.; Tse, V.K.; Wang, C.; Yeung, R.T.; Ma, J.T.; Ho, J.H.
Hypothalamic-pituitary function was studied in 31 patients before and after cranial irradiation for nasopharyngeal carcinoma. The estimated radiotherapy (RT) doses to the hypothalamus and pituitary were 3979 +/- 78 (+/- SD) and 6167 +/- 122 centiGrays, respectively. All patients had normal pituitary function before RT. One year after RT, there was a significant decrease in the integrated serum GH response to insulin-induced hypoglycemia. In the male patients, basal serum FSH significantly increased, while basal serum LH and testosterone did not change. Moreover, in response to LHRH, the integrated FSH response was increased while that of LH was decreased. Such discordant changes in FSH and LH may be explained by a defect in LHRH pulsatile release involving predominantly a decrease in pulse frequency. The peak serum TSH response to TRH became delayed in 28 patients, suggesting a defect in TRH release. Twenty-one patients were reassessed 2 yr after RT. Their mean basal serum T4 and plasma cortisol levels had significantly decreased. Hyperprolactinemia associated with oligomenorrhoea was found in 3 women. Further impairment in the secretion of GH, FSH, LH, TSH, and ACTH had occurred, and 4 patients had hypopituitarism. Thus, progressive impairment in hypothalamic-pituitary function occurs after cranial irradiation and can be demonstrated as early as 1 yr after RT
Argyropoulou, Maria I.; Kiortsis, Dimitrios Nikiforos
In childhood, the MR characteristics of the normal pituitary gland are well established. During the first 2 months of life the adenohypophysis demonstrates high signal. Pituitary gland height (PGH) decreases during the 1st year of life and then increases, reaching a plateau after puberty. The magnetization transfer ratio (MTR) increases in both sexes up to the age of 20 years. On dynamic contrast-enhanced studies, the posterior pituitary lobe enhances simultaneously with the straight sinus, and the adenohypophysis later, but within 30 s. In genetically determined dysfunctional states, the adenohypophysis may be normal, hypoplastic, or enlarged. Pituitary enlargement, observed in Prop 1 gene mutations, is characterized by a mass interposed between the anterior and posterior lobes. An ectopic posterior lobe (EPP), associated with a hypoplastic or absent pituitary stalk, may be observed in patients with hypopituitarism. Tumors of the hypothalamic-pituitary (HP) axis may be the origin of adenohypophyseal deficiencies. A small hypointense adenohypophysis is found in iron overload states and is often associated with hypogonadotrophic hypogonadism. Absence of the posterior lobe bright signal, with or without a thick pituitary stalk or a mass at any site from the median eminence to the posterior pituitary lobe, may be found in diabetes insipidus. Hydrocephalus, suprasellar arachnoid cysts, hypothalamic hamartomas and craniopharyngiomas may result in central precocious puberty (CPP). Increased PGH in girls with idiopathic CPP is useful for its differential diagnosis from premature thelarche (PT). Pituitary adenomas, observed mainly in adolescents, present the same MR characteristics as those in adults. (orig.)
Argyropoulou, Maria I. [University of Ioannina, Department of Radiology, Medical School, Ioannina (Greece); Kiortsis, Dimitrios Nikiforos [University of Ioannina, Department of Physiology, Medical School, Ioannina (Greece)
In childhood, the MR characteristics of the normal pituitary gland are well established. During the first 2 months of life the adenohypophysis demonstrates high signal. Pituitary gland height (PGH) decreases during the 1st year of life and then increases, reaching a plateau after puberty. The magnetization transfer ratio (MTR) increases in both sexes up to the age of 20 years. On dynamic contrast-enhanced studies, the posterior pituitary lobe enhances simultaneously with the straight sinus, and the adenohypophysis later, but within 30 s. In genetically determined dysfunctional states, the adenohypophysis may be normal, hypoplastic, or enlarged. Pituitary enlargement, observed in Prop 1 gene mutations, is characterized by a mass interposed between the anterior and posterior lobes. An ectopic posterior lobe (EPP), associated with a hypoplastic or absent pituitary stalk, may be observed in patients with hypopituitarism. Tumors of the hypothalamic-pituitary (HP) axis may be the origin of adenohypophyseal deficiencies. A small hypointense adenohypophysis is found in iron overload states and is often associated with hypogonadotrophic hypogonadism. Absence of the posterior lobe bright signal, with or without a thick pituitary stalk or a mass at any site from the median eminence to the posterior pituitary lobe, may be found in diabetes insipidus. Hydrocephalus, suprasellar arachnoid cysts, hypothalamic hamartomas and craniopharyngiomas may result in central precocious puberty (CPP). Increased PGH in girls with idiopathic CPP is useful for its differential diagnosis from premature thelarche (PT). Pituitary adenomas, observed mainly in adolescents, present the same MR characteristics as those in adults. (orig.)
Meczekalski, B; Katulski, K; Czyzyk, A; Podfigurna-Stopa, A; Maciejewska-Jeske, M
Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 (IGF-1) and low total triiodothyronine. The aim of this work is to review the available data concerning the effects of FHA on different aspects of women's health. Functional hypothalamic amenorrhea is related to profound impairment of reproductive functions including anovulation and infertility. Women's health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile. FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects. FHA patients should be carefully diagnosed and properly managed to prevent both short- and long-term medical consequences.
Chou, Sharon H; Chamberland, John P; Liu, Xiaowen; Matarese, Giuseppe; Gao, Chuanyun; Stefanakis, Rianna; Brinkoetter, Mary T; Gong, Huizhi; Arampatzi, Kalliopi; Mantzoros, Christos S
Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.
Full Text Available Vital hypothalamic neurons regulating hunger, wakefulness, reward-seeking, and body weight are often defined by unique expression of hypothalamus-specific neuropeptides. Gene-ablation studies show that some of these peptides, notably orexin/hypocretin (hcrt/orx, are themselves critical for stable states of consciousness and metabolic health. However, neuron-ablation studies often reveal more severe phenotypes, suggesting key roles for co-expressed transmitters. Indeed, most hypothalamic neurons, including hcrt/orx cells, contain fast transmitters glutamate and GABA, as well as several neuropeptides. What are the roles and relations between different transmitters expressed by the same neuron? Here, we consider signaling codes for releasing different transmitters in relation to transmitter and receptor diversity in behaviorally-defined, widely-projecting peptidergic neurons, such as hcrt/orx cells. We then discuss latest optogenetic studies of endogenous transmitter release from defined sets of axons in situ, which suggest that recently-characterized vital peptidergic neurons (e.g. hcrt/orx, proopiomelanocortin , and agouti-related peptide cells, as well as classical modulatory neurons (e.g. dopamine and acetylcholine cells, all use fast transmitters to control their postsynaptic targets. These optogenetic insights are complemented by recent observations of behavioral deficiencies caused by genetic ablation of fast transmission from specific neuropeptidergic and aminergic neurons. Powerful and fast (millisecond-scale GABAergic and glutamatergic signaling from neurons previously considered to be primarily modulatory raises new questions about the roles of slower co-transmitters they co-express.
Loh, Kim; Fukushima, Atsushi; Zhang, Xinmei; Galic, Sandra; Briggs, Dana; Enriori, Pablo J.; Simonds, Stephanie; Wiede, Florian; Reichenbach, Alexander; Hauser, Christine; Sims, Natalie A.; Bence, Kendra K.; Zhang, Sheng; Zhang, Zhong-Yin; Kahn, Barbara B.; Neel, Benjamin G.; Andrews, Zane B.; Cowley, Michael A.; Tiganis, Tony
SUMMARY In obesity, anorectic responses to leptin are diminished, giving rise to the concept of ‘leptin resistance’. Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high fat diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity. PMID:22000926
Vianna, Claudia R; Coppari, Roberto
Changes in physical activities and feeding habits have transformed the historically rare disease of obesity into a modern metabolic pandemic. Obesity occurs when energy intake exceeds energy expenditure over time. This energy imbalance significantly increases the risk for cardiovascular disease and type 2 diabetes mellitus and as such represents an enormous socioeconomic burden and health threat. To combat obesity, a better understanding of the molecular mechanisms and neurocircuitries underlying normal body weight homeostasis is required. In the 1940s, pioneering lesion experiments unveiled the importance of medial and lateral hypothalamic structures. In the 1980s and 1990s, several neuropeptides and peripheral hormones critical for appropriate feeding behavior, energy expenditure, and hence body weight homeostasis were identified. In the 2000s, results from metabolic analyses of genetically engineered mice bearing mutations only in selected neuronal groups greatly advanced our knowledge of the peripheral/brain feedback-loop modalities by which central neurons control energy balance. In this review, we will summarize these recent progresses with particular emphasis on the biochemical identities of hypothalamic neurons and molecular components underlying normal appetite, energy expenditure, and body weight homeostasis. We will also parse which of those neurons and molecules are critical components of homeostatic adaptive pathways against obesity induced by hypercaloric feeding.
Full Text Available Background: Traumatic brain injury (TBI is a leading cause of secondary hypopituitarism in children and adults, and is responsible for impaired quality of life, disabilities and compromised development. Alterations of pituitary function can occur at any time after the traumatic event, presenting in various ways and evolving during time, so they require appropriate screening for early detection and treatment. Although the exact pathophysiology is unknown, several mechanisms have been hypothesized, including hypothalamic-pituitary autoimmunity (HP-A. The aim of this study was to systematically review literature on the association between HP-A and TBI-induced hypopituitarism. Major pitfalls related to the HP-A investigation were also discussed. Methods: The PubMed database was searched with a string developed for this purpose, without temporal or language limits, for original articles assessing the association of HP-A and TBI-induced hypopituitarism. Results: Three articles from the same group met the inclusion criteria. Anti-pituitary and anti-hypothalamic antibodies were detected using indirect immunofluorescence in a significant number of patients with acute and chronic TBI. Elevated antibody titer was associated with an increased risk of persistent hypopituitarism, especially somatotroph and gonadotroph deficiency, while no correlations were found with clinical parameters. Conclusion: HPA seems to contribute to TBI-induced pituitary damage, although major methodological issues need to be overcome and larger studies are warranted to confirm these preliminary data.
Leloup, C; Allard, C; Carneiro, L; Fioramonti, X; Collins, S; Pénicaud, L
Brain plays a central role in energy homeostasis continuously integrating numerous peripheral signals such as circulating nutrients, and in particular blood glucose level, a variable that must be highly regulated. Then, the brain orchestrates adaptive responses to modulate food intake and peripheral organs activity in order to achieve the fine tuning of glycemia. More than fifty years ago, the presence of glucose-sensitive neurons was discovered in the hypothalamus, but what makes them specific and identifiable still remains disconnected from their electrophysiological signature. On the other hand, astrocytes represent the major class of macroglial cells and are now recognized to support an increasing number of neuronal functions. One of these functions consists in the regulation of energy homeostasis through neuronal fueling and nutrient sensing. Twenty years ago, we discovered that the glucose transporter GLUT2, the canonical "glucosensor" of the pancreatic beta-cell together with the glucokinase, was also present in astrocytes and participated in hypothalamic glucose sensing. Since then, many studies have identified other actors and emphasized the astroglial participation in this mechanism. Growing evidence suggest that astrocytes form a complex network and have to be considered as spatially coordinated and regulated metabolic units. In this review we aim to provide an updated view of the molecular and respective cellular pathways involved in hypothalamic glucose sensing, and their relevance in physiological and pathological states. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
van der Klaauw, Agatha A; Ziauddeen, Hisham; Keogh, Julia M; Henning, Elana; Dachi, Sekesai; Fletcher, Paul C; Farooqi, I Sadaf
The aim of this study was to use functional neuroimaging to investigate whether oxytocin modulates the neural response to visual food cues in brain regions involved in the control of food intake. Twenty-four normal weight volunteers received intranasal oxytocin (24 IU) or placebo in a double-blind, randomized crossover study. Measurements were made forty-five minutes after dosing. On two occasions, functional MRI (fMRI) scans were performed in the fasted state; the blood oxygen level-dependent (BOLD) response to images of high-calorie foods versus low-calorie foods was measured. Given its critical role in eating behaviour, the primary region of interest was the hypothalamus. Secondary analyses examined the parabrachial nuclei and other brain regions involved in food intake and food reward. Intranasal oxytocin administration suppressed hypothalamic activation to images of high-calorie compared to low-calorie food (P = 0.0125). There was also a trend towards suppression of activation in the parabrachial nucleus (P = 0.0683). No effects of intranasal oxytocin were seen in reward circuits or on ad libitum food intake. Further characterization of the effects of oxytocin on neural circuits in the hypothalamus is needed to establish the utility of targeting oxytocin signalling in obesity.
Watanabe, T; Morimoto, A; Murakami, N
We investigated the effects of endogenous pyrogen and prostaglandin E2 (PGE2) on the preoptic and anterior hypothalamic (POAH) neurons using brain slice preparations from the rat. Partially purified endogenous pyrogen did not change the activities of most of the neurons in the POAH region when applied locally through a micropipette attached to the recording electrode in proximity to the neurons. This indicates that partially purified endogenous pyrogen does not act directly on the neuronal activity in the POAH region. The partially purified endogenous pyrogen, applied into a culture chamber containing a brain slice, facilitated the activities in 24% of the total neurons tested, regardless of the thermal specificity of the neurons. Moreover, PGE2 added to the culture chamber facilitated 48% of the warm-responsive, 33% of the cold-responsive, and 29% of the thermally insensitive neurons. The direction of change in neuronal activity induced by partially purified endogenous pyrogen appears to be almost the same as that induced by PGE2 when these substances were applied by perfusion to the same neuron in the culture chamber. These results suggest that partially purified pyrogen applied to the perfusate of the culture chamber stimulates some constituents of brain tissue to synthesize and release prostaglandin, which in turn affects the neuronal activity of the POAH region.
Crump, Douglas; Lean, David; Trudeau, Vance L
We assessed octylphenol (OP), an estrogenic endocrine-disrupting chemical, and UV-B radiation, a known stressor in amphibian development, for their effects on hypothalamic gene expression and premetamorphic development in the leopard frog Rana pipiens. Newly hatched tadpoles were exposed for 10 days to OP alone at two different dose levels; to subambient UV-B radiation alone; and to two combinations of OP and UV-B. Control animals were exposed to ethanol vehicle (0.01%) exposure, a subset of tadpoles from each treatment group was raised to metamorphosis to assess differences in body weight and time required for hindlimb emergence. Tadpoles from one of the OP/UV-B combination groups had greater body weight and earlier hindlimb emergence (p weight or hindlimb emergence, indicating a potential mechanism of interaction between OP and UV-B. We hypothesized that the developing hypothalamus might be a potential environmental sensor for neurotoxicologic studies because of its role in the endocrine control of metamorphosis. We used a differential display strategy to identify candidate genes differentially expressed in the hypothalamic region of the exposed tadpoles. Homology cloning was performed to obtain R. pipiens glutamate decarboxylases--GAD65 and GAD67, enzymes involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). cDNA expression profiles revealed that OP and UV-B affected the levels of several candidate transcripts in tadpole (i.e., Nck, Ash, and phospholipase C gamma-binding protein 4 and brain angiogenesis inhibitor-3) and metamorph (i.e., GAD67, cytochrome C oxidase, and brain angiogenesis inhibitor-2 and -3) brains. This study represents a novel approach in toxicology that combines physiologic and molecular end points and indicates that levels of OP commonly found in the environment and subambient levels of UV-B alter the expression of important hypothalamic genes and disrupt tadpole growth patterns.
Sakata, Y; Morimoto, A; Takase, Y; Murakami, N
The effect of endogenous pyrogen (E.P.) injected directly into the tissue near the recording site were examined on the activities of the medullary temperature-responsive (TR) neurons in rabbits anesthetized with urethane. Endogenous pyrogen prepared from rabbit's whole blood was administered by a fine glass cannula (100-200 micrometer in diameter) in a fluid volume of 1 to 4 microliter. The cannula was fixed to the manipulator in parallel with a microelectrode and their tips were less than 0.05 mm apart. In rabbits with the intact preoptic/anterior hypothalamic (PO/AH) region, 4 warm-responsive neurons out of 7 were inhibited and 6 cold-responsive neuron out of 7 were excited by the direct administration of the E.P. In rabbits with lesions of the PO/AH, 5 warm-responsive neurons out of 9 were inhibited and 6 cold-responsive neurons out of 8 were facilitated by E.P. Antipyretics administered locally after the E.P. antagonized the pyretic effect, causing a return of the discharge of TR neuron to the control rate within 2.4 +/- 1.2 (mean +/- S.D.) min. The medullary TR neuron itself has the ability to respond to the E.P. and contributes to the development of fever.
Won, S J; Lin, M T
Polyadenylic.polyuridylic acid injected intravenously into rabbits produced a rapid-onset, monophasic fever. Pyrogenic tolerance occurred in rabbits following daily injections of polyadenylic.polyuridylic acid. However, direct injection of the agent into the preoptic anterior hypothalamic region of rabbit's brain produced a markedly different fever. After an intrahypothalamic injection of polyadenylic.polyuridylic acid, fever was delayed in onset and persisted for a longer period. At room temperature, the fever was due to both increased metabolism and cutaneous vasoconstriction. In a colder atmosphere the fever was due solely to increased metabolism, whereas in the heat the fever was due to reduction in cutaneous blood flow and respiratory evaporative heat loss. In addition, the fever induced by intravenous polyadenylic.polyuridylic acid injection was reversed by a cyclooxygenase inhibitor, but not by a protein synthesis inhibitor. Polyadenylic.polyuridylic acid was shown to stimulate PGE2 production from rabbit's hypothalamus in vitro. The results reveal that this agent is a prostaglandin-dependent pyrogen.
Zhang, Yalin; Kim, Min Soo; Jia, Baosen; Yan, Jingqi; Zuniga-Hertz, Juan Pablo; Han, Cheng; Cai, Dongsheng
It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.
Ja Hye Kim
Full Text Available The hypothalamus plays a key role in the regulation of body weight by balancing the intake of food, energy expenditure, and body fat stores, as evidenced by the fact that most monogenic syndromes of morbid obesity result from mutations in genes expressed in the hypothalamus. Hypothalamic obesity is a result of impairment in the hypothalamic regulatory centers of body weight and energy expenditure, and is caused by structural damage to the hypothalamus, radiotherapy, Prader-Willi syndrome, and mutations in the LEP, LEPR, POMC, MC4R and CART genes. The pathophysiology includes loss of sensitivity to afferent peripheral humoral signals, such as leptin, dysregulated insulin secretion, and impaired activity of the sympathetic nervous system. Dysregulation of 11β-hydroxysteroid dehydrogenase 1 activity and melatonin may also have a role in the development of hypothalamic obesity. Intervention of this complex entity requires simultaneous targeting of several mechanisms that are deranged in patients with hypothalamic obesity. Despite a great deal of theoretical understanding, effective treatment for hypothalamic obesity has not yet been developed. Therefore, understanding the mechanisms that control food intake and energy homeostasis and pathophysiology of hypothalamic obesity can be the cornerstone of the development of new treatments options. Early identification of patients at-risk can relieve the severity of weight gain by the provision of dietary and behavioral modification, and antiobesity medication. This review summarizes recent advances of the pathophysiology, endocrine characteristics, and treatment strategies of hypothalamic obesity.
Full Text Available The hypothalamus in the brain is the main center for appetite control and integrates signals from adipose tissue and the gastrointestinal tract. Antidepressants are known to modulate the activities of hypothalamic neurons and affect food intake, but the cellular and molecular mechanisms by which antidepressants modulate hypothalamic function remain unclear. Here we have investigated how hypothalamic neurons respond to treatment with antidepressants, including desipramine and sibutramine. In primary cultured rat hypothalamic cells, desipramine markedly suppressed the elevation of intracellular Ca(2+ evoked by histamine H1 receptor activation. Desipramine also inhibited the histamine-induced Ca(2+ increase and the expression of corticotrophin-releasing hormone in hypothalamic GT1-1 cells. The effect of desipramine was not affected by pretreatment with prazosin or propranolol, excluding catecholamine reuptake activity of desipramine as an underlying mechanism. Sibutramine which is also an antidepressant but decreases food intake, had little effect on the histamine-induced Ca(2+ increase or AMP-activated protein kinase activity. Our results reveal that desipramine and sibutramine have different effects on histamine H1 receptor signaling in hypothalamic cells and suggest that distinct regulation of hypothalamic histamine signaling might underlie the differential regulation of food intake between antidepressants.
Podfigurna-Stopa, Agnieszka; Luisi, Stefano; Lazzeri, Lucia; Ciani, Valentina; Meczekalski, Błazej; Petraglia, Felice
Functional hypothalamic disturbances may be the cause of secondary amenorrhea and are related to aberration in both the pattern of pulsatility and amplitude in the release of gonadotropin-releasing hormone (GnRH) in hypothalamus. Inhibin B, as an ovarian peptide plays a crucial role in reproduction function throughout regulation of folliculotropin (FSH) pituitary production and inhibiting GnRH secretion during the menstrual cycle. To measure and estimate serum inhibin B concentration in patients with functional hypothalamic amenorrhea. Material and methods. The study included 41 women suffering from functional hypothalamic amenorrhea. Secondary amenorrhea was defined as the lack of menstruation lasting at least 90 days not due to pregnancy, characterized by low serum concentrations of lutropin (LH < 5 mIU/ml)) and typical for functional hypothalamic disturbances anamnestic investigation. The control group consists of 40 healthy women with normal menstrual cycles and Body Mass Index (BMI between 18.5- 24.9 kg/m2). Medical history, examination and laboratory analysis of LH, FSH, estradiol (E), prolactin, testosterone and inhibin B were performed (ELISA--enzyme-linked immunosorbent assay). There are statistically lower serum inhibin B, FSH, LH, estradiol and prolactin concentrations in patients with functional hypothalamic amenorrhea in comparison to healthy women. Positive correlation between serum concentration of inhibin B and estradiol concentration was found in patients with functional hypothalamic amenorrhea. Patients with functional hypothalamic amenorrhea are characterized by statistical significant decrease in serum inhibin B concentration in comparison to the control group.
Berga, S L; Loucks-Daniels, T L; Adler, L J; Chrousos, G P; Cameron, J L; Matthews, K A; Marcus, M D
Women with functional hypothalamic amenorrhea are anovulatory because of reduced gonadotropin-releasing hormone drive. Several studies have documented hypercortisolemia, which suggests that functional hypothalamic amenorrhea is stress-induced. Further, with recovery (resumption of ovulation), cortisol decreased and gonadotropin-releasing hormone drive increased. Corticotropin-releasing hormone can increase cortisol and decrease gonadotropin-releasing hormone. To determine its role in functional hypothalamic amenorrhea, we measured corticotropin-releasing hormone in cerebrospinal fluid along with arginine vasopressin, another potent adrenocorticotropic hormone secretagog, and beta-endorphin, which is released by corticotropin-releasing hormone and can inhibit gonadotropin-releasing hormone. Corticotropin-releasing hormone, vasopressin, and beta-endorphin levels were measured in cerebrospinal fluid from 14 women with eumenorrhea and 15 women with functional hypothalamic amenorrhea. Levels of corticotropin-releasing hormone in cerebrospinal fluid and of vasopressin were comparable and beta-endorphin levels were lower in women with functional hypothalamic amenorrhea. In women with established functional hypothalamic amenorrhea, increased cortisol and reduced gonadotropin-releasing hormone are not sustained by elevated cerebrospinal-fluid corticotropin-releasing hormone, vasopressin, or beta-endorphin. These data do not exclude a role for these factors in the initiation of functional hypothalamic amenorrhea.
Kurup, Ravi Kumar; Kurup, Parameswara Achutha
The human hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neuronal transmission. The digoxin status and neurotransmitter patterns were studied in individuals with a predilection to fall in love. It was also studied in individuals with differing hemispheric dominance to find out the role of cerebral dominance in this respect. In individuals with a predilection to fall in love there was decreased digoxin synthesis, increased membrane Na+-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern correlated with that obtained in left hemispheric chemical dominance. Hemispheric dominance and hypothalamic digoxin could regulate the predisposition to fall in love.
Robert H. Lustig
Full Text Available Obesity is a common complication after craniopharyngioma therapy, occurring in up to 75% of survivors. Its weight gain is unlike that of normal obesity, in that it occurs even with caloric restriction, and attempts at lifestyle modification are useless to prevent or treat the obesity. The pathogenesis of this condition involves the inability to transduce afferent hormonal signals of adiposity, in effect mimicking a state of CNS starvation. Efferent sympathetic activity drops, resulting in malaise and reduced energy expenditure, and vagal activity increases, resulting in increased insulin secretion and adipogenesis. Lifestyle intervention is essentially useless in this syndrome, termed hypothalamic obesity. Pharmacologic treatment is also difficult, consisting of adrenergics to mimic sympathetic activity, or suppression of insulin secretion with octreotide, or both. Recently, bariatric surgery (Roux-en-Y gastric bypass, laparoscopic gastric banding, truncal vagotomy have also been attempted with variable results. Early and intensive management is required to mitigate the obesity and its negative consequences.
Wang, Jeff G; Lobo, Rogerio A
Polycystic ovarian morphology (PCOM) is occasionally observed in women with hypothalamic amenorrhea (HA). Although these women with HA/PCOM meet two of the Rotterdam criteria, they are excluded from the diagnosis of polycystic ovary syndrome (PCOS) by having HA. We explored the coexistence of these two disorders in women with HA/PCOM by analyzing their androgen response to gonadotropins and by following their clinical characteristics over time. Baseline and dynamic endocrine profiles during controlled ovarian hyperstimulation for women with HA/PCOM [n = 6, median (interquartile range) age 30 yr (28-31), body mass index (BMI) 19.2 kg/m(2) (18.0-19.2)] were retrospectively compared with those of women with PCOS [n = 10, age 33 (31-34), BMI 24.8 (23.2-27.6)] and normoovulatory controls [n = 20, age 33 (31-35), BMI 21.5(20.3-23.1)]. Long-term outcomes for five women with HA/PCOM were followed during their spontaneous recovery from HA. With the exception of decreased LH [0.7 (0.3-0.8) vs. 6.0 IU/liter (4.8-7.4); P = 0.003], FSH [3.9 (2.5-5.7) vs. 7.5 IU/liter (5.3-9.5); P < 0.025], and estradiol [20 (14-24) vs. 32 pg/ml (20-39); P < 0.027], baseline endocrine profiles of women with HA/PCOM did not differ significantly from those of normoovulatory controls in terms of 17alpha-hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, and total testosterone. However, controlled ovarian hyperstimulation with similar doses of gonadotropins resulted in an excess of androgen production compared with the controls [Deltaandrostenedione per dominant follicle 0.30 (0.23-0.37) vs. 0.10 ng/ml (0.05-0.18), P = 0.005; Deltatestosterone per dominant follicle 16 (7-24) vs. 6 ng/dl (2-12), P = 0.04], and these levels were comparable to those of women with PCOS. Recovery from HA/PCOM in some patients was associated with the development of oligomenorrhea and symptoms of androgen excess. Women with HA/PCOM may have inherently hyperandrogenic ovaries but
Full Text Available Several lines of evidence suggest that the hypothalamus is involved in trigeminal pain processing. However, the organization of descending hypothalamic projections to the spinal trigeminal nucleus caudalis (Sp5C remains poorly understood. Microinjections of the retrograde tracer, fluorogold (FG, into the Sp5C, in rats, reveal that five hypothalamic nuclei project to the Sp5C: the paraventricular nucleus, the lateral hypothalamic area, the perifornical hypothalamic area, the A11 nucleus and the retrochiasmatic area. Descending hypothalamic projections to the Sp5C are bilateral, except those from the paraventricular nucleus which exhibit a clear ipsilateral predominance. Moreover, the density of retrogradely FG-labeled neurons in the hypothalamus varies according to the dorso-ventral localization of the Sp5C injection site. There are much more labeled neurons after injections into the ventrolateral part of the Sp5C (where ophthalmic afferents project than after injections into its dorsomedial or intermediate parts (where mandibular and maxillary afferents, respectively, project. These results demonstrate that the organization of descending hypothalamic projections to the spinal dorsal horn and Sp5C are different. Whereas the former are ipsilateral, the latter are bilateral. Moreover, hypothalamic projections to the Sp5C display somatotopy, suggesting that these projections are preferentially involved in the processing of meningeal and cutaneous inputs from the ophthalmic branch of the trigeminal nerve in rats. Therefore, our results suggest that the control of trigeminal and spinal dorsal horn processing of nociceptive information by hypothalamic neurons is different and raise the question of the role of bilateral, rather than unilateral, hypothalamic control.
Liu, Mei; Alimov, Alexander; Wang, Haiping; Frank, Jacqueline A.; Katz, Wendy; Xu, Mei; Ke, Zun-Ji; Luo, Jia
Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16 days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by 9 folds in TD group. The loss of body weight (17–24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic AMPK is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight. PMID:24607345
Caron, Emilie; Ciofi, Philippe; Prevot, Vincent; Bouret, Sebastien G
It is increasingly accepted that alterations of the early life environment may have lasting impacts on physiological functions. In particular, epidemiological and animal studies have indicated that changes in growth and nutrition during childhood and adolescence can impair reproductive function. However, the precise biological mechanisms that underlie these programming effects of neonatal nutrition on reproduction are still poorly understood. Here, we used a mouse model of divergent litter size to investigate the effects of early postnatal overnutrition and undernutrition on the maturation of hypothalamic circuits involved in reproductive function. Neonatally undernourished females display attenuated postnatal growth associated with delayed puberty and defective development of axonal projections from the arcuate nucleus to the preoptic region. These alterations persist into adulthood and specifically affect the organization of neural projections containing kisspeptin, a key neuropeptide involved in pubertal activation and fertility. Neonatal overfeeding also perturbs the development of neural projections from the arcuate nucleus to the preoptic region, but it does not result in alterations in kisspeptin projections. These studies indicate that alterations in the early nutritional environment cause lasting and deleterious effects on the organization of neural circuits involved in the control of reproduction, and that these changes are associated with lifelong functional perturbations.
Sanders, Kristen M; Kawwass, Jennifer F; Loucks, Tammy; Berga, Sarah L
Functional hypothalamic amenorrhea is characterized by anovulation caused by reduced gonadotropin-releasing hormone drive and is associated with hypercortisolemia that has been linked to heightened hypothalamic-pituitary-adrenal reactivity to common psychological and metabolic challenges. We hypothesized that women with functional hypothalamic amenorrhea would display greater cortisol responses to exercise challenge than ovulatory women with eumenorrhea. We completed a cross-sectional comparison of 9 women with functional hypothalamic amenorrhea and 11 women with eumenorrhea who were of reproductive age, who weighed 90-110% ideal body weight, who did not exercise excessively, and who had no formal psychiatric diagnosis. Subjects completed a 20-minute submaximal exercise challenge using a cycle ergometer in a research exercise laboratory. Heart rate and circulatory cortisol, glucose, and lactate were measured at 10-minute intervals before, during, and after the exercise challenge. Baseline (t= -10 minutes) cortisol, glucose, lactate, and heart rate were comparable between groups. Glucose levels rose modestly during exercise by 2.9% in women with eumenorrhea (P=.4) but declined by 10.6% in functional hypothalamic amenorrhea (P<.03). The nadir in glucose levels in functional hypothalamic amenorrhea occurred at the end of the 20-minute exercise challenge (t= +20 min). Lactate levels rose comparably in both groups (P<.01). Heart rate increased significantly with exercise in both groups (P<.01), but the increase was smaller in subjects with functional hypothalamic amenorrhea (P<.01). Cortisol levels increased during the exercise challenge in both groups (P<.01) and peaked 10 minutes after the exercise ended (t= +30 min). At peak, subjects with functional hypothalamic amenorrhea displayed higher cortisol levels (147±22 [standard error of the mean] ng/mL) than women with eumenorrhea (96±12 ng/mL; P=.05). The mean percent increase over baseline was 62% in women with
Fujita, Akie; Bonnavion, Patricia; Wilson, Miryam H; Mickelsen, Laura E; Bloit, Julien; de Lecea, Luis; Jackson, Alexander C
Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons ( Hdc -Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain
Lukoshe, Akvile; van Dijk, Suzanne E; van den Bosch, Gerbrich E; van der Lugt, Aad; White, Tonya; Hokken-Koelega, Anita C
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, characterized by endocrine problems and hyperphagia, indicating hypothalamic-pituitary dysfunction. However, few studies have explored the underlying neurobiology of the hypothalamus and its functional connectivity with other brain regions. Thus, the aim of this study was to examine the anatomical differences of the hypothalamus, mammillary bodies, and pituitary gland as well as resting state functional connectivity of the hypothalamus in children with PWS. Twenty-seven children with PWS (13 DEL, 14 mUPD) and 28 typically developing children were included. Manual segmentations by a blinded investigator were performed to determine the volumes of the hypothalamus, mammillary bodies, and pituitary gland. In addition, brain-wide functional connectivity analysis was performed using the obtained masks of the hypothalamus. Children with PWS showed altered resting state functional connectivity between hypothalamus and right and left lateral occipital complex, compared to healthy controls. In addition, children with PWS had on average a 50% smaller pituitary volume, an irregular shape of the pituitary, and a longer pituitary stalk. Pituitary volume did not increase in volume during puberty in PWS. No volumetric differences in the hypothalamus and mammillary bodies were found. In all subjects, the posterior pituitary bright spot was observed. We report altered functional hypothalamic connectivity with lateral occipital complexes in both hemispheres, which are implicated in response to food and reward system, and absence of connectivity might therefore at least partially contribute to the preoccupation with food in PWS.
Pastor, Raúl; Aragon, Carlos M G
It is suggested that some of the behavioral effects of ethanol, including its psychomotor properties, are mediated by beta-endorphin and opioid receptors. Ethanol-induced increases in the release of hypothalamic beta-endorphin depend on the catalasemic conversion of ethanol to acetaldehyde. Here, we evaluated the locomotor activity in rats microinjected with ethanol directly into the hypothalamic arcuate nucleus (ArcN), the main site of beta-endorphin synthesis in the brain and a region with high levels of catalase expression. Intra-ArcN ethanol-induced changes in motor activity were also investigated in rats pretreated with the opioid receptor antagonist, naltrexone (0-2 mg/kg) or the catalase inhibitor 3-amino-1,2,4-triazole (AT; 0-1 g/kg). We found that ethanol microinjections of 64 or 128, but not 256 microg, produced locomotor stimulation. Intra-ArcN ethanol (128 microg)-induced activation was prevented by naltrexone and AT, whereas these compounds did not affect spontaneous activity. The present results support earlier evidence indicating that the ArcN and the beta-endorphinic neurons of this nucleus are necessary for ethanol to induce stimulation. In addition, our data suggest that brain structures that, as the ArcN, are rich in catalase may support the formation of ethanol-derived pharmacologically relevant concentrations of acetaldehyde and, thus be of particular importance for the behavioral effects of ethanol.
Bhatia, S C; Manchanda, S K; Kapoor, B K; Aneja, I S
Chemitrodes which permit electrical and chemical stimulation of the same hypothalamic loci were implanted in anterior hypothalamic and preoptic regions. These sites were stimulated electrically using biphasic square wave pulse (1 ms, 60 Hz) at a current strength ranging from 150-800 microA to evoke an aggressive response. At lower current strength of 150-200 micro A, defence response, a sort of non-specific response can be elicited from these regions. Increasing the current strength to 400 microA led to the recruitment of affective and somatic components and changed the response pattern either to affective attack or flight. The loci producing affective attack response were localized more laterally and ventrally while the loci producing flight response were located in the dorsomedial regions of the hypothalamus. In this response the animal made a goal-directed attempt to escape through an escape route. Increasing the current strength to 500 microA in the dorsomedial regions changed the flight response to violent flight, which involved vigorous running with unsheathed claws and attacking objects if obstructed. Similar increase in current strength at loci producing affective attack only led to a decrease in the latency of response and made the attack more vigorous. Microinfusion of carbachol in graded doses of 2-15 microgram at all these loci produced a profound affective display. At lower doses of 2 and 5 microgram, only some components of affective display like alertness, pupillary dilation and ear flatness were exhibited. Increasing the dose to 10 micrograms and 15 micrograms led to the recruitment of other affective components like piloerection, salivation, hissing and baring of teeth. Microinfusion of carbachol at all loci producing affective attack on electrical stimulation produced a prononced affective display while microinfusion of carbachol at loci producing flight response led to the development of defence posture. At six loci a typical flight response was
Oyola, Mario G; Handa, Robert J
Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism's response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic-pituitary-gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.
Full Text Available The mechanism of cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus (ARCN was studied in urethane-anesthetized adult male Wistar rats. At the baseline mean arterial pressure (BLMAP close to normal, ARCN stimulation elicited decreases in MAP and sympathetic nerve activity (SNA. The decreases in MAP elicited by ARCN stimulation were attenuated by either gamma-aminobutyric acid (GABA, neuropeptide Y (NPY, or beta-endorphin receptor blockade in the ipsilateral hypothalamic paraventricular nucleus (PVN. Combined blockade of GABA-A, NPY1 and opioid receptors in the ipsilateral PVN converted the decreases in MAP and SNA to increases in these variables. Conversion of inhibitory effects on the MAP and SNA to excitatory effects following ARCN stimulation was also observed when the BLMAP was decreased to below normal levels by an infusion of sodium nitroprusside. The pressor and tachycardic responses to ARCN stimulation at below normal BLMAP were attenuated by blockade of melanocortin 3/4 (MC3/4 receptors in the ipsilateral PVN. Unilateral blockade of GABA-A receptors in the ARCN increased the BLMAP and heart rate (HR revealing tonic inhibition of the excitatory neurons in the ARCN. ARCN stimulation elicited tachycardia regardless of the level of BLMAP. ARCN neurons projecting to the PVN were immunoreactive for glutamic acid decarboxylase 67 (GAD67, NPY, and beta-endorphin. These results indicated that: 1 at normal BLMAP, decreases in MAP and SNA induced by ARCN stimulation were mediated via GABA-A, NPY1 and opioid receptors in the PVN, 2 lowering of BLMAP converted decreases in MAP following ARCN stimulation to increases in MAP, and 3 at below normal BLMAP, increases in MAP and HR induced by ARCN stimulation were mediated via MC3/4 receptors in the PVN. These results provide a base for future studies to explore the role of ARCN in cardiovascular diseases.
Peper, Jiska S.; Brouwer, Rachel M.; van Leeuwen, Marieke; Schnack, Hugo G.; Boomsma, Dorret I.; Kahn, Rene S.; Pol, Hilleke E. Hulshoff
Objective: During puberty, the hypothalamus-pituitary-gonadal (HPG) axis is activated, leading to increases in luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex steroids (testosterone and estradiol) levels. We aimed to study the association between hypothalamic and pituitary
Andrea V. Rozo
Conclusion: These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.
Reis, Wagner L.; Yi, Chun-Xia; Gao, Yuanqing; Tschöp, Mathias H.; Stern, Javier E.
Hypothalamic inflammation, involving microglia activation in the arcuate nucleus (ARC), is proposed as a novel underlying mechanism in obesity, insulin and leptin resistance. However, whether activated microglia affects ARC neuronal activity, and consequently basal and hormonal-induced food intake,
Schneeberger, Marc; Gómez-Valadés, Alicia G; Altirriba, Jordi; Sebastián, David; Ramírez, Sara; Garcia, Ainhoa; Esteban, Yaiza; Drougard, Anne; Ferrés-Coy, Albert; Bortolozzi, Analía; Garcia-Roves, Pablo M; Jones, John G; Manadas, Bruno; Zorzano, Antonio; Gomis, Ramon; Claret, Marc
Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Prieto, Ruth; Pascual, José M
Norman McOmish Dott (1897-1973) developed surgical neurology in Edinburgh, Scotland, and was a scholar of worldwide renown. One of Dott's most notable contributions to neurosurgery was his understanding of hypothalamic physiology, mostly acquired through the comprehensive study of patients with lesions involving this region of the diencephalon, particularly craniopharyngiomas (CPs). Recognition of symptoms caused by hypothalamic disturbances allowed him to predict the accurate anatomical relationships between CPs and the hypothalamus, despite the rudimentary radiological methods available during the 1930s. His sophisticated knowledge permitted Dott to perform radical removals of CPs originating within the third ventricle floor with acceptable success. Between 1934 and 1937, he operated on 4 CP cases originating in the hypothalamus, achieving a satisfactory postoperative outcome in 3 of the 4 patients. Aware of the strong attachment of hypothalamic CPs to the infundibulo-tuberal area, Dott used a double transbasal and transventricular approach to these lesions, a strategy providing an optimal view and control of the tumor boundaries. The decisive mentorship of several legendary figures of physiology and neurosurgery greatly influenced Dott's surgical evolution. The experimental pituitary gland work he performed with Sir Edward Sharpey-Schäfer at the beginning of his career stirred Dott's curiosity about the issue of hypothalamus-pituitary relationships. As a result, he decided to move to Peter Bent Brigham Hospital (Boston, Massachusetts) in 1923, to train in neurosurgery and neuropathology under the guidance of the leaders in these fields, Harvey Williams Cushing (1869-1939) and Percival Sylvester Bailey (1892-1973). They inspired the young Dott and shared with him their clinical and pathological expertise, in addition to their surgical strategies for best approaching and removing these challenging tumors. In time, Dott would come to surpass his mentors. This
Berkseth, Kathryn E; Guyenet, Stephan J; Melhorn, Susan J; Lee, Donghoon; Thaler, Joshua P; Schur, Ellen A; Schwartz, Michael W
Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central nervous system injury and is detectable using either immunohistochemistry or in vivo magnetic resonance imaging (MRI). Obesity in rodents and humans is associated with gliosis of the arcuate nucleus, a key hypothalamic region for the regulation of energy homeostasis and adiposity, but whether this response is permanent or reversible is unknown. Here we combine terminal immunohistochemistry analysis with serial, noninvasive MRI to characterize the progression and reversibility of hypothalamic gliosis in high-fat diet (HFD)-fed mice. The effects of HFD feeding for 16 weeks to increase body weight and adiposity relative to chow were nearly normalized after the return to chow feeding for an additional 4 weeks in the diet-reversal group. Mice maintained on the HFD for the full 20-week study period experienced continued weight gain associated with the expected increases of astrocyte and microglial activation in the arcuate nucleus, but these changes were not observed in the diet-reversal group. The proopiomelanocortin neuron number did not differ between groups. Although MRI demonstrated a positive correlation between body weight, adiposity, and the gliosis-associated T2 signal in the mediobasal hypothalamus, it did not detect the reversal of gliosis among the HFD-fed mice after the return to chow diet. We conclude that hypothalamic gliosis associated with 16-week HFD feeding is largely reversible in rodents, consistent with the reversal of the HFD-induced obesity phenotype, and extend published evidence regarding the utility of MRI as a tool for studying obesity-associated hypothalamic gliosis in vivo.
Gardiner, JV; Bataveljic, A; Patel, NA; Bewick, GA; Roy, D; Campbell, D; Greenwood, HC; Murphy, KG; Hameed, S; Jethwa, PH; Ebling, FJP; Vickers, SP; Cheetham, S; Ghatei, MA; Bloom, SR
OBJECTIVE Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis. RESEARCH DESIGN AND METHODS We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanis...
Slavnov, V.N.; Markov, V.V.; Rudichenko, V.M.
Radioimmunoassay of vasopressin was conducted before and after drug tests and exercise for assessment of function of the hypothalamo-neurohypophyseal system in 165 patients with hypothalamic syndromes. It was shown that radioimmunoassay gave the adequate information for assessment of function of hypothalamo-neurohypophyseal system on the base of study of basal and stimulated vasopressin secretion. It permits to make an individual choice of the most effective drug for therapy of the hypothalamic syndrome of neuroendocrine-metabolic type
Full Text Available In this study, we examined alterations in the hypothalamic reward system related to high-fat diet (HFD preferences. We previously reported that hypothalamic 2-arachidonoylglycerol (2-AG and glial fibrillary acid protein (GFAP were increased after conditioning to the rewarding properties of a HFD. Here, we hypothesized that increased 2-AG influences the hypothalamic reward system.The conditioned place preference test (CPP test was used to evaluate HFD preferences. Hypothalamic 2-AG was quantified by gas chromatography-mass spectrometry. The expression of GFAP was examined by immunostaining and western blotting.Consumption of a HFD over either 3 or 7 days increased HFD preferences and transiently increased hypothalamic 2-AG levels. HFD consumption over 14 days similarly increased HFD preferences but elicited a long-lasting increase in hypothalamic 2-AG and GFAP levels. The cannabinoid 1 receptor antagonist O-2050 reduced preferences for HFDs after 3, 7, or 14 days of HFD consumption and reduced expression of GFAP after 14 days of HFD consumption. The astrocyte metabolic inhibitor Fluorocitrate blocked HFD preferences after 14 days of HFD consumption.High levels of 2-AG appear to induce HFD preferences, and activate hypothalamic astrocytes via the cannabinoid system. We propose that there may be two distinct stages in the development of HFD preferences. The induction stage involves a transient increase in 2-AG, whereas the maintenance stage involves a long lasting increase in 2-AG levels and activation of astrocytes. Accordingly, hypothalamic 2-AG may influence the development of HFD preferences.
Kaushik, Susmita; Rodriguez-Navarro, Jose Antonio; Arias, Esperanza; Kiffin, Roberta; Sahu, Srabani; Schwartz, Gary J.; Cuervo, Ana Maria; Singh, Rajat
Macroautophagy is a lysosomal degradative pathway that maintains cellular homeostasis by turning over cellular components. Here, we demonstrate a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance. We show that starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. The functional consequences of inhibiting autophagy are the...
Full Text Available Hypoxia-inducible factor (HIF is a nuclear transcription factor that responds to environmental and pathological hypoxia to induce metabolic adaptation, vascular growth, and cell survival. Here we found that HIF subunits and HIF2α in particular were normally expressed in the mediobasal hypothalamus of mice. Hypothalamic HIF was up-regulated by glucose to mediate the feeding control of hypothalamic glucose sensing. Two underlying molecular pathways were identified, including suppression of PHDs by glucose metabolites to prevent HIF2α degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2α protein synthesis. HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF inhibition in POMC neurons, revealing that HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing and caused energy imbalance to promote obesity development. The metabolic effects of HIF in hypothalamic POMC neurons were independent of leptin signaling or pituitary ACTH pathway. Hypothalamic gene delivery of HIF counteracted overeating and obesity under conditions of nutritional excess. In conclusion, HIF controls hypothalamic POMC gene to direct the central nutrient sensing in regulation of energy and body weight balance.
Foglesong, Grant D.; Huang, Wei; Liu, Xianglan; Slater, Andrew M.; Siu, Jason; Yildiz, Vedat; Salton, Stephen R. J.
Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneural-adipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF up-regulation or decrease of adiposity indicating a minor role of VGF in the hypothalamic-sympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF. PMID:26730934
Zhang, Hai; Zhang, Guo; Gonzalez, Frank J.; Park, Sung-min; Cai, Dongsheng
Hypoxia-inducible factor (HIF) is a nuclear transcription factor that responds to environmental and pathological hypoxia to induce metabolic adaptation, vascular growth, and cell survival. Here we found that HIF subunits and HIF2α in particular were normally expressed in the mediobasal hypothalamus of mice. Hypothalamic HIF was up-regulated by glucose to mediate the feeding control of hypothalamic glucose sensing. Two underlying molecular pathways were identified, including suppression of PHDs by glucose metabolites to prevent HIF2α degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2α protein synthesis. HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF inhibition in POMC neurons, revealing that HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing and caused energy imbalance to promote obesity development. The metabolic effects of HIF in hypothalamic POMC neurons were independent of leptin signaling or pituitary ACTH pathway. Hypothalamic gene delivery of HIF counteracted overeating and obesity under conditions of nutritional excess. In conclusion, HIF controls hypothalamic POMC gene to direct the central nutrient sensing in regulation of energy and body weight balance. PMID:21814490
José F. Tellez-Zenteno
Full Text Available José F. Tellez-Zenteno1, Cesar Serrano-Almeida2, Farzad Moien-Afshari11Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, CanadaAbstract: Gelastic seizures are epileptic events characterized by bouts of laughter. Laughter-like vocalization is usually combined with facial contraction in the form of a smile. Autonomic features such as flushing, tachycardia, and altered respiration are widely recognized. Conscious state may not be impaired, although this is often difficult to asses particularly in young children. Gelastic seizures have been associated classically to hypothalamic hamartomas, although different extrahypothalamic localizations have been described. Hypothalamic hamartomas are rare congenital lesions presenting with the classic triad of gelastic epilepsy, precocious puberty and developmental delay. The clinical course of patients with gelastic seizures associated with hypothalamic hamartomas is progressive, commencing with gelastic seizures in infancy, deteriorating into more complex seizure disorder resulting in intractable epilepsy. Electrophysiological, radiological, and pathophysiological studies have confirmed the intrinsic epileptogenicity of the hypothalamic hamartoma. Currently the most effective surgical approach is the trancallosal anterior interforniceal approach, however newer approaches including the endoscopic and other treatment such as radiosurgery and gamma knife have been used with success. This review focuses on the syndrome of gelastic seizures associated with hypothalamic hamartomas, but it also reviews other concepts such as status gelasticus and some aspects of gelastic seizures in other locations.Keywords: epilepsy, gelastic seizures, epilepsy surgery, hypothalamic hamartoma, intractable epilepsy
Joseph W McFadden
Full Text Available Modification of hypothalamic fatty acid (FA metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1 and fatty acid oxidation (FAOx, exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS, and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.
Amin, M S; Kader, M A; Huq, F I; Khan, N A
Hypothalamic hamartoma (HH) is one of the most important causes of central precocious puberty in male children. Hamartomas are malformations composed of ectopic gonadotropic hormone (GnRH) neurons which secrete pulsatile gonadotropin releasing hormone. They are generally observed in children under 3 years. A case of 11/3 year-old male child presented with premature development of secondary sexual characters i.e., growth of pubic and axillary hair, enlargement of penis and acne over the face for the last 5 months. On physical examination, his height was 1.02 m and his weight 18kg, enlarged penile length of which 58mm; testicles were enlarged in size right one measuring 32X25mm and the left 30X23mm. His hematological and other biochemical investigations revealed no abnormality. Plain radiographic examination revealed radiological bone age of about 8-9 years. Endocrinological findings were as follows: Follicle stimulating hormone (FSH): 1.5mIU/ml, Luteinizing hormone (LH): 9.1mIU/ml, Testosterone: 701ng/dl (Testosterone level less than 30ng/dl in prepubertal age). Thyroid function tests were normal. Patient showed no adrenal pathology on ultrasound and his testicular parenchyma was homogeneous echotexture with the size of 30X22X16mm on the right (volume 5.4ml) and 30X20X15mm on the left (volume 4.6ml). With above physical & endocrinological findings and age of the child, it was suspected as a case of central precocious puberty. Subsequently MR imaging of the brain done & showed an oval non-enhancing pedunculated hypothalamic mass arising from the tubercinereum that was iso to hypointense to brain parenchyma on T1 - and intermediate signal on T2-weighted images, 20X10X10mm in diameter, extending into suprasellar cistern. During follow up after 06 months of starting conservative medication with gonadotropin-releasing hormone (GnRH) analog (Leuprolide acetate), his progression of puberty has been arrested and the testosterone level 18ng/dl, which is normal for his age.
Poretti, Maria Belen; Frautschi, Camila; Luque, Eugenia Mercedes; Bianconi, Santiago; Martini, Ana Carolina; Stutz, Graciela; Vincenti, Laura Maria; Santillán, María Emilia; Ponzio, Marina Flavia; Schiöth, Helgi; Fiol De Cuneo, Marta Haydee; Carlini, Valeria Paola
It has been demonstrated that food intake and reproductive physiology are both simultaneously modulated to optimize reproductive success under fluctuating metabolic conditions. Ghrelin (Ghr) is an orexigenic peptide identified as the endogenous ligand of the growth hormone secretagogue receptor that is being investigated for its potential role on reproduction. Considering that data available so far are still limited and characterization of Ghr action mechanism on the reproductive system has not been fully elucidated, we studied the hypothalamus participation in Ghr effects on sperm functional activity, plasma levels of gonodotropins and histological morphology in mice testes after hypothalamic infusion of 0.3 or 3.0 nmol/day Ghr or artificial cerebrospinal fluid (ACSF) at different treatment periods. We found that Ghr 3.0 nmol/day administration for 42 days significantly reduced sperm concentration (Ghr 3.0 nmol/day=14.05±2.44 x106/ml vs. ACSF=20.33±1.35 x106/ml, p< 0.05) and motility (Ghr 3.0 nmol/day=59.40±4.20% vs. ACSF=75.80±1.40%, p< 0.05). In addition, histological studies showed a significant decrease percentage of spermatogonia (Ghr 3.0 nmol/day=6,76±0,68% vs. ACSF=9,56±0,41%, p< 0.05) and sperm (Ghr 3.0 nmol/day=24,24±1,92% vs. ACSF=31,20±3,06%, p< 0.05). These results were associated with a significant reduction in luteinizing hormone and testosterone plasma levels (p<0.05). As Ghr is an orexigenic peptide, body weight and food intake were measured. Results showed that Ghr increases both parameters; however, the effect did not last beyond the first week of treatment. Results presented in this work confirm that central Ghr administration impairs spermatogenesis and suggest that this effect is mediated by inhibition of hypothalamic-pituitary-gonadal axis.
McCormick, Cheryl M; Mathews, Iva Z
Chronic exposure to stress is known to affect learning and memory in adults through the release of glucocorticoid hormones by the hypothalamic-pituitary-adrenal (HPA) axis. In adults, glucocorticoids alter synaptic structure and function in brain regions that express high levels of glucocorticoid receptors and that mediate goal-directed behaviour and learning and memory. In contrast to relatively transient effects of stress on cognitive function in adulthood, exposure to high levels of glucocorticoids in early life can produce enduring changes through substantial remodeling of the developing nervous system. Adolescence is another time of significant brain development and maturation of the HPA axis, thereby providing another opportunity for glucocorticoids to exert programming effects on neurocircuitry involved in learning and memory. These topics are reviewed, as is the emerging research evidence in rodent models highlighting that adolescence may be a period of increased vulnerability compared to adulthood in which exposure to high levels of glucocorticoids results in enduring changes in adult cognitive function. Copyright 2009 Elsevier Inc. All rights reserved.
Čupić, Željko; Marković, Vladimir M.; Maćešić, Stevan; Stanojević, Ana; Damjanović, Svetozar; Vukojević, Vladana; Kolar-Anić, Ljiljana
Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.
Full Text Available Gonadotropin-releasing hormone (GnRH is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons.
Kunugi, Hiroshi; Hori, Hiroaki; Numakawa, Tadahiro; Ota, Miho
Depression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders.
Full Text Available Abstract Background The role of the endothelial cell (EC in blood flow regulation within the central nervous system has been little studied. Here, we explored EC participation in morphological changes of the anterior hypothalamic paraventricular nucleus (PVN microvasculature of female rats at two reproductive stages with different metabolic demand (virginity and lactation. We measured the inner capillary diameter (ICD of 800 capillaries from either the magnocellular or parvocellular regions. The space occupied by neural (somas, dendrites and axons and glial, but excluding vascular elements of the neurovascular compartment was also measured in 100-μm2 sample fields of both PVN subdivisions. Results The PVN of both groups of animals showed ICDs that ranged from 3 to 10 microns. The virgin group presented mostly capillaries with small ICD, whereas the lactating females exhibited a significant increment in the percentage of capillaries with larger ICD. The space occupied by the neural and glial elements of the neurovascular compartment did not show changes with lactation. Conclusions Our findings suggest that during lactation the microvasculature of the PVN of female rats undergoes dynamic, transitory changes in blood flow as represented by an increment in the ICD through a self-cytoplasmic volume modification reflected by EC changes. A model of this process is proposed.
Guimarães, D; Santos, J P; Carvalho, M L; Diniz, M S; House, B; Miller, V M
Lead is a potent toxicant associated with adverse cardiovascular effects and hypertension in children. Yet, few studies have determined if autonomic dysfunction associated with lead exposure involves brain regions which regulate autonomic responses. Central autonomic nuclei such as the nucleus tractus solitarius (NTS) and hypothalamic defence area (HDA) may be particularly sensitive to lead infiltration because they are adjacent to ventricles and areas with semi-permeable blood-brain-barriers. To understand if autonomic nuclei are sensitive to lead accumulation Wistar rats were exposed to lead from the gestational period and lead levels were quantified in brain regions that regulate arterial pressure: the NTS and the HDA. Energy dispersive X-ray fluorescence (EDXRF) was used to quantify total brain lead levels and revealed no differences between exposed and control tissues; measured values were close to the detection limit (2μg/g). Electrothermal atomic absorption spectrometry (ETAAS) was also used, which has a greater sensitivity, to quantify lead. There was ∼2.1μg/g lead in the NTS and ∼3.1μg/g lead in the HDA of exposed rats, and no lead in the control rats. There were greater lead levels in the HDA (∼50%) as compared with the NTS. Pathology studies revealed more prominent lead granules in the HDA as compared with the NTS. Increased microglia and astrocyte activation was also noted in the NTS of lead exposed rats as compared with the HDA. Regional differences in neuro-inflammatory responses likely contribute to heterogeneous lead accumulation, with enhanced clearance of lead in the NTS. Future studies will resolve the mechanisms underpinning tissue-specific lead accumulation. Copyright © 2014 Elsevier Inc. All rights reserved.
Lazutkaite, Greta; Soldà, Alice; Lossow, Kristina; Meyerhof, Wolfgang; Dale, Nicholas
Hypothalamic tanycytes are glial cells that line the wall of the third ventricle and contact the cerebrospinal fluid (CSF). While they are known to detect glucose in the CSF we now show that tanycytes also detect amino acids, important nutrients that signal satiety. Ca 2+ imaging and ATP biosensing were used to detect tanycyte responses to l-amino acids. The downstream pathway of the responses was determined using ATP receptor antagonists and channel blockers. The receptors were characterized using mice lacking the Tas1r1 gene, as well as an mGluR4 receptor antagonist. Amino acids such as Arg, Lys, and Ala evoke Ca 2+ signals in tanycytes and evoke the release of ATP via pannexin 1 and CalHM1, which amplifies the signal via a P2 receptor dependent mechanism. Tanycytes from mice lacking the Tas1r1 gene had diminished responses to lysine and arginine but not alanine. Antagonists of mGluR4 greatly reduced the responses to alanine and lysine. Two receptors previously implicated in taste cells, the Tas1r1/Tas1r3 heterodimer and mGluR4, contribute to the detection of a range of amino acids by tanycytes in CSF. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.
Kurup, Ravi Kumar; Kurup, Parameswara Achutha
The isoprenoid pathway produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in eating disorders. The patterns were compared in those with right hemispheric and left hemispheric dominance. The serum HMG CoA reductase activity, RBC membrane Na+-K+ ATPase activity, serum digoxin, magnesium, tryptophan catabolites (serotonin, quinolinic acid, strychnine, and nicotine), and tyrosine catabolites (morphine, dopamine, and noradrenaline) were measured in anorexia nervosa, bulimia nervosa, right hemispheric dominant, left hemispheric dominant, and bihemispheric dominant individuals. Digoxin synthesis was increased with upregulated tryptophan catabolism and downregulated tyrosine catabolism in those with anorexia nervosa and right hemispheric chemical dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism and upregulated tyrosine catabolism in those with bulimia nervosa and left hemispheric chemical dominance. The membrane Na+-K+ ATPase activity and serum magnesium were decreased in anorexia nervosa and right hemispheric chemical dominance while they were increased in bulimia nervosa and left hemispheric chemical dominance. Hypothalamic digoxin and hemispheric chemical dominance play a central role in the regulation of eating behavior. Anorexia nervosa represents the right hemispheric chemically dominant/hyperdigoxinemic state and bulimia nervosa the left hemispheric chemically dominant/hypodigoxinemic state.
Verjans, H.L.; Eik-Nes, K.B.
Testes of adult, male rats were exposed to a total dose of 1500 R of X-irradiation. Testicular weight decreased from day 8 after X-ray treatment. This decrease was, however, precded by an increment of the testis weight on day 4 following treatment. X-ray treatment of testes was associated with significant increase in serum FSH. Testicular irradiation had, however, no effect on ventral prostate and seminal vesicles weights. Serum testosterone increased only on day 1, 2 and 4 after irradiation, while serum LH levels tended to increase from day 8 post-irradiation. These changes were not significant, however, when compared with non-irradiated controls. At 7, 13 and 20 days following 1500 R of bilateral, testicular X-irradiation, the hypothalamic-pituitary unit was still capable of responding to exogenous gonadotrophin releasing factor. Serum FSH may in male rats be regulated at least partly by circulating steroids of testicular origin and partly by an unknown factor of non-interstitial cell nature. (author)
Nair-Collins, Michael; Northrup, Jesse; Olcese, James
The Uniform Determination of Death Act (UDDA) states that an individual is dead when "all functions of the entire brain" have ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some modest generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these findings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggesting that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord. © The Author(s) 2014.
Revel, Florent G; Masson-Pévet, Mireille; Pévet, Paul
In seasonal species, the photoperiod (i.e. day length) tightly regulates reproduction to ensure that birth occurs at the most favourable time of year. In mammals, a distinct photoneuroendocrine circuit controls this process via the pineal hormone melatonin. This hormone is responsible for the sea......In seasonal species, the photoperiod (i.e. day length) tightly regulates reproduction to ensure that birth occurs at the most favourable time of year. In mammals, a distinct photoneuroendocrine circuit controls this process via the pineal hormone melatonin. This hormone is responsible...... for the seasonal timing of reproduction, but the anatomical substrates and the cellular mechanisms through which melatonin modulates seasonal functions remain imprecise. Recently, several genes have been identified as being regulated by the photoperiod in the brain of seasonal mammals. These genes are thought....../GPR54 system and to the RFamide-related peptides.Interestingly, these systems involve different hypothalamic nuclei, suggesting that several brain loci may be crucial for melatonin to regulate reproduction, and thus represent key starting points to identify the long-sought-after mode and site...
Full Text Available The reversible phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by amino acid limitation. In response to dietary amino acid deficiency, the brain-specific activation of the eIF2α kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2α in the MBH is sufficient to regulate food intake. eIF2α signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2α phosphorylation could play a critical role in the onset of anorexia associated with certain diseases.
Remedios, Ryan; Kennedy, Ann; Zelikowsky, Moriel; Grewe, Benjamin F.; Schnitzer, Mark J.; Anderson, David J.
All animals possess a repertoire of innate (or instinctive) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents. We used microendoscopy to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.
Steculorum, Sophie M.; Collden, Gustav; Coupe, Berengere; Croizier, Sophie; Lockie, Sarah; Andrews, Zane B.; Jarosch, Florian; Klussmann, Sven; Bouret, Sebastien G.
A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation. PMID:25607843
Tyrka, Audrey R.; Wier, Lauren; Price, Lawrence H.; Ross, Nicole; Anderson, George M.; Wilkinson, Charles W.; Carpenter, Linda L.
Background Several decades of research link childhood parental loss with risk for major depression and other forms of psychopathology. A large body of preclinical work on maternal separation and some recent studies of humans with childhood parental loss have demonstrated alterations of hypothalamic-pituitary-adrenal (HPA) axis function which could predispose to the development of psychiatric disorders. Methods Eighty-eight healthy adults with no current Axis I psychiatric disorder participated in this study. Forty-four participants experienced parental loss during childhood, including 19 with a history of parental death and 25 with a history of prolonged parental separation. The loss group was compared to a matched group of individuals who reported no history of childhood parental separation or childhood maltreatment. Participants completed diagnostic interviews and questionnaires and the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Repeated measures general linear models were used to test the effects of parental loss, a measure of parental care, sex, and age on the hormone responses to the Dex/CRH test. Results Parental loss was associated with increased cortisol responses to the test, particularly in males. The effect of loss was moderated by levels of parental care; participants with parental desertion and very low levels of care had attenuated cortisol responses. ACTH responses to the Dex/CRH test did not differ significantly as a function of parental loss. Conclusions These findings are consistent with the hypothesis that early parental loss induces enduring changes in neuroendocrine function. PMID:18339361
Pentz, Ivana; Nakić Radoš, Sandra
The goal of the study was to examine differences between adolescents and young women with functional hypothalamic amenorrhea (FHA) and control groups in personality traits, eating attitudes and behaviours, and perception of parental behaviour. The FHA is stress-induced anovulation, both related to metabolic challenges, such as excessive exercise and malnutrition, and psychogenic challenges, such as perfectionism and poor coping strategies. Three groups of adolescents and young women participated in the study: the FHA group (N = 25), the organic anovulation group (N = 21) and the eumenorrheic group with regular menstrual cycle (N = 20). Questionnaires on multidimensional perfectionism, self-control methods, eating attitudes and behaviours and perception of parental behaviour were administered. A clinical interview (SCID) was conducted with each participant. The FHA group had higher levels of perfectionism traits, i.e. higher levels of concerns over mistakes and personal standards, compared to control groups. The FHA group did not engage in disordered eating behaviours more often in comparison with control groups, but reported more prevalent history of anorexia nervosa. The FHA group did not differ from controls in perception of parental rejection, emotional warmth or overprotection. The findings suggest that FHA can be characterised by the subtle psychological differences in personality traits, so the patients need to be diagnosed carefully.
Full Text Available The temporal organization of sleep is regulated by an interaction between the circadian clock and homeostatic processes. Light indirectly modulates sleep through its ability to phase shift and entrain the circadian clock. Light can also exert a direct, circadian-independent effect on sleep. For example, acute exposure to light promotes sleep in nocturnal animals and wake in diurnal animals. The mechanisms whereby light directly influences sleep and arousal are not well understood. In this review, we discuss the direct effect of light on sleep at the level of the retina and hypothalamus in rodents. We review murine data from recent publications showing the roles of rod-, cone- and melanopsin-based photoreception on the initiation and maintenance of light-induced sleep. We also present hypotheses about hypothalamic mechanisms that have been advanced to explain the acute control of sleep by light. Specifically, we review recent studies assessing the roles of the ventrolateral preoptic area and the suprachiasmatic nucleus. We also discuss how light might differentially promote sleep and arousal in nocturnal and diurnal animals respectively. Lastly, we suggest new avenues for research on this topic which is still in its early stages.
Ana P. Pinto
Full Text Available Abstract AIMS knowing the relationship between endoplasmic reticulum (ER stress and inflammation and based on the fact that downhill running-based overtraining (OT model increases hypothalamus levels of some pro-inflammatory cytokines, we verified the effects of three OT protocols on the levels of BiP, pIRE-1 (Ser734, pPERK (Thr981, pelF2alpha (Ser52, ATF-6 and GRP-94 proteins in the mouse hypothalamus after two weeks of recovery. METHODS the mice were randomized into control (CT, overtrained by downhill running (OTR/down, overtrained by uphill running (OTR/up and overtrained by running without inclination (OTR groups. After 2-week total recovery period (i.e., week 10, hypothalamus was removed and used for immunoblotting. RESULTS the OTR/down group exhibited high levels of BiP and ATF6. The other OT protocols showed higher levels of pPERK (Th981 and pelf-2alpha (Ser52 when compared with the CT group. CONCLUSION the current results suggest that after a 2-week total recovery period, the overtrained groups increased partially their ER stress protein levels, but without hypothalamic inflammation, which characterizes a physiological condition related to an adaptation mechanism.
Gordon, Catherine M; Ackerman, Kathryn E; Berga, Sarah L; Kaplan, Jay R; Mastorakos, George; Misra, Madhusmita; Murad, M Hassan; Santoro, Nanette F; Warren, Michelle P
The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation. Copyright © 2017 Endocrine Society
Miyamoto, T; Miyamoto, M; Yokota, N; Kubo, J; Hirata, K
We present a 31-year-old woman of multiple sclerosis. At age 28, she was admitted with complaints of echolalia and a gradual onset of weakness affecting the right upper and bilateral lower limbs. Brain MRI showed high intensity areas in the bilateral frontal gyri, lobuli paracentralis, and left anterior thalamus. Although she had been in remission for 3 years, she developed dysesthesia of left upper and lower limbs. Cervical T2 weighted MRI showed a new high signal intensity lesion in the spinal cord from the C2 to C3 level. The combination of the cerebral, thalamic and spinal cord lesions with remission and excerbations allowed the diagnosis of clinically MS to be made. She suffered amenorrhea from the onset of her illness. Serum prolactin was within the normal range. The LH and FSH basal secretions were decreased and there were low delayed secretions of LH and FSH after intravenous injection of 100 micrograms LHRH. We consider that her amenorrhea was caused by the hypothalamic lesion, supported by MR findings of dilatation of the third ventricle.
Meczekalski, Blazej; Podfigurna-Stopa, Agnieszka; Warenik-Szymankiewicz, Alina; Genazzani, Andrea Riccardo
Functional hypothalamic amenorrhea (FHA) is defined as a non-organic and reversible disorder in which the impairment of gonadotropin-releasing hormone (GnRH) pulsatile secretion plays a key role. There are main three types of FHA: stress-related amenorrhea, weight loss-related amenorrhea and exercise-related amenorrhea. The spectrum of GnRH-luteinizing hormone (LH) disturbances in FHA is very broad and includes lower mean frequency of LH pulses, complete absence of LH pulsatility, normal-appearing secretion pattern and higher mean frequency of LH pulses. Precise mechanisms underlying the pathophysiology of FHA are very complex and unclear. Numerous neuropeptides, neurotransmitters and neurosteroids play important roles in the physiological regulation of GnRH pulsatile secretion and there is evidence that different neuropeptides may be involved in the pathophysiology of FHA. Particular attention is paid to such substances as allopregnanolone, neuropeptide Y, corticotropin-releasing hormone, leptin, ghrelin and beta-endorphin. Some studies reveal significant changes in these mentioned substances in patients with FHA. There are also speculations about use some of these substances or their antagonists in the treatment of FHA.
Katayama, Koujyu; Yamashita, Yushiro; Yatsuga, Shuichi; Koga, Yasutoshi; Matsuishi, Toyojiro
We report a male patient with hypothalamic hamartoma (HH) who manifested central precocious puberty (CPP) at 4 years of age. Gonadotropin-releasing hormone (GnRH) analogue treatment was started at 6 years of age and his pubertal signs were suppressed. At 9 years of age, the patient was emotionally unstable, aggressive, and antisocial. He had severe attention deficit hyperactivity disorder (ADHD)-like behavior and conduct disorder. No seizure activity was observed. GnRH analogue treatment was discontinued for 8 months from 9 years and 4 months of age due to his mother's illness. During this period sexual urges were observed. Treatment with daily methylphenidate markedly improved his behavioral problems. However, his sexual urges were not suppressed until 3 months after the GnRH analogue treatment was restarted. The present case is unique because the patient's behavioral problems were observed despite the parahypothalamic type of HH and absence of seizures. This case is also rare because behavioral problems were observed without seizures, and no ADHD cases with hamartoma have been reported previously. Recently, clinical studies have described an association between psychiatric morbidity, including ADHD, and hyperandrogenism disorders. Our patient's ADHD-like symptoms might be due to hyperandrogenism. In such cases, GnRH analogue with methylphenidate could be effective for improving ADHD-like symptoms. Copyright © 2015. Published by Elsevier B.V.
Full Text Available Obesity and diabetes are increasing at an alarming rate worldwide, but the strategies for the prevention and treatment of these disorders remain inadequate. Brown adipose tissue (BAT is important for cold protection by producing heat using lipids and glucose as metabolic fuels. This thermogenic action causes increased energy expenditure and significant lipid/glucose disposal. In addition, BAT in white adipose tissue (WAT or beige cells have been found and they also exhibit the thermogenic action similar to BAT. These data provide evidence indicating BAT/beige cells as a potential target for combating obesity and diabetes. Recent discoveries of active BAT and beige cells in adult humans have further highlighted this potential. Growing studies have also shown the importance of central nervous system in the control of BAT thermogenesis and WAT browning using animal models. This review is focused on central neural thermoregulation, particularly addressing our current understanding of the importance of hypothalamic neural signaling in the regulation of BAT/beige thermogenesis and energy homeostasis.
Kondoh, Y; Uemura, T; Murase, M; Yokoi, N; Ishikawa, M; Hirahara, F
To longitudinally evaluate disturbances of the hypothalamic-pituitary-adrenal (HPA) axis in women with secondary progestin-negative hypothalamic amenorrhea. Retrospective cohort study. Yokohama City University, Yokohama, Japan. Twenty-four women with progestin-negative hypothalamic amenorrhea. Administration of human corticotropin-releasing hormone (hCRH) and treatment with a combination of estrogen and progesterone. Plasma cortisol and ACTH concentrations and period required for recovery from amenorrhea. Plasma ACTH concentrations 30 and 60 minutes after injection of hCRH and the percent maximum increment (%Cmax) of ACTH were significantly lower in the amenorrheic patients compared with the control group patients. The basal cortisol was significantly higher, and the %Cmax of cortisol was significantly lower. In the 16 patients who recovered from amenorrhea, there was a significant positive correlation (Y = 1.93X-10.8, r = 0.629) between the basal cortisol concentrations (X) and the period for recovery (Y). The serum E2 gradually increased before recovery, and this E2 increase was preceded by changes in the plasma cortisol concentration and the %Cmax values of cortisol and ACTH. The CRH test might be useful for evaluating the roles of stress and for estimating the period required for recovery in hypothalamic amenorrhea.
Sadagurski, Marianna; Landeryou, Taylor; Cady, Gillian; Kopchick, John J; List, Edward O; Berryman, Darlene E; Bartke, Andrzej; Miller, Richard A
Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived. Median longevity is also increased in mice with deletion of hypothalamic GH-releasing hormone (GHRH), which leads to isolated GH deficiency. The remarkable extension of longevity in hypopituitary Ames dwarf mice can be reversed by a 6-week course of GH injections started at the age of 2 weeks. Here, we demonstrate that mutations that interfere with GH production or response, in the Snell dwarf, Ames dwarf, or GHR(-/-) mice lead to reduced formation of both orexigenic agouti-related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the main hypothalamic projection areas: the arcuate nucleus (ARH), paraventricular nucleus (PVH), and dorsomedial nucleus (DMH). These mutations also reduce hypothalamic inflammation in 18-month-old mice. GH injections, between 2 and 8 weeks of age, reversed both effects in Ames dwarf mice. Disruption of GHR specifically in liver (LiGHRKO), a mutation that reduces circulating IGF-1 but does not lead to lifespan extension, had no effect on hypothalamic projections or inflammation, suggesting an effect of GH, rather than peripheral IGF-1, on hypothalamic development. Hypothalamic leptin signaling, as monitored by induction of pStat3, is not impaired by GHR deficiency. Together, these results suggest that early-life disruption of GH signaling produces long-term hypothalamic changes that may contribute to the longevity of GH-deficient and GH-resistant mice. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Choi, Sun Ju; Kim, Francis; Schwartz, Michael W; Wisse, Brent E
Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1-7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFalpha, as judged by induction of IkappaBalpha (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IkappaBalpha protein, and TNFalpha pretreatment reduced insulin-mediated p-Akt activation by 30% (P fatty acid (100, 250, or 500 microM for neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.
Full Text Available Abstract Background In mammals, the CNS vasculature is established during the postnatal period via active angiogenesis, providing different brain regions with capillary networks of various densities that locally supply adapted metabolic support to neurons. Thereafter this vasculature remains essentially quiescent excepted for specific pathologies. In the adult rat hypothalamus, a particularly dense network of capillary vessels is associated with the supraoptic (SON and paraventricular (PVN nuclei containing the magnocellular neurons secreting vasopressin and oxytocin, two neurohormones involved in the control of the body fluid homoeostasis. In the seventies, it was reported that proliferation of astrocytes and endothelial cells occurs within these hypothalamic nuclei when strong metabolic activation of the vasopressinergic and oxytocinergic neurons was induced by prolonged hyperosmotic stimulation. The aim of the present study was to determine whether such proliferative response to osmotic stimulus is related to local angiogenesis and to elucidate the cellular and molecular mechanisms involved. Results Our results provide evidence that cell proliferation occurring within the SON of osmotically stimulated adult rats corresponds to local angiogenesis. We show that 1 a large majority of the SON proliferative cells is associated with capillary vessels, 2 this proliferative response correlates with a progressive increase in density of the capillary network within the nucleus, and 3 SON capillary vessels exhibit an increased expression of nestin and vimentin, two markers of newly formed vessels. Contrasting with most adult CNS neurons, hypothalamic magnocellular neurons were found to express vascular endothelial growth factor (VEGF, a potent angiogenic factor whose production was increased by osmotic stimulus. When VEGF was inhibited by dexamethasone treatment or by the local application of a blocking antibody, the angiogenic response was strongly
Díaz-Casares, A; López-González, M V; Peinado-Aragonés, C A; González-Barón, S; Dawid-Milner, M S
To characterize the possible role of glutamate in the interaction between Hypothalamic Defense Area (HDA) and Parabrachial complex (PBc) nuclei, cardiorespiratory changes were analyzed in response to electrical stimulation of the HDA (1 ms pulses, 30-50 μA given at 100 Hz for 5s) before and after the microinjection of the nonspecific glutamate receptor antagonist kynurenic acid (50 nl, 5 nmol), NMDA receptor antagonist MK-801 (50 nl, 50 nmol), non-NMDA receptor antagonist CNQX (50 nl, 50 nmol) or metabotropic glutamate receptor antagonist MCPG (50 nl, 5 nmol) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (pHDA stimulation. Similarly, the magnitude of the tachycardia and the pressor response was decreased after the microinjection of MK-801 (pHDA stimulation but the respiratory response persisted unchanged after MK-801 or CNQX microinjection into the lPB. Kynurenic acid within the medial parabrachial region (mPB) abolished the tachycardia (pHDA stimulation. MK-801 and CNQX microinjection in this region decreased the magnitude of the tachycardia (pHDA stimulation was not changed after the microinjection of kynurenic acid, MK-801 or CNQX within the mPB. No changes were observed in the cardiorespiratory response evoked to HDA stimulation after MCPG microinjection within lPB and mPB. These results indicate that glutamate PBc receptors are involved in the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed. Copyright © 2012 Elsevier B.V. All rights reserved.
Torelli, G F; Meguid, M M; Miyata, G; Fetissov, S O; Carter, J L; Kim, H J; Muscaritoli, M; Rossi Fanelli, F
During sepsis, catabolism of proteins and associated changes in plasma amino acids occur. Tryptophan and tyrosine, and their derivatives serotonin (5-HT) and dopamine (DA), influence hypothalamic feeding-related areas and are associated with the onset of anorexia. We hypothesized that anorexia of sepsis is associated with changes in serotonin and dopamine in the ventromedial nucleus (VMN) of the hypothalamus. The aim of this study was to test our hypothesis by measuring intra-VMN changes of these two neurotransmitters at the onset of anorexia during sepsis. Fischer 344 male rats had an intracerebral guide cannula stereotaxically implanted into the VMN. Ten days later, in awake, overnight-food-deprived rats, a microdialysis probe was inserted through the in situ VMN cannula. Two hours thereafter, serial baseline serotonin and dopamine concentrations were measured. Then cecal ligation and puncture to induce sepsis or a control laparotomy was performed under isoflurane anesthesia. VMN microdialysis samples were serially collected every 30 min for 8 h after the surgical procedure to determine 5-HT and DA changes in response to sepsis. During the hypermetabolic response to sepsis, a strong association occurred between anorexia and a significant reduction of VMN dopamine concentration (P anorexia of sepsis. Six hours after operation, a single meal was offered for 20 min to assess the response of neurotransmitters to food ingestion. Food intake was minimal in anorectic septic rats (mean size of the after food-deprived meal in the Septic group was 0.03+/-0.01 g, that of the Control group was 1.27+/-0.14 g; P = 0.0001), while Control rats demonstrated anticipated changes in neurotransmitters in response to eating. We conclude that the onset of anorexia in septic rats is associated with a reduction in VMN dopamine.
Le Foll, Christelle; Irani, Boman G; Magnan, Christophe; Dunn-Meynell, Ambrose A; Levin, Barry E
We assessed the mechanisms by which specialized hypothalamic ventromedial nucleus (VMN) neurons utilize both glucose and long-chain fatty acids as signaling molecules to alter their activity as a potential means of regulating energy homeostasis. Fura-2 calcium (Ca(2+)) and membrane potential dye imaging, together with pharmacological agents, were used to assess the mechanisms by which oleic acid (OA) alters the activity of dissociated VMN neurons from 3- to 4-wk-old rats. OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations. In those neurons excited by both 2.5 mM glucose and OA, OA had a concentration-dependent effective excitatory concentration (EC(50)) of 13.1 nM. Neurons inhibited by both 2.5 mM glucose and OA had an effective inhibitory concentration (IC(50)) of 93 nM. At 0.5 mM glucose, OA had markedly different effects on these same neurons. Inhibition of carnitine palmitoyltransferase, reactive oxygen species formation, long-chain acetyl-CoA synthetase and ATP-sensitive K(+) channel activity or activation of uncoupling protein 2 (UCP2) accounted for only approximately 20% of OA's excitatory effects and approximately 40% of its inhibitory effects. Inhibition of CD36, a fatty acid transporter that can alter cell function independently of intracellular fatty acid metabolism, reduced the effects of OA by up to 45%. Thus OA affects VMN neuronal activity through multiple pathways. In glucosensing neurons, its effects are glucose dependent. This glucose-OA interaction provides a potential mechanism whereby such "metabolic sensing" neurons can respond to differences in the metabolic states associated with fasting and feeding.
Jason T Popesku
Full Text Available Dopamine (DA is a major neurotransmitter playing an important role in the regulation of vertebrate reproduction. We developed a novel method for the comparison of transcriptomic and proteomic data obtained from in vivo experiments designed to study the neuroendocrine actions of DA.Female goldfish were injected (i.p. with DA agonists (D1-specific; SKF 38393, or D2-specific; LY 171555 and sacrificed after 5 h. Serum LH levels were reduced by 57% and 75% by SKF 38393 and LY 171555, respectively, indicating that the treatments produced physiologically relevant responses in vivo. Bioinformatic strategies and a ray-finned fish database were established for microarray and iTRAQ proteomic analysis of the hypothalamus, revealing a total of 3088 mRNAs and 42 proteins as being differentially regulated by the treatments. Twenty one proteins and mRNAs corresponding to these proteins appeared on both lists. Many of the mRNAs and proteins affected by the treatments were grouped into the Gene Ontology categorizations of protein complex, signal transduction, response to stimulus, and regulation of cellular processes. There was a 57% and 14% directional agreement between the differentially-regulated mRNAs and proteins for SKF 38393 and LY 171555, respectively.The results demonstrate the applicability of advanced high-throughput genomic and proteomic analyses in an amendable well-studied teleost model species whose genome has yet to be sequenced. We demonstrate that DA rapidly regulates multiple hypothalamic pathways and processes that are also known to be involved in pathologies of the central nervous system.
Erkal, Haldun Suekrue; Serin, Meltem; Cakmak, Ahmet
Background and purpose: Optic pathway and chiasmatic-hypothalamic gliomas are rare childhood tumors. This study presents the experience in management of these tumors with radiation therapy. Materials and methods: Thirty-three children with the diagnosis of optic pathway and chiasmatic-hypothalamic gliomas were treated with radiation therapy from 1973 through 1994 in the Department of Radiation Oncology at Ankara University Faculty of Medicine. Twenty-four children had optic pathway gliomas and nine had chiasmatic-hypothalamic gliomas. Evidence of neurofibromatosis was present in six children. Subtotal resection was performed in 22 children and a biopsy in seven. The most common prescription for total tumor dose was 50 Gy, delivered in 2 Gy daily fractions. Follow-up ranged from 0.5 to 16.1 years (mean, 13.6 years). Results: Overall, progression-free and cause-specific survival probabilities for the entire group were 93%, 82% and 93%, respectively, at 5 years and 79%, 77% and 88%, respectively, at 10 years. Differences in overall, progression-free and cause-specific survival probabilities between optic pathway and chiasmatic-hypothalamic gliomas were not statistically significant. Absence of evidence of neurofibromatosis correlated with significantly better progression-free and cause-specific survival probabilities. Conclusion: Radiation therapy is effective in stabilization or improvement of vision and prevention of tumor progression in both optic pathway and chiasmatic-hypothalamic gliomas
Full Text Available Huntington's disease (HD is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP, heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4, glycogen synthase1 (Gys1 and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1. In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.
Begum, Ghazala; Stevens, Adam; Smith, Emma Bolton; Connor, Kristin; Challis, John R G; Bloomfield, Frank; White, Anne
Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.
Silva, Vagner R R; Katashima, Carlos K; Lenhare, Luciene; Silva, Carla G B; Morari, Joseane; Camargo, Rafael L; Velloso, Licio A; Saad, Mario A; da Silva, Adelino S R; Pauli, Jose Rodrigo; Ropelle, Eduardo Rochete
Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-β (TGF-β1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-β1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-β1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-β1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-β1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.
Sarah M Burke
Full Text Available The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone we measured the hypothalamic responsiveness to this chemo-signal in 39 prepubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 prepubertal children and 38 adolescents diagnosed with Gender Dysphoria (GD; DSM-5 exhibited sex-atypical (in accordance with their experienced gender, rather than sex-typical (in accordance with their natal sex hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in prepubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, prepubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and prepubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain.
Horjales-Araujo, E; Hellysaz, A; Broberger, C
The lateral hypothalamic area (LHA) constitutes a large component of the hypothalamus, and has been implicated in several aspects of motivated behavior. The LHA is of particular relevance to behavioral state control and the maintenance of arousal. Due to the cellular heterogeneity of this region, however, only some subpopulations of LHA cells have been properly anatomically characterized. Here, we have focused on cells expressing thyrotropin-releasing hormone (TRH), a peptide found in the LHA that has been implicated as a promoter of arousal. Immunofluorescence and in situ hybridization were used to map the LHA TRH population in the rat, and cells were observed to form a large ventral cluster that extended throughout almost the entire rostro-caudal axis of the hypothalamus. Almost no examples of coexistence were seen when sections were double-stained for TRH and markers of other LHA populations, including the peptides hypocretin/orexin, melanin-concentrating hormone and neurotensin. In the juxtaparaventricular area, however, a discrete group of TRH-immunoreactive cells were also stained with antisera against enkephalin and urocortin 3. Innervation from the metabolically sensitive hypothalamic arcuate nucleus was investigated by double-staining for peptide markers of the two centrally projecting groups of arcuate neurons, agouti gene-related peptide and α-melanocyte-stimulating hormone, respectively; both populations of terminals were observed forming close appositions on TRH cells in the LHA. The present study indicates that TRH-expressing cells form a unique population in the LHA that may serve as a link between metabolic signals and the generation of arousal. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
O'Donnell, Emma; Goodman, Jack M; Harvey, Paula J
Evidence indicates that hypoestrogenemia is linked with accelerated progression of atherosclerosis. Premenopausal women presenting with ovulatory disruption due to functional hypothalamic amenorrhea (FHA) are characterized by hypoestrogenemia. One common and reversible form of FHA in association with energy deficiency is exercise-associated amenorrhea (EAA). Articles were found via PubMed search for both original and review articles based on peer review publications between 1974 and 2011 reporting on cardiovascular changes in women with FHA, with emphasis placed on women with EAA. Despite participation in regular exercise training, hypoestrogenic women with EAA demonstrate paradoxical changes in cardiovascular function, including endothelial dysfunction, a known permissive factor for the progression and development of atherosclerosis. Such alterations suggest that the beneficial effects of regular exercise training on vascular function are obviated in the face of hypoestrogenemia. The long-term cardiovascular consequences of altered vascular function in response to ovulatory disruption in women with EAA remain to be determined. Retrospective data, however, suggest premature development and progression of coronary artery disease in older premenopausal women reporting a history of hypothalamic ovulatory disruption. Importantly, in women with EAA, estrogen therapy, folic acid supplementation without change in menstrual status, and resumption of menses restores endothelial function. In this review, we focus on the influence of hypoestrogenemia in association with energy deficiency in mediating changes in cardiovascular function in women with EAA, including endothelial function, regional blood flow, lipid profile, and autonomic control of blood pressure, heart rate, and baroreflex sensitivity. The influence of exercise training is also considered. With the premenopausal years typically considered to be cardioprotective in association with normal ovarian function
Russo, Cristina; Russo, Antonella; Pellitteri, Rosalia; Stanzani, Stefania
Feeding is a process controlled by a complex of associations between external and internal stimuli. The processes that involve learning and memory seem to exert a strong control over appetite and food intake, which is modulated by a gastrointestinal hormone, Ghrelin (Ghre). Recent studies claim that Ghre is involved in cognitive and neurobiological mechanisms that underlie the conditioning of eating behaviors. The expression of Ghre increases in anticipation of food intake based on learned behaviors. The hippocampal Ghre-containing neurons neurologically influence the orexigenic hypothalamus and consequently the learned feeding behavior. The CA1 field of Ammon's horn of the hippocampus (H-CA1) constitutes the most important neural substrate to control both appetitive and ingestive behavior. It also innervates amygdala regions that in turn innervate the hypothalamus. A recent study also implies that Ghre effects on cue-potentiated feeding behavior occur, at the least, via indirect action on the amygdala. In the present study, we investigate the neural substrates through which endogenous Ghre communicates conditioned appetite and feeding behavior within the CNS. We show the existence of a neural Ghre dependent pathway whereby peripherally-derived Ghre activates H-CA1 neurons, which in turn activate Ghre-expressing hypothalamic and amygdaloid neurons to stimulate appetite and feeding behavior. To highlight this pathway, we use two fluorescent retrograde tracers (Fluoro Gold and Dil) and immunohistochemical detection of Ghre expression in the hippocampus. Triple fluorescent-labeling has determined the presence of H-CA1 Ghre-containing collateralized neurons that project to the hypothalamus and amygdala monosynaptically. We hypothesize that H-Ghre-containing neurons in H-CA1 modulate food-intake behavior through direct pathways to the arcuate hypothalamic nucleus and medial amygdaloid nucleus. Copyright © 2017 Elsevier B.V. All rights reserved.
Dhanwal, Dinesh Kumar; Vyas, Anirudh; Sharma, Ashok; Saxena, Alpana
Tubercular meningitis (TBM) is the most dreaded form of extra pulmonary tuberculosis associated with high morbidity and mortality. Various hypothalamic pituitary hormonal abnormalities have been reported to occur years after recovery from disease but there are no systematic studies in the literature to evaluate the pituitary hypothalamic dysfunction in patients with TBM at the time of presentation. Therefore, the present study was designed to evaluate hypothalamic pituitary abnormalities in newly diagnosed patients with TBM. Patient case series. This prospective study included 75 untreated adult patients with TBM diagnosed as "definite", "highly probable" and "probable" TBM by Ahuja's criteria and in clinical stage 1, 2 or 3 at the time of presentation to hospital. Basal hormonal profile was measured by electrochemilumniscence technique for serum cortisol, luetinizing hormone (LH), follicular stimulating hormone (FSH), prolactin (PRL), thyrotropin (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4). All patients were subjected to MRI to image brain and hypothalamic pituitary axis and CT for adrenal glands. Thirty-two (42.7%) cases showed relative or absolute cortisol insufficiency. Twenty-three (30.7%) cases showed central hypothyroidism and 37 (49.3%) cases had hyperprolactinemia. No patient had evidence of diabetes insipidus. Multiple hormone deficiency was seen in 22 (29.3%) cases. MRI of hypothalamic pituitary axis using dynamic scanning and thin cuts revealed abnormalities in 10 (13.3%) of the cases. CT adrenal gland was normal in all the patients. Tubercular meningitis is associated with both hormonal and structural abnormalities in the hypothalamic pituitary axis at the time of diagnosis.
Sadagurski, Marianna; Cady, Gillian; Miller, Richard A
Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Early-life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM-HET3 mice in a sex-specific way: acarbose (ACA), 17-α-estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti-aging drugs on neuro-inflammation in hypothalamus and hippocampus. We found that age-associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA-treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba-1-positive microglia and GFAP-positive astrocytes, as well as age-associated overproduction of TNF-α. This effect was not observed in drug-treated female mice or in the hippocampus of the drug-treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF-α in both sexes at 12 months of age. Together, these results suggest that the extent of drug-induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long-lived nutrient restricted or mutant mice. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Full Text Available A large body of data has established the hypothalamic kisspeptin (KP and its receptor, KISS1R, as major players in the activation of the neuroendocrine reproductive axis at the time of puberty and maintenance of reproductive capacity in the adult. Due to its strategic location, this ligand-receptor pair acts as an integrator of cues from gonadal steroids as well as of circadian and seasonal variation-related information on the reproductive axis. Besides these cues, the activity of the hypothalamic KP signaling is very sensitive to the current metabolic status of the body. In conditions of energy imbalance, either positive or negative, a number of alterations in the hypothalamic KP signaling pathway have been documented in different mammalian models including nonhuman primates and human. Deficiency of metabolic fuels during fasting causes a marked reduction of Kiss1 gene transcript levels in the hypothalamus and, hence, decreases the output of KP-containing neurons. Food intake or exogenous supply of metabolic cues, such as leptin, reverses metabolic insufficiency-related changes in the hypothalamic KP signaling. Likewise, alterations in Kiss1 expression have also been reported in other situations of energy imbalance like diabetes and obesity. Information related to the body’s current metabolic status reaches to KP neurons both directly as well as indirectly via a complex network of other neurons. In this review article, we have provided an updated summary of the available literature on the regulation of the hypothalamic KP-Kiss1r signaling by metabolic cues. In particular, the potential mechanisms of metabolic impact on the hypothalamic KP-Kiss1r signaling, in light of available evidence, are discussed.
Heeley, Nicholas; Kirwan, Peter; Darwish, Tamana; Arnaud, Marion; Evans, Mark L; Merkle, Florian T; Reimann, Frank; Gribble, Fiona M; Blouet, Clemence
Dietary proteins are sensed by hypothalamic neurons and strongly influence multiple aspects of metabolic health, including appetite, weight gain, and adiposity. However, little is known about the mechanisms by which hypothalamic neural circuits controlling behavior and metabolism sense protein availability. The aim of this study is to characterize how neurons from the mediobasal hypothalamus respond to a signal of protein availability: the amino acid l-leucine. We used primary cultures of post-weaning murine mediobasal hypothalamic neurons, hypothalamic neurons derived from human induced pluripotent stem cells, and calcium imaging to characterize rapid neuronal responses to physiological changes in extracellular l-Leucine concentration. A neurochemically diverse subset of both mouse and human hypothalamic neurons responded rapidly to l-leucine. Consistent with l-leucine's anorexigenic role, we found that 25% of mouse MBH POMC neurons were activated by l-leucine. 10% of MBH NPY neurons were inhibited by l-leucine, and leucine rapidly reduced AGRP secretion, providing a mechanism for the rapid leucine-induced inhibition of foraging behavior in rodents. Surprisingly, none of the candidate mechanisms previously implicated in hypothalamic leucine sensing (K ATP channels, mTORC1 signaling, amino-acid decarboxylation) were involved in the acute activity changes produced by l-leucine. Instead, our data indicate that leucine-induced neuronal activation involves a plasma membrane Ca 2+ channel, whereas leucine-induced neuronal inhibition is mediated by inhibition of a store-operated Ca 2+ current. A subset of neurons in the mediobasal hypothalamus rapidly respond to physiological changes in extracellular leucine concentration. Leucine can produce both increases and decreases in neuronal Ca 2+ concentrations in a neurochemically-diverse group of neurons, including some POMC and NPY/AGRP neurons. Our data reveal that leucine can signal through novel mechanisms to rapidly
Wiegant, V.M.; Verhoef, C.J.; Burbach, J.P.H.; de Wied, D.
The concentrations of ..cap alpha..-, ..beta..- and ..gamma..-endorphin were determined by radioimmunoassay in HPLC fractionated extracts of post mortem hypothalamic tissue obtained from schizophrenic patients and controls. The hypothalamic concentration of ..cap alpha..- and ..gamma..-endorphin was significantly higher in patients than in controls. No difference was found in the concentration of ..beta..-endorphin, the putative precursor of ..cap alpha..- and ..gamma..-endorphins. These results suggest a deviant metabolism of ..beta..-endorphin in the brain of schizophrenic patients. Whether this phenomenon is related to the psychopathology, or is a consequence of ante mortem farmacotherapy, remains to be established.
Vito Salvador Hernandez
Full Text Available The arginine-vasopressin (AVP-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs are known for their role in hydro-electrolytic balance control via their projections to neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula, and other brain regions, in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA. The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS, consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN and supraoptic (SON nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptors mRNA were not detected, using the same method. Water-deprivation for 24 hrs, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze test, and this effect was mimicked by bilateral microinfusion of VP into the CeA. Anxious behavior induced by either water deprivation or VP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of central amygdala inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.
Crosby, Karen M; Baimoukhametova, Dinara V; Bains, Jaideep S; Pittman, Quentin J
Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK. Copyright © 2015 the authors 0270-6474/15/3513160-11$15.00/0.
The hypothalamic-pituitary-adrenal (HPA) axis is an extremely sensitive physiological system whose activation, with the consequent release of ACTH and glucocorticoids, is triggered by a wide range of psychological experiences and physiological perturbations (stressors). The HPA axis is also activated by a high number of pharmacological agents that markedly differ in structure and function, although the precise mechanisms remain in most cases unknown. Activation of the HPA axis is the consequence of the convergence of stimulatory inputs from different brain regions into the paraventricular nucleus of the hypothalamus (PVN), where the most important ACTH secretagogues (corticotrophin releasing factor, CRF, and arginin-vasopressin, AVP) are formed. Plasma levels of ACTH and corticosterone (the latter under more restricted conditions), are considered as good markers of stress for three main reasons: (a) their plasma levels are proportional to the intensity of emotional and systemic stressors, (b) daily repeated exposure to a stressor usually resulted in reduced ACTH response to the same stressor, that is termed adaptation or habituation; and (c) chronic exposure to stressful situations results in tonic changes in the HPA axis that can be used as indices of the accumulative impact of these situations. These changes can be evaluated under resting conditions (i.e. adrenal weight, CRF and AVP gene expression in the PVN) or after some challenges (administration of CRF, ACTH or dexamethasone) that are classical endocrinological tests. There is also evidence that the activation of the HPA axis may also reflect subtle changes in the characteristics of the stressful situations (unpredictability, lack of control, omission of expected rewards, presence of conspecifics), although this is a topic that requires further studies.
Wang, Shanshan; Sun, Hong; Liu, Sainan; Wang, Ting; Guan, Jinqun; Jia, Jianjun
One of the most common psychological consequences of stroke is post-stroke depression (PSD). While more than 30 percent of stroke patients eventually develop PSD, the neurobiological mechanisms underlying such a phenomenon have not been well investigated. Given the critical involvement of hypothalamic-pituitary-adrenal axis and endocannabinoid system in response to stressful stimuli, we evaluated the hypothesis that cannabinoid receptors in the hypothalamus are critical for modulation of post-stroke depression-like behaviors in rats. To this end, rats were treated with middle cerebral artery occlusion (MCAO) followed by chronic unpredictable mild stress (CUMS) treatment procedure. We then assessed the expression of CB1 and CB2 receptors in the hypothalamus, and evaluated the effects of pharmacological stimulations of CB1 or CB2 receptors on the expression and development of depression-like behaviors in PSD rats. We found that PSD rats exhibited decreased the expression of CB1 receptor, but not CB2 receptor, in the ventral medial hypothalamus (VMH). Such an effect was not observed in the dorsally adjacent brain regions. Furthermore, intra-VMH injections of CB2 receptor agonist, but not CB1 receptor agonist, attenuated the expression of depression-like behaviors in PSD rats. Finally, repeated intraperitoneal injections of CB1 or CB2 receptor agonists during CUMS treatment inhibited the development of depression-like behaviors in PSD rats. Taken together, these results suggest that decreased CB1 receptor expression is likely associated with the development of post-stroke depression, and CB2 receptor may be a potential therapeutic target for the treatment post-stroke depressive disorders. Copyright © 2016 Elsevier Inc. All rights reserved.
Altayar, Osama; Al Nofal, Alaa; Carranza Leon, B Gisella; Prokop, Larry J; Wang, Zhen; Murad, M Hassan
We conducted a systematic review and meta-analysis of studies that evaluated the effect of hormonal therapy [estrogen therapy including oral contraceptive pills (OCP)] and bisphosphonates in preventing bone loss in patients with functional hypothalamic amenorrhea (FHA). We searched several electronic databases for controlled and noncontrolled studies that enrolled females of any age presenting with FHA (including athletic, weight loss, and stress-associated amenorrhea/oligomenorrhea) through 9 January 2017. The outcomes of interest were fractures and bone mineral density (BMD). Random effects meta-analysis was used to pool outcomes across studies expressed as weighted mean difference and 95% confidence interval (CI). Nine studies reporting on 280 patients that received different hormonal therapies were included. We did not identify studies that evaluated bisphosphonates. Meta-analysis demonstrated a statistically significant increase in BMD of the lumbar spine in patients receiving hormonal therapy after a median follow-up of 12 months (weighted mean difference, 0.032 g/cm 2 ; 95% CI, 0.017 to 0.047; percentage change in BMD, 3.30%; 95% CI, 1.74 to 4.86). There was no substantial effect of receiving hormonal therapy on BMD of the femoral neck, trochanteric region, Ward triangle, or total body BMD. The quality of evidence was low because of the high risk of bias, imprecision (small sample size), and indirectness (as BMD is a surrogate outcome). None of the studies reported the incidence of fractures. The current evidence does not support using hormonal therapy for the sole purpose of improving bone health in patients with FHA. There are no data about bisphosphonates in this population.
B Silvano Zanutto
Full Text Available Rats, people, and many other omnivores eat in meals rather than continuously. We show by experimental test that eating in meals is regulated by a simple bang-bang control system, an idea foreshadowed by Le Magnen and many others, shown by us to account for a wide range of behavioral data, but never explicitly tested or tied to neurophysiological facts. The hypothesis is simply that the tendency to eat rises with time at a rate determined by satiety signals. When these signals fall below a set point, eating begins, in on-off fashion. The delayed sequelae of eating increment the satiety signals, which eventually turn eating off. Thus, under free conditions, the organism eats in bouts separated by noneating activities. We report an experiment with rats to test novel predictions about meal patterns that are not explained by existing homeostatic approaches. Access to food was systematically but unpredictably interrupted just as the animal tried to start a new meal. A simple bang-bang model fits the resulting meal-pattern data well, and its elements can be identified with neurophysiological processes. Hypothalamic inputs can provide the set point for longer-term regulation carried out by a comparator in the hindbrain. Delayed gustatory and gastrointestinal aftereffects of eating act via the nucleus of the solitary tract and other hindbrain regions as neural feedback governing short-term regulation. In this way, the model forges real links between a functioning feedback mechanism, neuro-hormonal data, and both short-term (meals and long-term (eating-rate regulation behavioral data.
Larsen, P J; Seier, V; Fink-Jensen, A
Cocaine- and amphetamine-regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalami......, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART-positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one-third of somatostatin cells were also CART......-immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin-releasing hormone, whereas very few of the corticotrophin-releasing hormone containing cells were CART-immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro...
Larsen, P J; Seier, V; Fink-Jensen, A; Holst, J J; Warberg, J; Vrang, N
Cocaine- and amphetamine-regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalamic neuroendocrine neurones. Adult male rats received a systemic injection of the neuronal tracer Fluorogold (FG) 2 days before fixation, and subsequent double- and triple-labelling immunoflourescence analysis demonstrated that neuroendocrine CART-containing neurones were present in the anteroventral periventricular, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART-positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one-third of somatostatin cells were also CART-immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin-releasing hormone, whereas very few of the corticotrophin-releasing hormone containing cells were CART-immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro-opiomelanocortin in the ventrolateral part, but completely absent from neuroendocrine neurones of the dorsomedial part. To assess the possible role of CART as a hypothalamic-releasing factor, immunoreactive CART was measured in blood samples from the long portal vessels connecting the median eminence with the anterior pituitary gland. Adult male rats were anaesthetized and the infundibular stalk exposed via a transpharyngeal approach. The long portal vessels were transected and blood collected in 30-min periods (one prestimulatory and three poststimulatory periods). Compared to systemic venous plasma samples, baseline concentrations of immunoreactive CART were elevated in portal plasma. Exposure to sodium nitroprusside hypotension triggered a two-fold elevation of portal CART42
Full Text Available Background: Both fractionated external beam radiotherapy and single fraction radiosurgery for pituitary adenomas are associated with the risk of hypothalamic-pituitary (HP axis dysfunction.Objective: To analyze the effect of treatment modality (Linac, TomoTherapy, or Gamma Knife on hypothalamic dose and correlate these with HP-Axis deficits after radiotherapy.Methods:Radiation plans of patients treated postoperatively for pituitary adenomas using Linac-based 3D Conformal Radiotherapy (CRT (n=11, TomoTherapy-based Intensity Modulated Radiation Therapy (IMRT (n=10, or Gamma Knife Stereotactic Radiosurgery (SRS(n=12 were retrospectively reviewed. Dose to the hypothalamus was analyzed and postradiotherapy hormone function including growth hormone (GH, thyroid (TSH, adrenal (ACTH, prolactin (PRL, and gonadotropins (FSH/LH were assessed. Results:Post-radiation, 13 of 27 (48% patients eligible for analysis developed at least one new hormone deficit, of which 8 of 11 (72% occurred in the Linac group, 4 of 8 (50% occurred in the TomoTherapy group, and 1 of 8 (12.5% occurred in the Gamma Knife group. Compared with fractionated techniques, Gamma Knife showed improved hypothalamic sparing for DMax Hypo, and V12Gy. For fractionated modalities, TomoTherapy showed improved dosimetric characteristics over Linac-based treatment with hypothalamic DMean (44.8 Gy vs. 26.8 Gy p=0.02, DMax (49.8 Gy vs. 39.1 Gy p=0.04, and V12Gy (100% vs. 76% p=0.004.Conclusion:Maximal dosimetric avoidance of the hypothalamus was achieved using Gamma Knife-based radiosurgery followed by TomoTherapy-based IMRT, and Linac-based 3D conformal radiation therapy, respectively.
Díaz-Casares, Amelia; López-González, Manuel Víctor; Peinado-Aragonés, Carlos Antonio; Lara, José Pablo; González-Barón, Salvador; Dawid-Milner, Marc Stefan
To analyze the role of parabrachial complex (PBc) in the modulation of cardiorespiratory response evoked from the hypothalamic defense area (HDA), cardiorespiratory changes were analyzed in spontaneously breathing anesthetised rats in response to electrical stimulation of the HDA (1 ms pulses, 30-50 microA, 100 Hz for 5 s) before and after the microinjection of muscimol (50 nl, 0.25 nmol, 5 s) within the PBc. HDA stimulation evoked an inspiratory facilitatory response, consisting of an increase in respiratory rate (pHDA stimulation (pHDA stimulation. The respiratory response persisted unchanged. Finally, extracellular recording of putative neurons from these regions were obtained during HDA stimulation to confirm functional interaction between HDA and parabrachial regions. 105 pontine cells were recorded during HDA stimulation, 57 from the lPB and 48 from the mPB-KF. In mPB-KF 34/48 (71%) and in lPB 38/57 (67%) cells were influenced from HDA. The results indicate that neurons from different regions of the PBc have an important function in mediating the cardiorespiratory response evoked from the HDA. The possible mechanisms involved in these interactions are discussed.
Full Text Available Secreted protein Sonic hedgehog (Shh ventralizes the neural tube by modulating the crucial balance between activating and repressing functions (GliA, GliR of transcription factors Gli2 and Gli3. This balance—the Shh-Gli code—is species- and context-dependent and has been elucidated for the mouse spinal cord. The hypothalamus, a forebrain region regulating vital functions like homeostasis and hormone secretion, shows dynamic and intricate Shh expression as well as complex regional differentiation. Here we asked if particular combinations of Gli2 and Gli3 and of GliA and GliR functions contribute to the variety of hypothalamic regions, i.e. we wanted to clarify the hypothalamic version of the Shh-Gli code. Based on mouse mutant analysis, we show that: 1 hypothalamic regional heterogeneity is based in part on differentially stringent requirements for Gli2 or Gli3; 2 another source of diversity are differential requirements for Shh of neural vs non-neural origin; 3 Gli2 is indispensable for the specification of a medial progenitor domain generating several essential hypothalamic nuclei plus the pituitary and median eminence; 4 the suppression of Gli3R by neural and non-neural Shh is essential for hypothalamic specification. Finally, we have mapped our results on a recent model which considers the hypothalamus as a transverse region with alar and basal portions. Our data confirm the model and are explained by it.
Hashiguchi, Hiroshi; Sheng, Zhenyu; Routh, Vanessa; Gerzanich, Volodymyr; Simard, J Marc; Bryan, Joseph
Assess direct versus indirect action(s) of ghrelin on hypothalamic NPY neurons. Electrophysiology was used to measure ion channel activity in NPY-GFP neurons in slice preparations. Ca2+ imaging was used to monitor ghrelin activation of isolated NPY GFP-labeled neurons. Immunohistochemistry was used to localize Trpm4, SUR1 and Kir6.2 in the hypothalamus. Acylated ghrelin depolarized the membrane potential (MP) of NPY-GFP neurons in brain slices. Depolarization resulted from a decreased input resistance (IR) in ~70% of neurons (15/22) or an increased IR in the remainder (7/22), consistent with the opening or closing of ion channels, respectively. Although tetrodotoxin (TTX) blockade of presynaptic action potentials reduced ghrelin-induced changes in MP and IR, ghrelin still significantly depolarized the MP and decreased IR in TTX-treated neurons, suggesting that ghrelin directly opens cation channel(s) in NPY neurons. In isolated NPY-GFP neurons, ghrelin produced a sustained rise of [Ca2+]c, with an EC50 ~110 pM. Pharmacologic studies confirmed that the direct action of ghrelin was through occupation of the growth hormone secretagogue receptor, GHS-R, and demonstrated the importance of the adenylate cyclase/cAMP/protein kinase A (PKA) and phospholipase C/inositol triphosphate (PLC/IP3) pathways as activators of 5' AMP-activated protein kinase (AMPK). Activation of isolated neurons was not affected by CNQX or TTX, but reducing [Na+]o suppressed activation, suggesting a role for Na+-permeable cation channels. SUR1 and two channel partners, Kir6.2 and Trpm4, were identified immunologically in NPY-GFP neurons in situ. The actions of SUR1 and Trpm4 modulators were informative: like ghrelin, diazoxide, a SUR1 agonist, elevated [Ca2+]c and glibenclamide, a SUR1 antagonist, partially suppressed ghrelin action, while 9-phenanthrol and flufenamic acid, selective Trpm4 antagonists, blocked ghrelin actions on isolated neurons. Ghrelin activation was unaffected by nifedipine and
Sousa-Ferreira, Lígia; Aveleira, Célia; Botelho, Mariana; Álvaro, Ana Rita; Pereira de Almeida, Luís; Cavadas, Cláudia
A significant number of children undergo maternal exposure to antidepressants and they often present low birth weight. Therefore, it is important to understand how selective serotonin reuptake inhibitors (SSRIs) affect the development of the hypothalamus, the key center for metabolism regulation. In this study we investigated the proliferative actions of fluoxetine in fetal hypothalamic neuroprogenitor cells and demonstrate that fluoxetine induces the proliferation of these cells, as shown by increased neurospheres size and number of proliferative cells (Ki-67+ cells). Moreover, fluoxetine inhibits the differentiation of hypothalamic neuroprogenitor cells, as demonstrated by decreased number of mature neurons (Neu-N+ cells) and increased number of undifferentiated cells (SOX-2+ cells). Additionally, fluoxetine-induced proliferation and maintenance of hypothalamic neuroprogenitor cells leads to changes in the mRNA levels of appetite regulator neuropeptides, including Neuropeptide Y (NPY) and Cocaine-and-Amphetamine-Regulated-Transcript (CART). This study provides the first evidence that SSRIs affect the development of hypothalamic neuroprogenitor cells in vitro with consequent alterations on appetite neuropeptides. PMID:24598761
Takahashi, Hiroyuki; Takata, Fuyuko; Matsumoto, Junichi; Machida, Takashi; Yamauchi, Atsushi; Dohgu, Shinya; Kataoka, Yasufumi
Insulin signaling in the hypothalamus plays an important role in food intake and glucose homeostasis. Hypothalamic neuronal functions are modulated by glial cells; these form an extensive network connecting the neurons and cerebral vasculature, known as the neurovascular unit (NVU). Brain pericytes are periendothelial accessory structures of the blood-brain barrier and integral members of the NVU. However, the interaction between pericytes and neurons is largely unexplored. Here, we investigate whether brain pericytes could affect hypothalamic neuronal insulin signaling. Our immunohistochemical observations demonstrated the existence of pericytes in the mouse hypothalamus, exhibiting immunoreactivity of platelet-derived growth factor receptor β (a pericyte marker), and laminin, a basal lamina marker. We then exposed a murine hypothalamic neuronal cell line, GT1-7, to conditioned medium obtained from primary cultures of rat brain pericytes. Pericyte-conditioned medium (PCM), but not astrocyte- or aortic smooth muscle cell-conditioned medium, increased the insulin-stimulated phosphorylation of Akt in GT1-7 cells in a concentration-dependent manner. PCM also enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor β without changing its expression or localization in cytosolic or plasma membrane fractions. These results suggest that pericytes, rather than astrocytes, increase insulin sensitivity in hypothalamic neurons by releasing soluble factors under physiological conditions in the NVU. Copyright © 2015 Elsevier Inc. All rights reserved.
Sterkenburg, A. S.; Hoffmann, A.; Gebhardt, U.; Waldeck, E.; Springer, S.; Mueller, H. L.
Background: Severe obesity due to hypothalamic involvement has major impact on prognosis in long-term survivors of childhood craniopharyngioma. The long-term effects of rehabilitation efforts on weight development and obesity in these patients are not analyzed up to now. Patients and Methods: 108
Kjaer, A; Knigge, U; Rouleau, A; Garbarg, M; Warberg, J
The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.
Conclusions: We identified novel neuronal targets and cellular mechanisms underlying PR/PRR actions in critical hypothalamic neurons involved in cardiometabolic regulation. This fundamental mechanistic information regarding central PR/PRR actions is essential for the development of novel RAS-based therapeutic targets for the treatment of cardiometabolic disorders in obesity and hypertension.
Neuropeptide Y (NPY) is a well-established orexigenic peptide and hypothalamic paraventricular nucleus (PVH) is one major brain site that mediates the orexigenic action of NPY. NPY induces abundant expression of C-Fos, an indicator for neuronal activation, in the PVH, which has been used extensively...
Laceulle, O.M.; Nederhof, Esther; van Aken, M.A.G.; Ormel, Johan
The hypothalamic-pituitary-adrenal (HPA) axis has been proposed to be a key mechanism underlying the link between adversity and mental health, but longitudinal studies on adversity and HPA-axis functioning are scarce. Here, we studied adversity-driven changes in HPA-axis functioning during
Unmehopa, Unga A.; van Heerikhuize, Joop J.; Spijkstra, Wenda; Woods, John W.; Howard, Andrew D.; Zycband, Emanuel; Feighner, Scott D.; Hreniuk, Donna L.; Palyha, Oksana C.; Guan, Xiao-Ming; Macneil, Douglas J.; van der Ploeg, Lex H. T.; Swaab, Dick F.
Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R
Unmehopa, U.A.; Heerikhuize, J.J. van; Spijkstra, W.; Woods, J.W.; Howard, A.D.; Zycband, E.; Feighner, S.D.; Hreniuk, D.L.; Palyha, O.C.; Guan, X.-M.; MacNeil, D.J.; Ploeg, L.H.T.; Swaab, D.F.
Melanin-concentrating hormone (MCH) exerts a positive regulation on appetite and binds to the G protein-coupled receptors, MCH1R and MCH2R. In rodents, MCH is produced by neurons in the lateral hypothalamus with projections to various hypothalamic and other brain sites. In the present study, MCH1R
Pfefferbaum, Betty; Tucker, Phebe; Nitiéma, Pascal
Background: The hypothalamic-pituitary-adrenal (HPA) axis constitutes an important biological component of the stress response commonly studied through the measurement of cortisol. Limited research has examined HPA axis dysregulation in youth exposed to disasters. Objective: This study examined HPA axis activation in adolescent Hurricane Katrina…
van Breda, E.; Keizer, H.A.; Kuipers, H.; Wolffenbuttel, B.H.R.
The data of the present case demonstrate that the abuse of androgenic anabolic steroids (AAS) may lead to serious health effects. Although most clinical attention is usually directed towards peripheral side effects, the most serious central side effect, hypothalamic-pituitary-dysfunction, is often
Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course ...
Lopez-Duran, Nestor L.; Olson, Sheryl L.; Hajal, Nastassia J.; Felt, Barbara T.; Vazquez, Delia M.
The purpose of this study was to examine the association between hypothalamic-pituitary-adrenal axis (HPA-axis) reactivity and proactive and reactive aggression in pre-pubertal children. After a 30-min controlled base line period, 73 7-year-old children (40 males and 33 females) were randomly assigned to one of two experimental tasks designed to…
Le Tissier, Paul; Campos, Pauline; Lafont, Chrystel; Romanò, Nicola; Hodson, David J; Mollard, Patrice
The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic-pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment.
Dekkers, J. C.; Geenen, R.; Godaert, G. L.; Glaudemans, K. A.; Lafeber, F. P.; van Doornen, L. J.; Bijlsma, J. W.
There is evidence that the hypothalamic pituitary adrenal (HPA) axis is subresponsive in patients with rheumatoid arthritis (RA). We assessed HPA axis responses to experimental stressors mimicking daily life challenges in patients with RA to determine whether HPA axis activity is associated with Th1
Huizink, Anja C.; Ferdinand, Robert F.; Ormel, Johan; Verhulst, Frank C.
Aims To identify early onset cannabis users by measuring basal hypothalamic-pituitary-adrenal (HPA) axis activity, which may be a risk factor for early onset substance use when showing low activity. Design In a prospective cohort study, adolescents who initiated cannabis use at an early age (9-12
Lauritsen, Mette Petri; Pinborg, Anja; Loft, Anne
OBJECTIVE: To evaluate revised criteria for polycystic ovarian morphology (PCOM) in the diagnosis of polycystic ovary syndrome (PCOS) in anovulatory infertility. DESIGN: Prospective cohort study. PATIENTS: WHO Group II anovulatory infertile women (n = 75). MEASUREMENTS: Clinical, sonographic......, but according to AMH levels, the ovaries remain multifollicular. PERSPECTIVES: A better distinction between hypothalamic amenorrhoea and PCOS could improve treatment strategies for anovulatory infertility....
Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske
Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have
Dwarkasing, J.T.; Dijk, van M.; Dijk, F.J.; Boekschoten, M.V.; Faber, J.; Argiles, J.M.; Laviano, A.; Müller, M.R.; Witkamp, R.F.; Norren, van K.
Background Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an
Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske
Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have
El-Shehaby, Amr M N; Reda, Wael A; Abdel Karim, Khaled M; Emad Eldin, Reem M; Nabeel, Ahmed M
OBJECTIVE Because of their critical and central location, it is deemed necessary to fractionate when considering irradiating optic pathway/hypothalamic gliomas. Stereotactic fractionated radiotherapy is considered safer when dealing with gliomas in this location. In this study, the safety and efficacy of single-session stereotactic radiosurgery for optic pathway/hypothalamic gliomas were reviewed. METHODS Between December 2004 and June 2014, 22 patients with optic pathway/hypothalamic gliomas were treated by single-session Gamma Knife radiosurgery. Twenty patients were available for follow-up for a minimum of 1 year after treatment. The patients were 5 to 43 years (median 16 years) of age. The tumor volume was 0.15 to 18.2 cm 3 (median 3.1 cm 3 ). The prescription dose ranged from 8 to 14 Gy (median 11.5 Gy). RESULTS The mean follow-up period was 43 months. Five tumors involved the optic nerve only, and 15 tumors involved the chiasm/hypothalamus. Two patients died during the follow-up period. The tumors shrank in 12 cases, remained stable in 6 cases, and progressed in 2 cases, thereby making the tumor control rate 90%. Vision remained stable in 12 cases, improved in 6 cases, and worsened in 2 cases in which there was tumor progression. Progression-free survival was 83% at 3 years. CONCLUSIONS The initial results indicate that single-session Gamma Knife radiosurgery is a safe and effective treatment option for optic pathway/hypothalamic gliomas.
Luiten, P.G.M.; Horst, G.J. ter; Karst, H.; Steffens, A.B.
By application of the anterograde transport technique of Phaseolus vulgaris leuco-agglutinin the descending autonomic projection of the paraventricular hypothalamic nucleus was investigated. The Phaseolus lectin technique allowed the detection of the cells of origin in the paraventricular PVN, the
Sterkenburg, A. S.; Hoffmann, A.; Gebhardt, U.; Waldeck, E.; Springer, S.; Mueller, H. L.
Background: Severe obesity due to hypothalamic involvement has major impact on prognosis in long-term survivors of childhood craniopharyngioma. The long-term effects of rehabilitation efforts on weight development and obesity in these patients are not analyzed up to now. Patients and Methods: 108
Full Text Available Abstract Background Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA. As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change. Methods 27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement, grade 1 (n = 8, compression without involvement, or grade 2 (n = 12, severe involvement. Results Despite having similar body mass indexes (BMI, the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, The data for the whole population before and 6–18 months after surgery showed increases in BMI (P Conclusion The hypothalamic involvement by the craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement.
Hsu, Eugenie A; Miller, Jennifer L; Perez, Francisco A; Roth, Christian L
Hypothalamic obesity, a treatment-resistant condition common to survivors of craniopharyngioma (CP), is strongly associated with a poor quality of life in this population. Oxytocin (OT), a hypothalamic neuropeptide, has been shown to play a role in the regulation of energy balance and to have anorexigenic effects in animal studies. Naltrexone (NAL), an opiate antagonist, has been shown to deter hedonic eating and to potentiate OT's effects. In this parent-observed study, we tested the administration of intranasal OT for 10 weeks (phase 1), followed by a combination of intranasal OT and NAL for 38 weeks (phase 2) in a 13-year-old male with confirmed hypothalamic obesity and hyperphagia post-CP resection. Treatment resulted in 1) reduction in body mass index (BMI) z score from 1.77 to 1.49 over 10 weeks during phase 1; 2) reduction in BMI z score from 1.49 to 0.82 over 38 weeks during phase 2; 3) reduced hyperphagia during phases 1 and 2; 4) continued hedonic high-carbohydrate food-seeking in the absence of hunger during phases 1 and 2; and 5) sustained weight reduction during decreased parental monitoring and free access to unlocked food in the home during the last 10 weeks of phase 2. This successful intervention of CP-related hypothalamic obesity and hyperphagia by OT alone and in combination with NAL is promising for conducting future studies of this treatment-recalcitrant form of obesity. Copyright © 2017 Endocrine Society
McNeilly, Alison D; Macfarlane, David P; O'Flaherty, Emmett
Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5bet...
Wu, Xueyan; Balesar, R.A.; Lu, Jing; Farajnia, Sahar; Zhu, Qiongbin; Huang, Manli; Bao, Ai-Min; Swaab, D.F.
In depression, disrupted circadian rhythms reflect abnormalities in the central circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Although many SCN neurons are said to be GABAergic, it was not yet known whether and how SCN GABA changes occur in the SCN in depression. We,
Yi, Chun-Xia; Al-Massadi, Omar; Donelan, Elizabeth; Lehti, Maarit; Weber, Jon; Ress, Chandler; Trivedi, Chitrang; Müller, Timo D.; Woods, Stephen C.; Hofmann, Susanna M.
Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing
Morselli, Eugenia; Fuente-Martin, Esther; Finan, Brian; Kim, Min; Frank, Aaron; Garcia-Caceres, Cristina; Navas, Carlos Rodriguez; Gordillo, Ruth; Neinast, Michael; Kalainayakan, Sarada P.; Li, Dan L.; Gao, Yuanqing; Yi, Chun-Xia; Hahner, Lisa; Palmer, Biff F.; Tschöp, Matthias H.; Clegg, Deborah J.
High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor alpha (ER alpha) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1 alpha
Yi, Chun-Xia; Al-Massadi, Omar; Donelan, Elizabeth; Lehti, Maarit; Weber, Jon; Ress, Chandler; Trivedi, Chitrang; Müller, Timo D; Woods, Stephen C; Hofmann, Susanna M
Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (l dlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention. Copyright © 2012 Elsevier Inc. All rights reserved.
Bohus, B.; Wimersma Greidanus, T.B. van; Wied, D. de
Behavioral and endocrine profiles were established of homozygous (HO-DI) and heterozygous (HE-DI) rats with hereditary hypothalamic diabetes insipidus in comparison to Wistar strain rats. HO-DI rats were inferior in acquiring and maintaining active and passive avoidance behavior. Behavioral deficits
Meijneke, Ruud W H; Schouten-van Meeteren, Antoinette Y N; de Boer, Nienke Y; van Zundert, Suzanne; van Trotsenburg, Paul A S; Stoelinga, Femke; van Santen, Hanneke M
Hypothalamic obesity after treatment for craniopharyngioma is a well-recognized, severe problem. Treatment of hypothalamic obesity is difficult and often frustrating for the patient, the parents and the professional care-giver. Because hypothalamic obesity is caused by an underlying medical disorder, it is often assumed that regular diet and exercise are not beneficial to reduce the extraordinarily high body mass index, and in fact, lifestyle interventions have been shown to be insufficient in case of extreme hypothalamic obesity. Nevertheless, it is important to realize that also in this situation, informal care delivered by the family and appropriate parenting styles are required to minimize the obesity problem. We present a case in which weight gain in the home situation was considered unstoppable, and a very early mortality due to complications of the severe increasing obesity was considered inevitable. A permissive approach toward food intake became leading with rapid weight increase since a restrictive lifestyle was considered a senseless burden for the child. By admission to our hospital for a longer period of time, weight reduction was realized, and the merely permissive approach could be changed into active purposeful care by adequate information, instruction, guidance and encouragement of the affected child and her parents. This case illustrates that, although this type of obesity has a pathological origin, parental and environmental influences remain of extreme importance.
Laurent, Heidemarie K.; Duncan, Larissa G.; Lightcap, April; Khan, Faaiza
Mindfulness in the parenting relationship has been proposed to help both parents and children better regulate stress, though this has not yet been shown at the physiological level. In this study, we tested relations between maternal mindfulness in parenting and both mothers' and their infants' hypothalamic-pituitary-adrenal (HPA) axis activity…
Burke, S.M.; Cohen-Kettenis, P.T.; Veltman, D.J.; Klink, D.T.; Bakker, J.
The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the
Lawson, Elizabeth A.; Donoho, Daniel; Miller, Karen K.; Misra, Madhusmita; Meenaghan, Erinne; Lydecker, Janet; Wexler, Tamara; Herzog, David B.; Klibanski, Anne
Context: Anorexia nervosa (AN) and functional hypothalamic amenorrhea (HA) are associated with low bone density, anxiety, and depression. Women with AN and HA have elevated cortisol levels. Significant hypercortisolemia, as in Cushing’s disease, causes bone loss. It is unknown whether anxiety and depression and/or cortisol dysregulation contribute to low bone density in AN or HA.
Tuiten, A.; Laan, E.; Panhuysen, G.; Everaerd, W.; de Haan, E.; Koppeschaar, H.; Vroon, P.
Psychosexual dysfunction is often suggested the cause of the disturbed eating habits associated with hypothalamic secondary amenorrhea. In contrast, we explored the possibility that impaired sexual function may result from reduced levels of testosterone in amenorrheic subjects as a consequence of
Prince van Leeuwen, A.; Creemers, H.E.; Greaves-Lord, K.; Verhulst, F.C.; Ormel, J.; Huizink, A.C.
Aims: To investigate the relationship of life-time and repeated cannabis use with hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents. Design: Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco
van Leeuwen, Andrea Prince; Creemers, Hanneke E.; Greaves-Lord, Kirstin; Verhulst, Frank C.; Ormel, Johan; Huizink, Anja C.
Aims To investigate the relationship of life-time and repeated cannabis use with hypothalamic-pituitary-adrenal (HPA) axis reactivity to social stress in a general population sample of adolescents. Design Adolescents who reported life-time or repeated cannabis use, life-time or repeated tobacco use
Meerlo, P; Koehl, M; van der Borght, K; Turek, FW
Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine
P.C. Guest (Paul); D. Martins-de-Souza (Daniel); H. Rahmoune (Hassan); S. Bahn (Sabine); P.C. Guest (Paul)
textabstractOver the last few decades, evidence has been emerging that the pathogenesis of psychiatric disorders such as schizophrenia can involve perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. Variations in the manifestation of these effects could be related to the differences in
Huizink, Anja C.; Ferdinand, Robert F.; Ormel, Johan; Verhulst, Frank C.
Aims To identify early onset cannabis users by measuring basal hypothalamic-pituitary-adrenal (HPA) axis activity, which may be a risk factor for early onset substance use when showing low activity. Design In a prospective cohort study, adolescents who initiated cannabis use at an early age (9-12
Full Text Available Early postnatal environments may have long-term and potentially irreversible consequences on hypothalamic neurons involved in energy homeostasis. Litter size is an important life history trait and negatively correlated with milk intake in small mammals, and thus has been regarded as a naturally varying feature of the early developmental environment. Here we investigated the long-term effects of litter size on metabolic phenotype and hypothalamic neuropeptide mRNA expression involved in the regulation of energy homeostasis, using the offspring reared from large (10-12 and small (3-4 litter sizes, of Brandt's voles (Lasiopodomys brandtii, a rodent species from Inner Mongolia grassland in China.Hypothalamic leptin signaling and neuropeptides were measured by Real-Time PCR. We showed that offspring reared from small litters were heavier at weaning and also in adulthood than offspring from large litters, accompanied by increased food intake during development. There were no significant differences in serum leptin levels or leptin receptor (OB-Rb mRNA in the hypothalamus at weaning or in adulthood, however, hypothalamic suppressor of cytokine signaling 3 (SOCS3 mRNA in adulthood increased in small litters compared to that in large litters. As a result, the agouti-related peptide (AgRP mRNA increased in the offspring from small litters.These findings support our hypothesis that natural litter size has a permanent effect on offspring metabolic phenotype and hypothalamic neuropeptide expression, and suggest central leptin resistance and the resultant increase in AgRP expression may be a fundamental mechanism underlying hyperphagia and the increased risk of overweight in pups of small litters. Thus, we conclude that litter size may be an important and central determinant of metabolic fitness in adulthood.
Full Text Available OBJECTIVE: Early life nutrition is critical for the development of hypothalamic neurons involved in energy homeostasis. We previously showed that intrauterine and early postnatal overnutrition programmed hypothalamic neurons expressing the appetite stimulator neuropeptide Y (NPY and suppressor proopiomelanocortin (POMC in offspring at weaning. However, the long-term effects of such programming and its interactions with post-weaning high-fat-diet (HFD consumption are unclear. RESEARCH DESIGN AND METHODS: Female Sprague Dawley rats were exposed to chow or HFD for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1, litters were adjusted to 3/litter to induce postnatal overnutrition (vs. 12 in control. At postnatal day 20, half of the rats from each maternal group were weaned onto chow or HFD for 15 weeks. Hypothalamic appetite regulators, and fuel (glucose and lipid metabolic markers were measured. RESULTS: Offspring from obese dams gained more weight than those from lean dams independent of post-weaning diet. Maternal obesity interacted with post-weaning HFD consumption to cause greater levels of hyperphagia, adiposity, hyperlipidemia, and glucose intolerance in offspring. This was linked to increased hypothalamic NPY signaling and leptin resistance in adult offspring. Litter size reduction had a detrimental impact on insulin and adiponectin, while hypothalamic NPY and POMC mRNA expression were suppressed in the face of normal energy intake and weight gain. CONCLUSIONS: Maternal obesity, postnatal litter size reduction and post-weaning HFD consumption caused obesity via different neuroendocrine mechanism. There were strong additive effects of maternal obesity and post-weaning HFD consumption to increase the metabolic disorders in offspring.
Benzler, J; Ganjam, G K; Legler, K; Stöhr, S; Krüger, M; Steger, J; Tups, A
The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important
Mohr, Margaret A; Sisk, Cheryl L
During puberty, the brain goes through extensive remodeling, involving the addition of new neurons and glia to brain regions beyond the canonical neurogenic regions (i.e., dentate gyrus and olfactory bulb), including limbic and hypothalamic cell groups associated with sex-typical behavior. Whether these pubertally born cells become functionally integrated into neural circuits remains unknown. To address this question, we gave male Syrian hamsters daily injections of the cell birthdate marker bromodeoxyuridine throughout puberty (postnatal day 28-49). Half of the animals were housed in enriched environments with access to a running wheel to determine whether enrichment increased the survival of pubertally born cells compared with the control environment. At 4 wk after the last BrdU injection, animals were allowed to interact with a receptive female and were then killed 1 h later. Triple-label immunofluorescence for BrdU, the mature neuron marker neuronal nuclear antigen, and the astrocytic marker glial fibrillary acidic protein revealed that a proportion of pubertally born cells in the medial preoptic area, arcuate nucleus, and medial amygdala differentiate into either mature neurons or astrocytes. Double-label immunofluorescence for BrdU and the protein Fos revealed that a subset of pubertally born cells in these regions is activated during sociosexual behavior, indicative of their functional incorporation into neural circuits. Enrichment affected the survival and activation of pubertally born cells in a brain region-specific manner. These results demonstrate that pubertally born cells located outside of the traditional neurogenic regions differentiate into neurons and glia and become functionally incorporated into neural circuits that subserve sex-typical behaviors.
Snyers, An; Janssens, Geert; Twickler, Marcel B.; Hermus, Ad R.; Takes, Robert P.; Kappelle, Arnoud C.; Merkx, Matthias A.W.; Dirix, Piet; Kaanders, Johannes H.A.M.
Purpose: To evaluate the long-term outcome after surgery and radiotherapy for patients with sinonasal cancer and assess late toxicity, with special emphasis on hypothalamic-pituitary dysfunction. Methods and Materials: A retrospective analysis of 168 patients treated for sinonasal cancer in a single institute between 1986 and 2006. A more detailed analysis was performed on a subgroup of 76 patients with adenocarcinoma or squamous cell carcinoma treated with curative intent. Long-term survivors were evaluated for late toxicity by a multidisciplinary team using the late effects of normal tissues (LENT SOMA) scoring system. Additional endocrinologic tests were performed for assessment of hypothalamic-pituitary function. Results: Five-year actuarial local control and overall survival rates were 62% and 35% for all patients and 64% and 42% for the subgroup with squamous cell carcinoma and adenocarcinoma. In multivariate analysis, T stage was the only significant factor predicting local relapse (79% at 5 years for T1-T3 vs. 53% for T4; p = 0.006). Sinonasal mucosal melanomas had the highest rate of regional failure (33% at 5 years). Thirteen of 21 patients (62%) evaluated at the late morbidity clinic had hormonal disturbances, of whom 5 (24%) had definitive evidence of hypopituitarism with multiple hormonal deficiencies. Conclusion: Local failure is the dominant cause of treatment failure for patients with sinonasal cancer, with T4 stage the only independent predictor. Because of a high rate of radiation-induced hypopituitarism, we recommend endocrinologic surveillance for these patients
Sakakibara, M; Deura, C; Minabe, S; Iwata, Y; Uenoyama, Y; Maeda, K-I; Tsukamura, H
Female rats show a gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) surge in the presence of a preovulatory level of oestrogen, whereas males do not because of brain defeminisation during the developmental period by perinatal oestrogen converted from androgen. The present study aimed to identify the site(s) of oestrogen action and the critical period for defeminising the mechanism regulating the GnRH/LH surge. Animals given perinatal treatments, such as steroidal manipulations, brain local implantation of oestradiol (E(2) ) or administration of an NMDA antagonist, were examined for their ability to show an E(2) -induced LH surge at adulthood. Lordosis behaviour was examined to compare the mechanisms defeminising the GnRH/LH surge and sexual behaviour. A single s.c. oestradiol-benzoate administration on either the day before birth (E21), the day of birth (D0) or day 5 (D5) postpartum completely abolished the E(2) -induced LH surge at adulthood in female rats, although the same treatment did not inhibit lordosis. Perinatal castration on E21 or D0 partially rescued the E2-induced LH surge in genetically male rats, whereas castration from E21 to D5 totally rescued lordosis. Neonatal E(2) implantation in the anterior hypothalamus including the anteroventral periventricular nucleus (AVPV)/preoptic area (POA) abolished the E(2) -induced LH surge in female rats, whereas E(2) implantation in the mid and posterior hypothalamic regions had no inhibitory effect on the LH surge. Lordosis was not affected by neonatal E(2) implantation in any hypothalamic regions. In male rats, neonatal NMDA antagonist treatment rescued lordosis but not the LH surge. Taken together, these results suggest that an anterior hypothalamic region such as the AVPV/POA region is a perinatal site of oestrogen action where the GnRH/LH regulating system is defeminised to abolish the oestrogen-induced surge. The mechanism for defeminisation of the GnRH/LH surge system might be different from
Stark, Romana; Reichenbach, Alex; Andrews, Zane B
The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin
Surkin, P N; Di Rosso, M E; Correa, F; Elverdin, J C; Genaro, A M; De Laurentiis, A; Fernández-Solari, J
Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 μL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1β increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS
van Bodegom, Miranda; Homberg, Judith R.; Henckens, Marloes J. A. G.
Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA
Fick, Laura J; Belsham, Denise D
Obesity and type 2 diabetes mellitus represent a significant global health crisis. These two interrelated diseases are typified by perturbed insulin signaling in the hypothalamus. Using novel hypothalamic cell lines, we have begun to elucidate the molecular and intracellular mechanisms involved in the hypothalamic control of energy homeostasis and insulin resistance. In this review, we present evidence of insulin and glucose signaling pathways that lead to changes in neuropeptide gene expression. We have identified some of the molecular mechanisms involved in the control of de novo hypothalamic insulin mRNA expression. And finally, we have defined key mechanisms involved in the etiology of cellular insulin resistance in hypothalamic neurons that may play a fundamental role in cases of high levels of insulin or saturated fatty acids, often linked to the exacerbation of obesity and diabetes.
Aschbacher, K.; Rodriguez-Fernandez, M.; Wietmarschen, H. van; Tomiyama, A.; Jain, S.; Epel, E.; Doyle III, F.J.; Greef, J. van der
Glucocorticoids contribute to obesity and metabolic syndrome; however, the mechanisms are unclear, and prognostic measures are unavailable. A systems level understanding of the hypothalamic-pituitary-adrenal (HPA) -leptin axis may reveal novel insights. Eighteen obese premenopausal women provided
A. Lukoshe (Akvile); Van Dijk, S.E. (Suzanne E.); G.E. van den Bosch (Gerbrich); A. van der Lugt (Aad); T.J.H. White (Tonya); A.C.S. Hokken-Koelega (Anita)
textabstractBackground: Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, characterized by endocrine problems and hyperphagia, indicating hypothalamic-pituitary dysfunction. However, few studies have explored the underlying neurobiology of the hypothalamus and its functional
Rege Sugárka Papp; Rege Sugárka Papp; Miklos ePalkovits; Miklos ePalkovits
The projections from the dorsolateral hypothalamic area (DLH) to the lower brainstem have been investigated by using biotinylated dextran amine (BDA), an anterograde tracer in rats. The DLH can be divided into 3 areas (dorsomedial hypothalamus, perifornical area, lateral hypothalamic area), and further subdivided into 8 subdivisions. After unilateral stereotaxic injections of BDA into individual DLH subdivisions, the correct sites of injections were controlled histologically, and the distribu...
Papp, Rege S.; Palkovits, Miklós
The projections from the dorsolateral hypothalamic area (DLH) to the lower brainstem have been investigated by using biotinylated dextran amine (BDA), an anterograde tracer in rats. The DLH can be divided into 3 areas (dorsomedial hypothalamus, perifornical area, lateral hypothalamic area), and further subdivided into 8 subdivisions. After unilateral stereotaxic injections of BDA into individual DLH subdivisions, the correct sites of injections were controlled histologically, and the distribu...
Bisenius, Erin S; Veeramachaneni, D N Rao; Sammonds, Ginger E; Tobet, Stuart
The preoptic/anterior hypothalamic area (POA/AH) is one of the most sexually dimorphic areas of the vertebrate brain and plays a pivotal role in regulating male sexual behavior. Vinclozolin is a fungicide thought to be an environmental antiandrogen, which disrupts masculine sexual behavior when administered to rabbits during development. In this study, we examined several characteristics of the rabbit POA/AH for sexual dimorphism and endocrine disruption by vinclozolin. Pregnant rabbits were dosed orally with vinclozolin (10 mg/kg body weight) or carrot paste vehicle once daily for 6 wk beginning at midgestation and continuing through nursing until Postpartum Week 4. At 6 wk, offspring were perfused with 4% paraformaldehyde and brains processed for immunocytochemical localization of tyrosine hydroxylase, calbindin, gonadotropin-releasing hormone (GnRH), or Nissl stain. There were significant sex differences in the distribution of calbindin in the POA/AH and the size of cells in the dorsal POA/AH (values greater in females than in males), but not in the number or distribution of tyrosine hydroxylase or GnRH neurons. In both sexes, exposure to vinclozolin significantly increased calbindin expression in the ventral POA/AH and significantly decreased number of GnRH neurons selectively in the region of the organum vasculosum of the lamina terminalis (OVLT) but not more caudally in the POA/AH. This is the first documentation of a sexually dimorphic region in the rabbit brain, and further supports the use of this species as a model for studying the influence of vinclozolin on reproductive development with potential application to human systems.
Hutchison, J.B.; Schumacher, M.; Steimer, T.; Gahr, M.
In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells
Full Text Available Diets rich in saturated fat produce inflammation, gliosis, and neuronal stress in the mediobasal hypothalamus (MBH. Here, we show that microglia mediate this process and its functional impact. Although microglia and astrocytes accumulate in the MBH of mice fed a diet rich in saturated fatty acids (SFAs, only the microglia undergo inflammatory activation, along with a buildup of hypothalamic SFAs. Enteric gavage specifically with SFAs reproduces microglial activation and neuronal stress in the MBH, and SFA treatment activates murine microglia, but not astrocytes, in culture. Moreover, depleting microglia abrogates SFA-induced inflammation in hypothalamic slices. Remarkably, depleting microglia from the MBH of mice abolishes inflammation and neuronal stress induced by excess SFA consumption, and in this context, microglial depletion enhances leptin signaling and reduces food intake. We thus show that microglia sense SFAs and orchestrate an inflammatory process in the MBH that alters neuronal function when SFA consumption is high.
Kopylova, O.V.; Stepanenko, O.A.
The 168 children born to parents exposed after the Chernobyl accident were examined to study the hypothalamic-pituitary-thyroid system function in descendants of the Chernobyl survivors. Clinical, hormonal, ultrasound examinations and challenge test with tyroliberynum were conducted. Some abnormalities that might explain the functional strain of the hypothalamic-pituitary system were identified being of a great role in origination and progress of thyroid disease. The prolonged strain leads to decreased production of thyroid hormone, which causes an increased secretion of thyroid stimulating hormone. Under the influence of TSH the thyroid gland in the first stage becomes increased in its mass, which leads to the formation of endemic goiter. Stable and permanent thyroid gland enlargement often leads to formation of the nodular goiter and other proliferative processes, namely to carcinogenesis
Aitta-Aho, Teemu; Pappa, Elpiniki; Burdakov, Denis; Apergis-Schoute, John
The hypothalamic hypocretin/orexin (HO) system holds a central role in the regulation of several physiological functions critical for food-seeking behavior including mnemonic processes for effective foraging behavior. It is unclear however whether physiological increases in HO neuronal activity can support such processes. Using a designer rM3Ds receptor activation approach increasing HO neuronal activity resulted in improved short-term memory for novel locations. When tested on a non-spatial novelty object recognition task no significant difference was detected between groups indicating that hypothalamic HO neuronal activation can selectively facilitate short-term spatial memory for potentially supporting memory for locations during active exploration. Copyright Â© 2016 Elsevier Inc. All rights reserved.
Inge, Thomas H; Pfluger, Paul; Zeller, Meg; Rose, Susan R; Burget, Lukas; Sundararajan, Sumana; Daniels, Stephen R; Tschöp, Matthias H
A 14-year-old boy presented with daytime somnolence, intermittent emesis and hypothyroidism. Neuroimaging revealed a calcified suprasellar intracranial mass, suspected to be a craniopharyngioma. Subtotal resection of the tumor confirmed the diagnosis. Extreme obesity (BMI >60 kg/m(2)) and hyperinsulinemia followed tumor resection and cranial irradiation. Dietary interventions were unsuccessful, and pharmacologic intervention (i.e. octreotide) only slowed the rate of weight gain. Radiography documented the suprasellar mass. Following surgical resection and radiotherapy, hypothalamic-pituitary deficiencies were found. Preprandial and postprandial excursions of insulin, active ghrelin and leptin were measured before and after gastric bypass surgery. Panhypopituitarism, hypothalamic obesity and hyperinsulinemia following craniopharyngioma therapy. Severe caloric restriction, octreotide, and pituitary hormone replacement did not produce weight loss. Gastric bypass surgery led to reduced food cravings, significant weight loss, and amelioration of obesity-related comorbidities. Correction of fasting hyperinsulinemia, normalization of postprandial insulin responses, and reductions in active ghrelin and leptin concentrations were also observed.
van Opstal, Anna M.; Akintola, Abimbola A.; Elst, Marjan van der
The hypothalamus is a crucial structure in the brain that responds to metabolic cues and regulates energy homeostasis. Patients with type 2 diabetes demonstrate a lack of hypothalamic neuronal response after glucose ingestion, which is suggested to be an underlying cause of the disease. In this s......The hypothalamus is a crucial structure in the brain that responds to metabolic cues and regulates energy homeostasis. Patients with type 2 diabetes demonstrate a lack of hypothalamic neuronal response after glucose ingestion, which is suggested to be an underlying cause of the disease...... effect. Our data provide proof of concept for future experiments testing the potential of intranasal application of insulin to ameliorate defective homeostatic control in patients with type 2 diabetes....
Andersson, Ulrika; Treebak, Jonas Thue; Nielsen, Jakob Nis
. In recovery, glucose feeding increased plasma glucose and insulin concentrations whereas ghrelin and PYY decreased to (ghrelin) or below (PPY) resting levels. It is concluded that 1 h of strenuous exercise in rats does not elicit significant changes in hypothalamic AMPK activity despite an increase in plasma...... ghrelin. Thus, changes in energy metabolism during or after exercise are likely not coordinated by changes in hypothalamic AMPK activity.......Recent studies have demonstrated that AMP-activated protein kinase (AMPK) in the hypothalamus is involved in the regulation of food intake. Because exercise is known to influence appetite and cause substrate depletion, it may also influence AMPK in the hypothalamus. Male rats that either rested...
Dinan, Timothy G
Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis characterized by hypercortisolism, adrenal hyperplasia and abnormalities in negative feedback is the most consistently described biological abnormality in melancholic depression. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the main secretagogues of the HPA\\/stress system. Produced in the parvicellular division of the hypothalamic paraventricular nucleus the release of these peptides is influenced by inputs from monoaminergic neurones. In depression, anterior pituitary CRH1 receptors are down-regulated and response to CRH infusion is blunted. By contrast, vasopressin V3 receptors on the anterior pituitary show enhanced response to AVP stimulation and this enhancement plays a key role in maintaining HPA overactivity.
Radioimmunoassay of the hypothalamic-hypophyseal-ovarian interrelationships was performed in 87 patients with cervical cancer and 37 practically healthy women. The basal level of the follicle-stimulating hormone (ESH), luteinizing hormone (LH) and estradiol as well as their response to the administration of the releasing factor of the hypothalamus (luliberin) were studied. Some disorders that manifested thermselved in the decreased level of estradiol, were established in the patients with cervical cancer even before irradiation. Concomitant radiation therapy resulted in pronounced changes in the activities of the hypothalamic-hypophyseal-ovarian system that manifested themselves in the lowered rate of LH increment in response to the administration of luliberin and the absence of estradiol response to the load. These changes persisted long after the termination of concomitant radiation therapy
Tonon, M C; Lanfray, D; Castel, H; Vaudry, H; Morin, F
The hypothalamus senses hormones and nutrients in order to regulate energy balance. In particular, detection of hypothalamic glucose levels has been shown to regulate both feeding behavior and peripheral glucose homeostasis, and impairment of this regulatory system is believed to be involved in the development of obesity and diabetes. Several data clearly demonstrate that glial cells are key elements in the perception of glucose, constituting with neurons a "glucose-sensing unit". Characterization of this interplay between glia and neurons represents an exciting challenge, and will undoubtedly contribute to identify new candidates for therapeutic intervention. The purpose of this review is to summarize the current data that stress the importance of glia in central glucose-sensing. The nature of the glia-to-neuron signaling is discussed, with a special focus on the endozepine ODN, a potent anorexigenic peptide that is highly expressed in hypothalamic glia. © Georg Thieme Verlag KG Stuttgart · New York.
Full Text Available Inflammation has been implicated in the hypothalamic leptin and insulin resistance resulting defective food intake during high fat diet period. To investigate hypothalamic inflammation in dietary induced obesity (DIO and obesity resistant (DIO-R rats, we established rat models of DIO and DIO-R by feeding high fat diet for 10 weeks. Then we switched half of DIO and DIO-R rats to chow food and the other half to high fat diet for the following 8 weeks to explore hypothalamic inflammation response to the low fat diet intervention. Body weight, caloric intake, HOMA-IR, as well as the mRNA expression of hypothalamic TLR4, NF-κB, TNF-α, IL-1β, and IL-6 in DIO/HF rats were significantly increased compared to DIO-R/HF and CF rats, whereas IL-10 mRNA expression was lower in both DIO/HF and DIO-R/HF rats compared with CF rats. Switching to chow food from high fat diet reduced the body weight and improved insulin sensitivity but not affecting the expressions of studied inflammatory genes in DIO rats. Take together, upregulated hypothalamic inflammation may contribute to the overeating and development of obesity susceptibility induced by high fat diet. Switching to chow food had limited role in correcting hypothalamic inflammation in DIO rats during the intervention period.
Full Text Available Hypothalamus is a key area involved in the control of metabolism and food intake via the integrations of numerous signals (hormones, neurotransmitters, metabolites from various origins. These factors modify hypothalamic neurons activity and generate adequate molecular and behavioral responses to control energy balance. In this complex integrative system, a new concept has been developed in recent years, that includes reactive oxygen species (ROS as a critical player in energy balance. ROS are known to act in many signaling pathways in different peripheral organs, but also in hypothalamus where they regulate food intake and metabolism by acting on different types of neurons, including proopiomelanocortin (POMC and agouti-related protein (AgRP/neuropeptide Y (NPY neurons. Hypothalamic ROS release is under the influence of different factors such as pancreatic and gut hormones, adipokines (leptin, apelin,..., neurotransmitters and nutrients (glucose, lipids,.... The sources of ROS production are multiple including NADPH oxidase, but also the mitochondria which is considered as the main ROS producer in the brain. ROS are considered as signaling molecules, but conversely impairment of this neuronal signaling ROS pathway contributes to alterations of autonomic nervous system and neuroendocrine function, leading to metabolic diseases such as obesity and type 2 diabetes.In this review we focus our attention on factors that are able to modulate hypothalamic ROS release in order to control food intake and energy metabolism, and whose deregulations could participate to the development of pathological conditions. This novel insight reveals an original mechanism in the hypothalamus that controls energy balance and identify hypothalamic ROS signaling as a potential therapeutic strategy to treat metabolic disorders.
Bagheri; Pourbakhtyaran; Talebi Kiasari; Taherkhanchi; Salarian; Sadeghi
Introduction Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare disease. To date, there have been only few reported cases of ROHHAD syndrome. Case Presentation We report a 5-year-old- Iranian girl who had normal growth and development until her 4th year of life. At that time, the patient developed weight gain, constipation, coldness in the extremities, and hyperhidros...
Drougard, Anne; Fournel, Audren; Valet, Philippe; Knauf, Claude
Hypothalamus is a key area involved in the control of metabolism and food intake via the integrations of numerous signals (hormones, neurotransmitters, metabolites) from various origins. These factors modify hypothalamic neurons activity and generate adequate molecular and behavioral responses to control energy balance. In this complex integrative system, a new concept has been developed in recent years, that includes reactive oxygen species (ROS) as a critical player in energy balance. ROS are known to act in many signaling pathways in different peripheral organs, but also in hypothalamus where they regulate food intake and metabolism by acting on different types of neurons, including proopiomelanocortin (POMC) and agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons. Hypothalamic ROS release is under the influence of different factors such as pancreatic and gut hormones, adipokines (leptin, apelin,…), neurotransmitters and nutrients (glucose, lipids,…). The sources of ROS production are multiple including NADPH oxidase, but also the mitochondria which is considered as the main ROS producer in the brain. ROS are considered as signaling molecules, but conversely impairment of this neuronal signaling ROS pathway contributes to alterations of autonomic nervous system and neuroendocrine function, leading to metabolic diseases such as obesity and type 2 diabetes. In this review we focus our attention on factors that are able to modulate hypothalamic ROS release in order to control food intake and energy metabolism, and whose deregulations could participate to the development of pathological conditions. This novel insight reveals an original mechanism in the hypothalamus that controls energy balance and identify hypothalamic ROS signaling as a potential therapeutic strategy to treat metabolic disorders.
Dwarkasing, Jvalini T.; van Dijk, Miriam; Dijk, Francina J.; Boekschoten, Mark V.; Faber, Joyce; Argilès, Josep M.; Laviano, Alessandro; Müller, Michael; Witkamp, Renger F.; van Norren, Klaske
Background Appetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an increased food intake subsequently to the loss of body weight. We hypothesise that in this model, appetite-regulating systems in the hypothalamus, which apparently fail in anorexia, are still able t...
Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van, Klaske
Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still ab...
Liu, Xianglan; McMurphy, Travis; Xiao, Run; Slater, Andrew; Huang, Wei; Cao, Lei
Activation of the hypothalamus-adipocyte axis is associated with an antiobesity and anticancer phenotype in animal models of melanoma and colon cancer. Brain-derived neurotrophic factor (BDNF) is a key mediator in the hypothalamus leading to preferential sympathoneural activation of adipose tissue and the ensuing resistance to obesity and cancer. Here, we generated middle age obese mice by high fat diet feeding for a year and investigated the effects of hypothalamic gene transfer of BDNF on a...
Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van, Klaske
Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still ab...
Quiñones, Mar; Al-Massadi, Omar; Gallego, Rosalía; Fernø, Johan; Diéguez, Carlos; López, Miguel; Nogueiras, Ruben
Objective Glucagon receptor antagonists and humanized glucagon antibodies are currently studied as promising therapies for obesity and type II diabetes. Among its variety of actions, glucagon reduces food intake, but the molecular mechanisms mediating this effect as well as glucagon resistance are totally unknown. Methods Glucagon and adenoviral vectors were administered in specific hypothalamic nuclei of lean and diet-induced obese rats. The expression of neuropeptides controlling food intake was performed by in situ hybridization. The regulation of factors of the glucagon signaling pathway was assessed by western blot. Results The central injection of glucagon decreased feeding through a hypothalamic pathway involving protein kinase A (PKA)/Ca2+-calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMP-activated protein kinase (AMPK)-dependent mechanism. More specifically, the central injection of glucagon increases PKA activity and reduces protein levels of CaMKKβ and its downstream target phosphorylated AMPK in the hypothalamic arcuate nucleus (ARC). Consistently, central glucagon significantly decreased AgRP expression. Inhibition of PKA and genetic activation of AMPK in the ARC blocked glucagon-induced anorexia in lean rats. Genetic down-regulation of glucagon receptors in the ARC stimulates fasting-induced hyperphagia. Although glucagon was unable to decrease food intake in DIO rats, glucagon sensitivity was restored after inactivation of CaMKKβ, specifically in the ARC. Thus, glucagon decreases food intake acutely via PKA/CaMKKβ/AMPK dependent pathways in the ARC, and CaMKKβ mediates its obesity-induced hypothalamic resistance. Conclusions This work reveals the molecular underpinnings by which glucagon controls feeding that may lead to a better understanding of disease states linked to anorexia and cachexia. PMID:26909312
Lee, Richard; Sawa, Akira
In this review, we provide a brief summary of several key studies that broaden our understanding of stress and its epigenetic control of the hypothalamic-pituitary-adrenal axis (HPA)-axis function and behavior. Clinical and animal studies suggest a link among exposure to stress, dysregulation of the HPA-axis, and susceptibility to neuropsychiatric illnesses. Recent studies have supported the notion that exposure to glucocorticoids and stress in various forms, duration, and intensity during di...
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Altayar, Osama; Al Nofal, Alaa; Carranza Leon, B. Gisella; Prokop, Larry J.; Wang, Zhen; Murad, M. Hassan
Objective: We conducted a systematic review and meta-analysis of studies that evaluated the effect of hormonal therapy [estrogen therapy including oral contraceptive pills (OCP)] and bisphosphonates in preventing bone loss in patients with functional hypothalamic amenorrhea (FHA). Methods: We searched several electronic databases for controlled and noncontrolled studies that enrolled females of any age presenting with FHA (including athletic, weight loss, and stress-associated amenorrhea/olig...
Javed, Asma; Kashyap, Rahul; Lteif, Aida N
Asma Javed,1 Rahul Kashyap,2 Aida N Lteif1 1Pediatric and Adolescent Medicine, Division of Pediatric Endocrinology Mayo Clinic, Rochester, MN, USA; 2Department of Anesthesia and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA Objective: To compare the reproductive, metabolic, and skeletal profiles of young athletic women with functional hypothalamic amenorrhea (FHA) as well as clinical or biochemical hyperandrogenism (FHA-EX+HA) with body mass index matched women with FHA due to exe...
Matsuwaki, Takashi; Nishihara, Masugi; Sato, Tsuyoshi; Yoda, Tetsuya; Iwakura, Yoichiro; Chida, Dai
Exposure to chronic stressors results in dysregulation of the hypothalamic-pituitary-adrenal axis and a disruption in reproduction. CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis induces the secretion of ACTH from the pituitary, which stimulates adrenal steroidogenesis via the specific cell-surface melanocortin 2 receptor (MC2R). Previously, we demonstrated that MC2R(-/-) mice had undetectable levels of corticosterone despite high ACTH levels. Here, we evaluated the reproductive functions of female MC2R(-/-) mice and analyzed the mechanism of the disrupted cyclicity of these mice. The expression of CRH in the paraventricular nucleus was significantly increased in MC2R(-/-) mice under nonstressed conditions. Although MC2R(-/-) females were fertile, they showed a prolonged estrous cycle. After hormonal stimulation, MC2R(-/-) females produced nearly-normal numbers of eggs, but slightly less than MC2R(+/-) females, and showed near-normal ovarian histology. During diestrus, the number of GnRH-positive cells in the medial preoptic area was significantly reduced in MC2R(-/-) females. CRH type 1 receptor antagonist restored estrous cyclicity in MC2R(-/-) females. Kisspeptin-positive areas in the arcuate nucleus were comparable, whereas kisspeptin-positive areas in the anteroventral periventricular nucleus in MC2R(-/-) females were significantly reduced compared with MC2R(+/-) females, suggesting that arcuate nucleus kisspeptin is not involved, but anteroventral periventricular nucleus kisspeptin may be involved, in the maintenance of estrous cyclicity. Our findings show that high levels of hypothalamic CRH disturb estrous cyclicity in the female animals and that the MC2R(-/-) female is a unique animal model of functional hypothalamic amenorrhea.
Meczekalski, B.; Katulski, K.; Czyzyk, A.; Podfigurna-Stopa, A.; Maciejewska-Jeske, M.
Introduction Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). The final consequences are complex hormonal changes manifested by profound hypoes...
Miller, K K; Lawson, E A; Mathur, V; Wexler, T L; Meenaghan, E; Misra, M; Herzog, D B; Klibanski, A
Anorexia nervosa and normal-weight hypothalamic amenorrhea are characterized by hypogonadism and hypercortisolemia. However, it is not known whether these endocrine abnormalities result in reductions in adrenal and/ or ovarian androgens or androgen precursors in such women, nor is it known whether relative androgen deficiency contributes to abnormalities in bone density and body composition in this population. Our objective was to determine whether endogenous androgen and dehydroepiandrosterone sulfate (DHEAS) levels: 1) are reduced in women with anorexia nervosa and normal-weight hypothalamic amenorrhea, 2) are reduced further by oral contraceptives in women with anorexia nervosa, and 3) are predictors of weight, body composition, or bone density in such women. We conducted a cross-sectional study at a general clinical research center. A total of 217 women were studied: 137 women with anorexia nervosa not receiving oral contraceptives, 32 women with anorexia nervosa receiving oral contraceptives, 21 normal-weight women with hypothalamic amenorrhea, and 27 healthy eumenorrheic controls. Testosterone, free testosterone, DHEAS, bone density, fat-free mass, and fat mass were assessed. Endogenous total and free testosterone, but not DHEAS, were lower in women with anorexia nervosa than in controls. More marked reductions in both free testosterone and DHEAS were observed in women with anorexia nervosa receiving oral contraceptives. In contrast, normal-weight women with hypothalamic amenorrhea had normal androgen and DHEAS levels. Lower free testosterone, total testosterone, and DHEAS levels predicted lower bone density at most skeletal sites measured, and free testosterone was positively associated with fat-free mass. Androgen levels are low, appear to be even further reduced by oral contraceptive use, and are predictors of bone density and fat-free mass in women with anorexia nervosa. Interventional studies are needed to confirm these findings and determine whether
Bethea, Cynthia L; Kim, Aaron; Cameron, Judy L
A body of knowledge implicates an increase in output from the locus ceruleus (LC) during stress. We questioned the innervation and function of the LC in our macaque model of Functional Hypothalamic Amenorrhea, also known as Stress-Induced Amenorrhea. Cohorts of macaques were initially characterized as highly stress resilient (HSR) or stress-sensitive (SS) based upon the presence or absence of ovulation during a protocol involving 2 menstrual cycles with psychosocial and metabolic stress. Afte...
Lin, Eleanor; Grinspoon, Steven; Wang, Thomas; Miller, Karen K.
Natriuretic peptides, which are important regulators of salt handling and blood pressure, are 60 – 75% higher in healthy young women than in men, consistent with a gender dimorphism. In this randomized, placebo-controlled study in women with functional hypothalamic amenorrhea, we show that administration of oral contraceptives increases natriuretic peptide levels and that end-of-study free testosterone levels are inversely associated with NT-proBNP levels, consistent with the hypothesis that ...
Stolbova, Sarka; Benes, Marek; Petruzelkova, Lenka; Lebl, Jan; Kolouskova, Stanislava
Hypothalamic dysfunction leading to severe obesity is a serious long-term consequence of paediatric craniopharyngioma. It compromises quality of life, leads to long-term metabolic hazards, and may shorten life expectancy. Therefore, a proactive approach is required. Conventional treatment of hypothalamic obesity is difficult and hardly successful. Experience with bariatric surgery is limited, especially in younger patients. Two retrospective studies recently reported on classic bariatric surgery in a small series of individuals after craniopharyngioma. Of these, one included nine paediatric patients who underwent laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB) or biliopancreatic diversion (BPD). The immediate effects were promising: The mean weight loss was 20.9 kilograms at 6 months and 15.1 kilograms at 12 months. A duodenal-jejunal bypass sleeve (DBJS; EndoBarrier) is a mini-invasive, endoscopically placed and fully reversible bariatric procedure. We reported a boy diagnosed with craniopharyngioma at 10 years old who underwent surgery and radiotherapy. His body weight increased to 139 kilograms and body mass index (BMI) to 46.1 kg/m2 (+4.0 SD) within the subsequent 4.5 years. Fifteen months after DJBS placement, he lost 32.8 kilograms, and his BMI dropped to 32.7 kg/m2 (+2.9 SD). Thus, DJBS proved to be a promising procedure in the treatment of hypothalamic obesity. We suggest performing it in children and adolescents with hypothalamic obesity to prevent or attenuate its devastating long-term sequelae. Copyright© of YS Medical Media ltd.
López, Miguel; Varela, Luis; Vázquez, María J; Rodríguez-Cuenca, Sergio; González, Carmen R; Velagapudi, Vidya R; Morgan, Donald A; Schoenmakers, Erik; Agassandian, Khristofor; Lage, Ricardo; de Morentin, Pablo Blanco Martínez; Tovar, Sulay; Nogueiras, Rubén; Carling, David; Lelliott, Christopher
Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here, we demonstrate that either whole body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipog...
De Bellis, A; Sinisi, A A; Pane, E; Dello Iacovo, A; Bellastella, G; Di Scala, G; Falorni, A; Giavoli, C; Gasco, V; Giordano, R; Ambrosio, M R; Colao, A; Bizzarro, A; Bellastella, A
Antipituitary antibodies (APA) but not antihypothalamus antibodies (AHA) are usually searched for in autoimmune hypopituitarism. Our objective was to search for AHA and characterize their hypothalamic target in patients with autoimmune hypopituitarism to clarify, on the basis of the cells stained by these antibodies, the occurrence of autoimmune subclinical/clinical central diabetes insipidus (CDI) and/or possible joint hypothalamic contribution to their hypopituitarism. We conducted a cross-sectional cohort study. Ninety-five APA-positive patients with autoimmune hypopituitarism, 60 without (group 1) and 35 with (group 2) lymphocytic hypophysitis, were studied in comparison with 20 patients with postsurgical hypopituitarism and 50 normal subjects. AHA by immunofluorescence and posterior pituitary function were evaluated; then AHA-positive sera were retested by double immunofluorescence to identify the hypothalamic cells targeted by AHA. AHA were detected at high titer in 12 patients in group 1 and in eight patients in group 2. They immunostained arginine vasopressin (AVP)-secreting cells in nine of 12 in group 1 and in four of eight in group 2. All AVP cell antibody-positive patients presented with subclinical/clinical CDI; in contrast, four patients with GH/ACTH deficiency but with APA staining only GH-secreting cells showed AHA targeting CRH- secreting cells. The occurrence of CDI in patients with lymphocytic hypophysitis seems due to an autoimmune hypothalamic involvement rather than an expansion of the pituitary inflammatory process. To search for AVP antibody in these patients may help to identify those of them prone to develop an autoimmune CDI. The detection of AHA targeting CRH-secreting cells in some patients with GH/ACTH deficiency but with APA targeting only GH-secreting cells indicates that an autoimmune aggression to hypothalamus is jointly responsible for their hypopituitarism.
Ren, Hongxia; Lu, Taylor Y.; McGraw, Timothy E.; Accili, Domenico
The central nervous system (CNS) uses glucose independent of insulin. Nonetheless, insulin receptors and insulin-responsive glucose transporters (Glut4) often colocalize in neurons (Glut4 neurons) in anatomically and functionally distinct areas of the CNS. The apparent heterogeneity of Glut4 neurons has thus far thwarted attempts to understand their function. To answer this question, we used Cre-dependent, diphtheria toxin?mediated cell ablation to selectively remove basal hypothalamic Glut4 ...
Zhang, Juan; Zhou, Yunting; Chen, Cheng; Yu, Feiyuan; Wang, Yun; Gu, Jiang; Ma, Lian; Ho, Guyu
Hypothalamic glucose-sensing neurons regulate the expression of genes encoding feeding-related neuropetides POMC, AgRP, and NPY - the key components governing metabolic homeostasis. AMP-activated protein kinase (AMPK) is postulated to be the molecular mediator relaying glucose signals to regulate the expression of these neuropeptides. Whether other signaling mediator(s) plays a role is not clear. In this study, we investigated the role of ERK1/2 using primary hypothalamic neurons as the model system. The primary neurons were differentiated from hypothalamic progenitor cells. The differentiated neurons possessed the characteristic neuronal cell morphology and expressed neuronal post-mitotic markers as well as leptin-regulated orexigenic POMC and anorexigenic AgRP/NPY genes. Treatment of cells with glucose dose-dependently increased POMC and decreased AgRP/NPY expression with a concurrent suppression of AMPK phosphorylation. In addition, glucose treatment dose-dependently increased the ERK1/2 phosphorylation. Blockade of ERK1/2 activity with its specific inhibitor PD98059 partially (approximately 50%) abolished glucose-induced POMC expression, but had little effect on AgRP/NPY expression. Conversely, blockade of AMPK activity with its specific inhibitor produced a partial (approximately 50%) reversion of low-glucose-suppressed POMC expression, but almost completely blunted the low-glucose-induced AgRP/NPY expression. The results indicate that ERK1/2 mediated POMC but not AgRP/NPY expression. Confirming the in vitro findings, i.c.v. administration of PD98059 in rats similarly attenuated glucose-induced POMC expression in the hypothalamus, but again had little effect on AgRP/NPY expression. The results are indicative of a novel role of ERK1/2 in glucose-regulated POMC expression and offer new mechanistic insights into hypothalamic glucose sensing. © 2015 Society for Endocrinology.
Genazzani, Alessandro D; Despini, Giulia; Czyzyk, Adam; Podfigurna, Agnieszka; Simoncini, Tommaso; Meczekalski, Blazej
Functional hypothalamic amenorrhea (FHA) is a relatively frequent disease due to the combination of metabolic, physical, or psychological stressors. It is characterized by the low endogenous GnRH-induced gonadotropin secretion, thus triggering the ovarian blockade and a hypoestrogenic condition. Up to now various therapeutical strategies have been proposed, both using hormonal treatment as well as neuroactive compounds. Since carnitine, namely l-acetyl-carnitine (LAC), has been demonstrated to be effective in the modulation of the central hypothalamic control of GnRH secretion, we aimed to evaluate whether a combined integrative treatment for 12 weeks of LAC (250 mg/die) and l-carnitine (500 mg/die) was effective in improving the endocrine and metabolic pathways in a group of patients (n = 27) with FHA. After the treatment, interval mean LH plasma levels increased while those of cortisol and amylase decreased significantly. When patients were subdivided according to baseline LH levels, only hypo-LH patients showed the significant increase of LH plasma levels and the significant decrease of both cortisol and amylase plasma levels. The increased 17OHP/cortisol ratio, as index of the adrenal activity, demonstrated the reduced stress-induced adrenal activity. In conclusion, our data sustain the hypothesis that the integrative administration of LAC plus l-carnitine reduced both the metabolic and the neuroendocrine impairment of patients with FHA.
Jacola, Lisa M; Conklin, Heather M; Scoggins, Matthew A; Ashford, Jason M; Merchant, Thomas E; Mandrell, Belinda N; Ogg, Robert J; Curtis, Elizabeth; Wise, Merrill S; Indelicato, Daniel J; Crabtree, Valerie M
Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity. © The Author 2016. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: email@example.com.
Hermann L. Müller
Full Text Available Childhood craniopharyngiomas are rare embryogenic malformations of the sellar region, presumably derived from Rathke cleft epithelium. The overall survival rates after neurosurgical intervention and/or irradiation are high (92%. However, the quality of survival is frequently impaired due to endocrine deficiencies, sleep disturbances, daytime sleepiness, and severe obesity caused by hypothalamic lesions. Based on self-assessment using nutritional diaries, caloric intake was similar in patients and BMI-matched controls. Analyses of physical activity by accelerometric measurements showed a markedly lower level of physical activity. Significant daytime sleepiness and disturbances of circadian rhythms have been demonstrated in obese childhood craniopharyngioma patients. Daytime sleepiness and obesity in these patients were both correlated with low nocturnal and early morning melatonin levels. Polysomnographic studies in patients with severe daytime sleepiness revealed sleeping patterns typical for secondary narcolepsy. Reports on a beneficial effect of treatment with central stimulating agents supported the hypothesis that secondary narcolepsy should be considered as a rare cause for severe daytime sleepiness in patients with childhood craniopharyngioma.
Hawks, Brian W.; Li, Wei; Garlow, Steven J.
Cocaine-Amphetamine Regulated Transcript (CART) peptides are implicated in a wide range of behaviors including in the reinforcing properties of psychostimulants, feeding and energy balance and stress and anxiety responses. We conducted a complex trait analysis to examine natural variation in the regulation of CART transcript abundance (CARTta) in the hypothalamus. CART transcript abundance was measured in total hypothalamic RNA from 26 BxD recombinant inbred (RI) mouse strains and in the C57BL/6 (B6) and DBA/2J (D2) progenitor strains. The strain distribution pattern for CARTta was continuous across the RI panel, which is consistent with this being a quantitative trait. Marker regression and interval mapping revealed significant quantitative trait loci (QTL) on mouse chromosome 4 (around 58.2cM) and chromosome 11 (between 20–36cM) that influence CARTta and account for 31% of the between strain variance in this phenotype. There are numerous candidate genes and QTL in these chromosomal regions that may indicate shared genetic regulation between CART expression and other neurobiological processes referable to known actions of this neuropeptide. PMID:18199428
Quilter Claire R
Full Text Available Abstract Background The serotonin pathways have been implicated in behavioural phenotypes in a number of species, including human, rat, mouse, dog and chicken. Components of the pathways, including the receptors, are major targets for drugs used to treat a variety of physiological and psychiatric conditions in humans. In our previous studies we have identified genetic loci potentially contributing to maternal infanticide in pigs, which includes a locus on the porcine X chromosome long arm. The serotonin receptor HTR2C maps to this region, and is therefore an attractive candidate for further study based on its function and its position in the genome. Results In this paper we describe the structure of the major transcripts produced from the porcine HTR2C locus using cDNA prepared from porcine hypothalamic and pooled total brain samples. We have confirmed conservation of sites altered by RNA editing in other mammalian species, and identified polymorphisms in the gene sequence. Finally, we have analysed expression and editing of HTR2C in hypothalamus samples from infanticidal and control animals. Conclusions The results confirm that although the expression of the long transcriptional variant of HTR2C is raised in infanticidal animals, the overall patterns of editing in the hypothalamus are similar between the two states. Sequences associated with the cDNA and genomic structures of HTR2C reported in this paper are deposited in GenBank under accession numbers FR720593, FR720594 and FR744452.
Trivin, Christine; Busiah, Kanetee; Mahlaoui, Nizar; Recasens, Christophe; Souberbielle, Jean-Claude; Zerah, Michel; Sainte-Rose, Christian; Brauner, Raja
Background Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change. Methods 27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement), grade 1 (n = 8, compression without involvement), or grade 2 (n = 12, severe involvement). Results Despite having similar body mass indexes (BMI), the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement. PMID:19341477
Li, Qingjie; Yu, Quan; Lin, Li; Zhang, Heng; Peng, Miao; Jing, Chunxia; Xu, Geyang
Peroxisome proliferator-activated receptor-γ (PPARγ) regulates fatty acid storage, glucose metabolism, and food intake. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. However, the effects of PPARγ on ghrelin production are still unclear. In the present study, the effects of PPARγ on ghrelin production were examined in lean- or high-fat diet-induced obese (DIO) C57BL/6J mice and mHypoE-42 cells, a hypothalamic cell line. 3rd intracerebroventricular injection of adenoviral-directed overexpression of PPARγ (Ad-PPARγ) reduced hypothalamic and plasma ghrelin, food intake in both lean C57BL/6J mice and diet-induced obese mice. These changes were associated with a significant increase in mechanistic target of rapamycin complex 1 (mTORC1) activity. Overexpression of PPARγ enhanced mTORC1 signaling and suppressed ghrelin production in cultured mHypoE-42 cells. Our results suggest that hypothalamic PPARγ plays a vital role in ghrelin production and food intake in mice. Copyright © 2018 Elsevier Ltd. All rights reserved.
Gali Ramamoorthy, Thanuja; Begum, Ghazala; Harno, Erika; White, Anne
The prevalence of obesity in adults and children has increased globally at an alarming rate. Mounting evidence from both epidemiological studies and animal models indicates that adult obesity and associated metabolic disorders can be programmed by intrauterine and early postnatal environment- a phenomenon known as “fetal programming of adult disease.” Data from nutritional intervention studies in animals including maternal under- and over-nutrition support the developmental origins of obesity and metabolic syndrome. The hypothalamic neuronal circuits located in the arcuate nucleus controlling appetite and energy expenditure are set early in life and are perturbed by maternal nutritional insults. In this review, we focus on the effects of maternal nutrition in programming permanent changes in these hypothalamic circuits, with experimental evidence from animal models of maternal under- and over-nutrition. We discuss the epigenetic modifications which regulate hypothalamic gene expression as potential molecular mechanisms linking maternal diet during pregnancy to the offspring's risk of obesity at a later age. Understanding these mechanisms in key metabolic genes may provide insights into the development of preventative intervention strategies. PMID:25954145
Shaikh, M Guftar; Grundy, Richard G; Kirk, Jeremy M W
Obesity following hypothalamic damage is often severe and resistant to lifestyle changes. Disruption of hypothalamic feedback mechanisms that maintain energy homeostasis may be responsible for this intractable obesity. Adipocytokines including insulin and leptin are also known to be important regulators of appetite and weight. To investigate the role of insulin, leptin, adiponectin and resistin in the aetiology of hypothalamic obesity (HO). This was a cross-sectional study of three groups of children, those with HO, congenital hypopituitarism (CH) and simple obesity (SO). A total of 69 children (HO=28, CH=18, SO=23) had leptin, resistin, adiponectin and insulin measured. Although fasting hyperinsulinaemia and insulin resistance were demonstrated, no differences in insulin or insulin resistance were seen between the groups. The HO group, however, had higher levels of leptin, adiponectin and resistin, which persisted even after adjusting for fat mass, compared with the other groups (Pfasting hyperinsulinaemia or insulin resistance were seen between the groups; however, leptin levels are elevated, even after adjusting for fat mass, suggesting that an element of leptin resistance is associated with HO. This is consistent with the inability of leptin to act on the hypothalamus, either due to transport across the blood-brain barrier or dysfunctional receptors. The lack of response to leptin may be more important in the development of obesity in these individuals, and the fasting hyperinsulinaemia is a result of the increased adipose tissue rather than the cause of the weight gain.
Pillot, Bruno; Duraffourd, Céline; Bégeot, Martine; Joly, Aurélie; Luquet, Serge; Houberdon, Isabelle; Naville, Danielle; Vigier, Michèle; Gautier-Stein, Amandine; Magnan, Christophe; Mithieux, Gilles
The hypothalamic melanocortin system—the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)—is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment. PMID:21544212
Full Text Available The hypothalamic melanocortin system--the melanocortin receptor of type 4 (MC4R and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia, and agouti-related protein (AgRP, antagonist, inducing hyperphagia--is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment.
Thanuja eGali Ramamoorthy
Full Text Available The prevalence of obesity in adults and children has increased globally at an alarming rate. Mounting evidence from both epidemiological studies and animal models indicates that adult obesity and associated metabolic disorders can be programmed by intrauterine and early postnatal environment- a phenomenon known as fetal programming of adult disease. Data from nutritional intervention studies in animals including maternal under- and over-nutrition support the developmental origins of obesity and metabolic syndrome. The hypothalamic neuronal circuits located in the arcuate nucleus controlling appetite and energy expenditure are set early in life and are perturbed by maternal nutritional insults. In this review, we focus on the effects of maternal nutrition in programming permanent changes in these hypothalamic circuits, with experimental evidence from animal models of maternal under- and over-nutrition. We discuss the epigenetic modifications which regulate hypothalamic gene expression as potential molecular mechanisms linking maternal diet during pregnancy to the offspring’s risk of obesity at a later age. Understanding these mechanisms in key metabolic genes may provide insights into the development of preventative intervention strategies.
Morselli, E; Frank, A P; Palmer, B F; Rodriguez-Navas, C; Criollo, A; Clegg, D J
In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and estrogen receptor alpha (ERα), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ERα total-body knockout mice when exposed to a HFD, thus confirming the key role of ERα in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ERα is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function.
Meczekalski, Blazej; Czyzyk, Adam; Podfigurna-Stopa, Agnieszka; Rydzewski, Bogdan; Sroczynski, Jakub; Lipinska, Małgorzata; Sokalski, Jerzy; Krawczynski, Maciej; Jamsheer, Aleksander; Katulski, Krzysztof; Genazzani, Alessandro
A case report of a patient diagnosed with Camurati-Engelmann Disease (CED) in association with the functional hypothalamic amenorrhea disturbances. CED is a very rare genetically determined disorder classified as a type of bone dysplasia. Case report. Department of Gynecological Endocrinology, 3rd grade Medical University Hospital. Twenty-one years old female patient with CED admitted to the hospital because of primary amenorrhea. Her history revealed skeletal deformities and hearing impairment. Clinical examination, ultrasound, laboratory evaluations (including serum gonadotropins (FSH, LH) at basal state and after stimulation with gonadotropin-releasing hormone, serum basal estradiol) radiological studies (X-ray of the head, the lumbar spine and lower extremities; a computed tomography of the head), G-banding karyotype, polymerase chain reaction and DNA sequencing. Hormonal serum evaluations were made using an enzyme-linked immunosorbent assay. The exon 4 of the transforming growth factor beta 1 gene was amplified by a polymerase chain reaction and the product was directly sequenced. The hormonal analysis was characteristic for the hypogonadotropic hypogonadism. Radiological and molecular analyses confirmed CED diagnosis. The hypothalamic amenorrhea in a patient with CED may be explained as a consequence of fat hypotrophy and very low body mass index. Therefore, impairment within hypothalamic-pituitary axis in patients with CED should be treated with special attention.
Full Text Available A major question in systems neuroscience is how a single population of neurons can interact with the rest of the brain to orchestrate complex behavioral states. The hypothalamus contains many such discrete neuronal populations that individually regulate arousal, feeding, and drinking. For example, hypothalamic neurons that express hypocretin (Hcrt neuropeptides can sense homeostatic and metabolic factors affecting wakefulness and orchestrate organismal arousal. Neurons that express agouti-related protein (AgRP can sense the metabolic needs of the body and orchestrate a state of hunger. The organum vasculosum of the lamina terminalis (OVLT can detect the hypertonicity of blood and orchestrate a state of thirst. Each hypothalamic population is sufficient to generate complicated behavioral states through the combined efforts of distinct efferent projections. The principal challenge to understanding these brain systems is therefore to determine the individual roles of each downstream projection for each behavioral state. In recent years, the development and application of temporally precise, genetically encoded tools have greatly improved our understanding of the structure and function of these neural systems. This review will survey recent advances in our understanding of how these individual hypothalamic populations can orchestrate complicated behavioral states due to the combined efforts of individual downstream projections.
Maegan L. Askew
Full Text Available This study used immunohistochemical methods to investigate the possibility that hypothalamic neurons that contain 11-β-hydroxysteroid dehydrogenase type 2 (HSD2 are involved in the control of feeding by rats via neuroanatomical associations with the α subtype of estrogen receptor (ERα, catecholamines, and/or oxytocin. An aggregate of HSD2-containing neurons is located laterally in the hypothalamus, and the numbers of these neurons were greatly increased by estradiol treatment in ovariectomized rats compared to numbers in male rats and in ovariectomized rats that were not given estradiol. However, HSD2-containing neurons were anatomically segregated from ERα-containing neurons in the Ventromedial Hypothalamus and the Arcuate Nucleus. There was an absence of oxytocin-immunolabeled fibers in the area of HSD2-labeled neurons. Taken together, these findings provide no support for direct associations between hypothalamic HSD2 and ERα or oxytocin neurons in the control of feeding. In contrast, there was catecholamine-fiber labeling in the area of HSD2-labeled neurons, and these fibers occasionally were in close apposition to HSD2-labeled neurons. Therefore, we cannot rule out interactions between HSD2 and catecholamines in the control of feeding; however, given the relative sparseness of the appositions, any such interaction would appear to be modest. Thus, these studies do not conclusively identify a neuroanatomical substrate by which HSD2-containing neurons in the hypothalamus may alter feeding, and leave the functional role of hypothalamic HSD2-containing neurons subject to further investigation.
Liviu C. Andrei
Full Text Available Sustained development is a concept associating other concepts, in its turn, in the EU practice, e.g. regionalism, regionalizing and afferent policies, here including structural policies. This below text, dedicated to integration concepts, will limit on the other hand to regionalizing, otherwise an aspect typical to Europe and to the EU. On the other hand, two aspects come up to strengthen this field of ideas, i.e. the region (al-regionalism-(regional development triplet has either its own history or precise individual outline of terms.
Ciriello, J; Caverson, M M; McMurray, J C; Bruckschwaiger, E B
Experiments were done to investigate whether hypothalamic hypocretin-1 (hcrt-1; orexin-A) neurons that sent axonal projections to cardiovascular responsive sites in the nucleus of the solitary tract (NTS) co-expressed leucine-enkephalin (L-Enk), and to determine the effects of co-administration of hcrt-1 and D-Ala2,D-Leu5-Enkephalin (DADL) into NTS on mean arterial pressure (MAP) and heart rate. In the first series, in the Wistar rat the retrograde tract-tracer fluorogold (FG) was microinjected (50nl) into caudal NTS sites at which L-glutamate (0.25 M; 10 nl) elicited decreases in MAP and where fibers hcrt-1 immunoreactive fibers were observed that also contained L-Enk immunoreactivity. Of the number of hypothalamic hcrt-1 immunoreactive neurons identified ipsilateral to the NTS injection site (1207 ± 78), 32.3 ± 2.3% co-expressed L-Enk immunoreactivity and of these, 2.6 ± 1.1% were retrogradely labeled with FG. Hcrt-1/L-Enk neurons projecting to NTS were found mainly within the perifornical region. In the second series, the region of caudal NTS found to contain axons that co-expressed hcrt-1 and L-Enk immunoreactivity was microinjected with a combination of hcrt-1 and DADL in α-chloralose anesthetized Wistar rats. Microinjection of DADL into NTS elicited depressor and bradycardia responses similar to those elicited by microinjection of hcrt-1. An hcrt-1 injection immediately after the DADL injection elicited an almost twofold increase in the magnitude of the depressor and bradycardia responses compared to those elicited by hcrt-1 alone. Prior injections of the non-specific opioid receptor antagonist naloxone or the specific opioid δ-receptor antagonist ICI 154,129 significantly attenuated the cardiovascular responses to the combined hcrt-1-DADL injections. Taken together, these data suggest that activation of hypothalamic-opioidergic neuronal systems contribute to the NTS hcrt-1 induced cardiovascular responses, and that this descending hypothalamo
Matsuzaki, Toshiya; Iwasa, Takeshi; Munkhzaya, Munkhsaikhan; Tungalagsuvd, Altankhuu; Kawami, Takako; Murakami, Masahiro; Yamasaki, Mikio; Yamamoto, Yuri; Kato, Takeshi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru
Oxytocin (OT) affects the central nervous system and is involved in a variety of social and non-social behaviors. Recently, the role played by OT in energy metabolism and its organizational effects on estrogen receptor alpha (ER-α) during the neonatal period have gained attention. In this study, the developmental changes in the hypothalamic mRNA levels of OT, the OT receptor (OTR), and ER-α were evaluated in male and female rats. In addition, the fasting-induced changes in the hypothalamic mRNA levels of OT and the OTR were evaluated. Hypothalamic explants were taken from postnatal day (PND) 10, 20, and 30 rats, and the mRNA level of each molecule was measured. Hypothalamic OT mRNA expression increased throughout the developmental period in both sexes. The rats' hypothalamic OTR mRNA levels were highest on PND 10 and decreased throughout the developmental period. In the male rats, the hypothalamic mRNA levels of ER-α were higher on PND 30 than on PND 10. On the other hand, no significant differences in hypothalamic ER-α mRNA expression were detected among the examined time points in the female rats, although hypothalamic ER-α mRNA expression tended to be higher on PND 30 than on PND 10. Significant positive correlations were detected between hypothalamic OT and ER-α mRNA expression in both the male and female rats. Hypothalamic OT mRNA expression was not affected by fasting at any of the examined time points in either sex. These results indicate that hypothalamic OT expression is not sensitive to fasting during the developmental period. In addition, as a positive correlation was detected between hypothalamic OT and ER-α mRNA expression, these two molecules might interact with each other to induce appropriate neuronal development. Copyright © 2015 Elsevier Ltd. All rights reserved.
Borg, Melissa L; Omran, Simin Fallah; Weir, Jacquelyn; Meikle, Peter J; Watt, Matthew J
Obesity is characterised by increased storage of fatty acids in an expanded adipose tissue mass and in peripheral tissues such as the skeletal muscle and liver, where it is associated with the development of insulin resistance. Insulin resistance also develops in the central nervous system with high-fat feeding. The capacity for hypothalamic cells to accumulate/store lipids, and the effects of obesity remain undefined. The aims of this study were (1) to examine hypothalamic lipid content in mice with increased dietary fat intake and in obese ob/ob mice fed a low-fat diet, and (2) to determine whether endurance exercise training could reduce hypothalamic lipid accumulation in high-fat fed mice. Male C57BL/6 mice were fed a low- (LFD) or high-fat diet (HFD) for 12 weeks; ob/ob mice were maintained on a chow diet. HFD-exercise (HFD-ex) mice underwent 12 weeks of high-fat feeding with 6 weeks of treadmill exercise training (increasing from 30 to 70 min day(-1)). Hypothalamic lipids were assessed by unbiased mass spectrometry. The HFD increased body mass and hepatic lipid accumulation, and induced glucose intolerance, while the HFD-ex mice had reduced body weight and improved glucose tolerance. A total of 335 lipid molecular species were identified and quantified. Lipids known to induce insulin resistance, including ceramide (22%↑), diacylglycerol (25%↑), lysophosphatidylcholine (17%↑), cholesterol esters (60%↑) and dihexosylceramide (33%↑), were increased in the hypothalamus of HFD vs. LFD mice. Hypothalamic lipids were unaltered with exercise training and in the ob/ob mice, suggesting that obesity per se does not alter hypothalamic lipids. Overall, hypothalamic lipid accumulation is regulated by dietary lipid content and is refractory to change with endurance exercise training.
Blacktop, Jordan M; Todd, Ryan P; Sorg, Barbara A
Addiction involves drug-induced neuroplasticity in the circuitry of motivated behavior, which includes the medial forebrain bundle and the lateral hypothalamic area. Emerging at the forefront of neuroplasticity regulation are specialized extracellular matrix (ECM) structures that form perineuronal nets (PNNs) around certain neurons, mainly parvalbumin positive (PV + ), fast-spiking interneurons (FSINs), making them a promising target for the regulation of drug-induced neuroplasticity. Despite the emerging significance of PNNs in drug-induced neuroplasticity and the well-established role of the lateral hypothalamic area (LHA) in reward, reinforcement, and motivation, very little is known about how PNN-expressing neurons control drug-seeking behavior. We found that a discrete region of the anterior dorsal LHA (LHAad) exhibited robust PNN and dense ECM expression. Approximately 87% of parvalbumin positive (PV + ) neurons co-expressed the PNN marker Wisteria floribunda agglutinin (WFA), while 62% of WFA positive (WFA + ) neurons co-expressed PV in the LHAad of drug naïve rats. Removal of PNNs within this brain region via chrondroitinase ABC (Ch-ABC) administration abolished acquisition of cocaine-induced CPP and significantly attenuated the acquisition of cocaine self-administration (SA). Removal of LHAad PNNs did not affect locomotor activity, sucrose intake, sucrose-induced CPP, or acquisition of sucrose SA in separate groups of cocaine naïve animals. These data suggest that PNN-dependent neuroplasticity within the LHAad is critical for the acquisition of both cocaine-induced CPP and SA but is not general to all rewards, and that PNN degradation may have utility for the management of drug-associated behavioral plasticity and memory in cocaine addicts. Published by Elsevier Ltd.
Gotthardt, Juliet D; Verpeut, Jessica L; Yeomans, Bryn L; Yang, Jennifer A; Yasrebi, Ali; Roepke, Troy A; Bello, Nicholas T
Clinical studies indicate alternate-day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into four groups and either maintained on ad libitum HFD, received alternate-day access to HFD (IMF-HFD), and switched to ad libitum low-fat diet (LFD; 10% fat) or received IMF of LFD (IMF-LFD). After 4 weeks, IMF-HFD (∼13%) and IMF-LFD (∼18%) had significantly lower body weights than the HFD. Body fat was also lower (∼40%-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (∼12%-13%) compared with the HFD and IMF-HFD groups. Oral glucose tolerance area under the curve was lower in the IMF-HFD (∼50%), whereas the insulin tolerance area under the curve was reduced in all diet interventions (∼22%-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (∼55%-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with the ad libitum-fed groups, whereas NE content was higher (∼19%-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (∼65%-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and neuropeptide Y, suggesting the counterregulatory processes of short-term weight loss are associated with an IMF dietary strategy.
Timper, Katharina; Brüning, Jens C.
ABSTRACT The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. PMID:28592656
Timper, Katharina; Brüning, Jens C
The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. © 2017. Published by The Company of Biologists Ltd.
Full Text Available The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed.
Kurup, Ravi Kumar; Kurup, Parameswara Achutha
The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. It was considered pertinent to assess the pathway in inflammatory bowel disease (ulcerative colitis and regional ileitis). Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. All the patients with inflammatory bowel disease were right-handed/left hemispheric dominant by the dichotic listening test. The following parameters were measured in patients with inflammatory bowel disease and in individuals with differing hemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free-radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition and RBC membrane Na+-K+ ATPase activity. Statistical analysis was done by ANOVA. In patients with inflammatory bowel disease there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Inflammatory bowel disease is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to immune activation, defective glycoprotein bowel antigen presentation, and autoimmunity and a schizophreniform psychosis important in its pathogenesis. The biochemical patterns obtained in inflammatory bowel disease is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with peptic ulcer disease were right
Tsunekawa, Taku; Banno, Ryoichi; Mizoguchi, Akira; Sugiyama, Mariko; Tominaga, Takashi; Onoue, Takeshi; Hagiwara, Daisuke; Ito, Yoshihiro; Iwama, Shintaro; Goto, Motomitsu; Suga, Hidetaka; Sugimura, Yoshihisa; Arima, Hiroshi
Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT). In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Full Text Available Hypothalamic obesity is often complicated in patients with craniopharyngioma due to hypothalamic damage by the tumor itself, treatment modalities, and associated multiple pituitary hormone deficiency. Hypothalamic obesity causes secondary diseases such as nonalcoholic fatty liver disease (NAFLD and diabetes mellitus (DM. We report a 19-year-old female who was diagnosed with craniopharyngioma, developed hypothalamic obesity after tumor resection, and progressed to hepatopulmonary syndrome. She manifested NAFLD 1 year after tumor resection. Two years later, the craniopharyngioma recurred, and she underwent a second resection. Three years after her second operation, she was diagnosed with type 2 DM, after which she did not visit the outpatient clinic for 2 years and then suddenly reappeared with a weight loss of 25.8 kg that had occurred over 21 months. One month later, she presented to the Emergency Department with dyspnea. Laboratory findings revealed liver dysfunction and hypoxia with increased alveolar artery oxygen gradient. Liver biopsy showed portal hypertension and micronodular cirrhosis. Echocardiography and a lung perfusion scan demonstrated a right to left shunt. She was finally diagnosed with hepatopulmonary syndrome and is currently awaiting a donor for liver transplantation. Patients surviving craniopharyngioma need to be followed up carefully to detect signs of hypothalamic obesity and monitored for the development of other comorbidities such as DM, NAFLD, and hepatopulmonary syndrome.
Jung, Dai; Seo, Go Hun; Kim, Yoon-Myung; Choi, Jin-Ho; Yoo, Han-Wook
Hypothalamic obesity is often complicated in patients with craniopharyngioma due to hypothalamic damage by the tumor itself, treatment modalities, and associated multiple pituitary hormone deficiency. Hypothalamic obesity causes secondary diseases such as nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM). We report a 19-year-old female who was diagnosed with craniopharyngioma, developed hypothalamic obesity after tumor resection, and progressed to hepatopulmonary syndrome. She manifested NAFLD 1 year after tumor resection. Two years later, the craniopharyngioma recurred, and she underwent a second resection. Three years after her second operation, she was diagnosed with type 2 DM, after which she did not visit the outpatient clinic for 2 years and then suddenly reappeared with a weight loss of 25.8 kg that had occurred over 21 months. One month later, she presented to the Emergency Department with dyspnea. Laboratory findings revealed liver dysfunction and hypoxia with increased alveolar artery oxygen gradient. Liver biopsy showed portal hypertension and micronodular cirrhosis. Echocardiography and a lung perfusion scan demonstrated a right to left shunt. She was finally diagnosed with hepatopulmonary syndrome and is currently awaiting a donor for liver transplantation. Patients surviving craniopharyngioma need to be followed up carefully to detect signs of hypothalamic obesity and monitored for the development of other comorbidities such as DM, NAFLD, and hepatopulmonary syndrome.
Full Text Available Protein tyrosine phosphatase 1B (PTP1B regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD, remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3 was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT. In hypothalamic organotypic cultures, incubation with TNFα led to increased p-STAT3, accompanied by decreased Tnf and increased Il10 mRNA expression, in KO compared to WT. Incubation with p-STAT3 inhibitors or microglial depletion eliminated the differences in inflammation between genotypes. These data indicate an important role of JAK2-STAT3 signaling negatively regulated by PTP1B in microglia, which attenuates hypothalamic inflammation under HFD conditions.
Full Text Available Abstract Background The structural arrangement of the γ-aminobutyric acid type A receptor (GABAAR is known to be crucial for the maintenance of cerebral-dependent homeostatic mechanisms during the promotion of highly adaptive neurophysiological events of the permissive hibernating rodent, i.e the Syrian golden hamster. In this study, in vitro quantitative autoradiography and in situ hybridization were assessed in major hypothalamic nuclei. Reverse Transcription Reaction-Polymerase chain reaction (RT-PCR tests were performed for specific GABAAR receptor subunit gene primers synthases of non-hibernating (NHIB and hibernating (HIB hamsters. Attempts were made to identify the type of αβγ subunit combinations operating during the switching ON/OFF of neuronal activities in some hypothalamic nuclei of hibernators. Results Both autoradiography and molecular analysis supplied distinct expression patterns of all α subunits considered as shown by a strong (p 1 ratio (over total α subunits considered in the present study in the medial preoptic area (MPOA and arcuate nucleus (Arc of NHIBs with respect to HIBs. At the same time α2 subunit levels proved to be typical of periventricular nucleus (Pe and Arc of HIB, while strong α4 expression levels were detected during awakening state in the key circadian hypothalamic station, i.e. the suprachiasmatic nucleus (Sch; 60%. Regarding the other two subunits (β and γ, elevated β3 and γ3 mRNAs levels mostly characterized MPOA of HIBs, while prevalently elevated expression concentrations of the same subunits were also typical of Sch, even though this time during the awakening state. In the case of Arc, notably elevated levels were obtained for β3 and γ2 during hibernating conditions. Conclusion We conclude that different αβγ subunits are operating as major elements either at the onset of torpor or during induction of the arousal state in the Syrian golden hamster. The identification of a brain regional
Anne K. McGavigan
Full Text Available Bariatric surgery, such as vertical sleeve gastrectomy (VSG, causes remarkable improvements in cardiometabolic health, including hypertension remission. However, the mechanisms responsible remain undefined and poorly studied. Therefore, we developed and validated the first murine model of VSG that recapitulates the blood pressure-lowering effect of VSG using gold-standard radiotelemetry technology. We used this model to investigate several potential mechanisms, including body mass, brain endoplasmic reticulum (ER stress signaling and brain inflammatory signaling, which are all critical contributors to the pathogenesis of obesity-associated hypertension. Mice fed on a high-fat diet underwent sham or VSG surgery and radiotelemeter implantation. Sham mice were fed ad libitum or were food restricted to match their body mass to VSG-operated mice to determine the role of body mass in the ability of VSG to lower blood pressure. Blood pressure was then measured in freely moving unstressed mice by radiotelemetry. VSG decreased energy intake, body mass and fat mass. Mean arterial blood pressure (MAP was reduced in VSG-operated mice compared with both sham-operated groups. VSG-induced reductions in MAP were accompanied by a body mass-independent decrease in hypothalamic ER stress, hypothalamic inflammation and sympathetic nervous system tone. Assessment of gut microbial populations revealed VSG-induced increases in the relative abundance of Gammaproteobacteria and Enterococcus, and decreases in Adlercreutzia. These results suggest that VSG reduces blood pressure, but this is only partly due to the reduction in body weight. VSG-induced reductions in blood pressure may be driven by a decrease in hypothalamic ER stress and inflammatory signaling, and shifts in gut microbial populations.
Caraty, A.; Reviers, M.-M. de; Pelletier, J.; Dubois, M.P.
A highly sensitive and specific radioimmunoassay for LRF was applied to the measurement of endogenous LRF in various hypothalamic extracts. Specific antiserum was obtained by injecting LRF conjugated to human serum albumin with glutaraldehyde. Thyrotropin-releasing hormone, lysine vasopressin, oxytocin, noradrenaline, LH, FSH and cortical extracts did not appear to affect the assay, and the maximum cross-reaction observed with the LRF analogs tested was 8.5% with LRF 2-10. The best detection limit (0.4 pg/tube) was usually obtained when the labelled LRF had been purified by polyacrylamide gel electrophoresis. Within and between-assay coefficients of variation were 8.0 and 12.6% respectively (from B/Bo=20 to 80%). Synthetic LRF administered to rams by intravenous injection was readily detectable in the peripheral plasma. However, the direct measurement of plasma endogenous LRF may give misleading results due to non-specific interference by plasma factors. No endogenous LRF could be detected in plasma methanol or acetone extracts obtained from rats and rams in various physiological conditions. The inhibition curves parallel to the synthetic LRF curve were obtained by diluting the crude hypothalamic extracts of rams and rats, and a good correlation (r=0,997) with the Ramirez-McCann bioassay resulted, indicating that using radioimmunoassay to determine hypothalamic LRF content may be fruitful in studying hypothalamo-pituitary gonad interactions. The LRF content of rat and ovine hypothalami ranged from 2-8 to 20-80 ng of LRF, respectively
Taksande, BG; Kotagale, NR; Nakhate, KT; Mali, PD; Kokare, DM; Hirani, K; Subhedar, NK; Chopde, CT; Ugale, RR
BACKGROUND AND PURPOSE Agmatine, a multifaceted neurotransmitter, is abundantly expressed in the hypothalamic paraventricular nucleus (PVN). Our aim was to assess (i) the effect of agmatine on feeding behaviour and (ii) its association, if any, with neuropeptide Y (NPY). EXPERIMENTAL APPROACH Satiated rats fitted with intra-PVN cannulae were administered agmatine, alone or jointly with (i) α2-adrenoceptor agonist, clonidine, or antagonist, yohimbine; (ii) NPY, NPY Y1 receptor agonist, [Leu31, Pro34]-NPY, or antagonist, BIBP3226; or (iii) yohimbine and NPY. Cumulative food intake was monitored at different post-injection time points. Furthermore, the expression of hypothalamic NPY following i.p. treatment with agmatine, alone or in combination with yohimbine (i.p.), was evaluated by immunocytochemistry. KEY RESULTS Agmatine robustly increased feeding in a dose-dependent manner. While pretreatment with clonidine augmented, yohimbine attenuated the orexigenic response to agmatine. Similarly, NPY and [Leu31, Pro34]-NPY potentiated the agmatine-induced hyperphagia, whereas BIBP3226 inhibited it. Moreover, yohimbine attenuated the synergistic orexigenic effect induced by the combination of NPY and agmatine. Agmatine increased NPY immunoreactivity in the PVN fibres and in the cells of the hypothalamic arcuate nucleus (ARC) and this effect was prevented by pretreatment with yohimbine. NPY immunoreactivity in the fibres of the ARC, dorsomedial, ventromedial and lateral nuclei of the hypothalamus was not affected by any of the above treatments. CONCLUSIONS AND IMPLICATIONS The orexigenic effect of agmatine is coupled to increased NPY activity mediated by stimulation of α2-adrenoceptors within the PVN. This signifies the importance of agmatine or α2-adrenoceptor modulators in the development of novel therapeutic agents to treat feeding-related disorders. PMID:21564088
Maillard, Julien; Park, Soyoung; Croizier, Sophie; Vanacker, Charlotte; Cook, Joshua H; Prevot, Vincent; Tauber, Maithe; Bouret, Sebastien G
Prader-Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavioral outcomes of PWS, an understanding of its effects on the development of hypothalamic circuits remains elusive. Here, we show that mice lacking Magel2, one of the genes responsible for the etiology of PWS, display an abnormal development of ARH axonal projections. Notably, the density of anorexigenic α-melanocyte-stimulating hormone axons was reduced in adult Magel2-null mice, while the density of orexigenic agouti-related peptide fibers in the mutant mice appeared identical to that in control mice. On the basis of previous findings showing a pivotal role for metabolic hormones in hypothalamic development, we also measured leptin and ghrelin levels in Magel2-null and control neonates and found that mutant mice have normal leptin and ghrelin levels. In vitro experiments show that Magel2 directly promotes axon growth. Together, these findings suggest that a loss of Magel2 leads to the disruption of hypothalamic feeding circuits, an effect that appears to be independent of the neurodevelopmental effects of leptin and ghrelin and likely involves a direct neurotrophic effect of Magel2. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Báez-Ruiz, Adrián; Luna-Moreno, Dalia; Carmona-Castro, Agustín; Cárdenas-Vázquez, René; Díaz-Muñoz, Mauricio; Carmona-Alcocer, Vania; Fuentes-Granados, Citlalli; Manuel, Miranda-Anaya
Obesity is a world problem that requires a better understanding of its physiological and genetic basis, as well as the mechanisms by which the hypothalamus controls feeding behavior. The volcano mouse Neotomodon alstoni develops obesity in captivity when fed with regular chow diet, providing a novel model for the study of obesity. Females develop obesity more often than males; therefore, in this study, we analysed in females, in proestrous lean and obese, the differences in hypothalamus expression of receptors for leptin, ghrelin (growth hormone secretagogue receptor GHS-R), and VPAC, and correlates for plasma levels of total ghrelin. The main comparisons are between mice fed ad libitum and mice after 24 hours of fasting. Mice above 65 g body weight were considered obese, based on behavioral and physiological parameters such as food intake, plasma free fatty acids, and glucose tolerance. Hypothalamic tissue from obese and lean mice was analysed by western blot. Our results indicate that after ad libitum food access, obese mice show no significant differences in hypothalamic leptin receptors, but a significant increase of 60% in the GHS-R, and a nearly 62% decrease in VPAC2 was noted. After a 24-hour fast, plasma ghrelin increased nearly two fold in both lean and obese mice; increases of hypothalamic leptin receptors and GHS-R were also noted, while VPAC2 did not change significantly; levels of plasma free fatty acids were 50% less after fasting in obese than in lean animals. Our results indicate that in obese N. alstoni mice, the levels of orexigenic receptors in the hypothalamus correlate with overfeeding, and the fact that lean and obese females respond in different ways to a metabolic demand such as a 24-hour fast.
Kelley, Ann E; Baldo, Brian A; Pratt, Wayne E; Will, Matthew J
Work over the past decade has supported the idea that discrete aspects of appetitive motivation are differentially mediated by separate but interacting neurochemical systems within the nucleus accumbens (Acb). We review herein a series of studies in rats comparing the effects of manipulating Acb amino acid, opioid, acetylcholine, and dopamine systems on tests of free-feeding and food-reinforced operant responding. Results from our laboratory and in the literature support three general conclusions: (1) GABA output neurons localized exclusively within the Acb shell directly influence hypothalamic effector mechanisms for feeding motor patterns, but do not participate in the execution of more complex food-seeking strategies; (2) enkephalinergic neurons distributed throughout the Acb and caudate-putamen mediate the hedonic impact of palatable (high sugar/fat) foods, and these neurons are under modulatory control by striatal cholinergic interneurons; and (3) dopamine transmission in the Acb governs general motoric and arousal processes related to response selection and invigoration, as well as motor learning-related plasticity. These dissociations may reflect the manner in which these neurochemical systems differentially access pallido-thalamo-cortical loops reaching the voluntary motor system (in the case of opioids and dopamine), versus more restricted efferent connections to hypothalamic motor/autonomic control columns (in the case of Acb shell GABA and glutamate systems). Moreover, we hypothesize that while these systems work in tandem to coordinate the anticipatory and consummatory phases of feeding with hypothalamic energy-sensing substrates, the striatal opioid network evolved a specialized capacity to promote overeating of energy-dense foods beyond acute homeostatic needs, to ensure an energy reserve for potential future famine.
Genazzani, A D; Stomati, M; Bersi, C; Luisi, S; Fedalti, M; Santuz, M; Esposito, G; Petraglia, F; Genazzani, A R
Stress-induced neuroendocrine activities influence the regulation of endocrine glands and axes. Weight loss-related hypothalamic amenorrhea is a typical stress-induced physiopathological condition. It is characterized by increased adrenal cortex activation and by reduced GH, LH, FSH and gonadal steroid hormone levels. The aim of the present study was to investigate the effects of pivagabine, a neurotropic drug (1800 mg/day for 7 days) or placebo administration on ACTH, cortisol, GH, LH, FSH and PRL plasma levels in patients with hypothalamic amenorrhea related to weight loss. Hormonal parameters and the pulsatile release of cortisol (6-hour pulsatility, sampling every 10 minutes) were evaluated before and after 7 days of treatment. Pivagabine administration significantly reduced mean plasma ACTH (from 21.7+/-1.7 to 15.4+/-1.2 pg/ml, p<0.05) and cortisol levels (from 12.2+/-0.7 to 9.7+/-0.7 ng/ml, p<0.05) and increased GH levels (from 1.4+/-0.5 to 3.0+/-0.9 ng/ml, p<0.05). A significant reduction of cortisol pulse amplitude was observed (p<0.01) while no change in pulse frequency occurred. No changes were observed in placebo-treated subjects. LH, FSH and PRL levels were not modified by placebo or pivagabine administration. In conclusion, in patients with hypothalamic amenorrhea related to weight loss pivagabine induced a significant decrease of cortisol secretion and an increase of GH release by pivagabine administration, suggesting that this drug exerts a specific neuroendocrine modulatory role.
Genazzani, A D; Bersi, C; Luisi, S; Fruzzetti, F; Malavasi, B; Luisi, M; Petraglia, F; Genazzani, A R
To evaluate adrenal steroid hormone secretion in response to corticotropin-releasing factor (CRF) or to adrenocorticotropin hormone in women with hypothalamic amenorrhea. Controlled clinical study. Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Italy. Fifteen women with hypothalamic amenorrhea were enrolled in the study. Eight normal cycling women were used as control group. Blood samples were collected before and after an injection of ovine CRF (0.1 microg/kg iv bolus) or after synthetic ACTH (0.25 mg iv). Plasma levels of ACTH, 17-hydroxypregnenolone (17OHPe), progesterone (P), dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone (17OHP), cortisol (F), 11-deoxycortisol (S) and androstenedione (A). Basal plasma concentrations of ACTH, cortisol, 11-deoxycortisol, DHEA and 17OHPe were significantly higher in patients than in controls, whereas plasma levels of progesterone and 17-OHP were significantly lower in patients than in controls. In amenorrheic women the ratio of 17-OHPe/DHEA, of 17-OHPe/17-OHP and of 11-deoxycortisol/cortisol were significantly higher than in controls, while a significant reduction in the ratio of 17-OHP/androstenedione, of 17-OHP/11-deoxycortisol was obtained. In response to corticotropin-releasing factor test, plasma levels of ACTH, cortisol, 17-OHP, 11-deoxycortisol, DHEA and androstenedione were significantly lower in patients than in controls. In response to adrenocorticotropin hormone, plasma levels of 17-OHP, androstenedione and androstenedione/cortisol were significantly higher in patients than in controls. Patients suffering for hypothalamic amenorrhea showed an increased activation of hypothalamus-pituitary-adrenal (HPA) axis, as shown by the higher basal levels and by augmented adrenal hormone response to corticotropin-releasing factor administration. These data suggest a possible derangement of adrenal androgen enzymatic pathway.
Brundu, Benedetta; Loucks, Tammy L; Adler, Lauri J; Cameron, Judy L; Berga, Sarah L
The proximate cause of functional hypothalamic amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated. We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW). The study is a cross-sectional comparison. The study was set in a general clinical research center at an academic medical center. Fifteen women with FHA who were of normal body weight and 14 EW participated. Blood samples were collected at 15-min intervals for 24 h, followed by procurement of 25 ml CSF. Cortisol, cortisol-binding globulin (CBG), and SHBG levels in blood and CSF were the main outcome measures. CSF cortisol concentrations were 30% greater when serum cortisol was 16% higher in FHA compared with EW. Circulating CBG, but not SHBG, was increased in FHA and, thus, the circulating free cortisol index was similar in FHA and EW. Because CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound. The hypothalamic-pituitary-adrenal axis is activated in FHA. The maintenance of CRH drive despite increased CSF cortisol indicates resistance to cortisol feedback inhibition. The mechanisms mediating feedback resistance likely involve altered hippocampal corticosteroid reception and serotonergic and GABAergic neuromodulation.
Bekdash, Rola; Zhang, Changqing; Sarkar, Dipak
Hypothalamic proopiomelanocortin (POMC) neurons, one of the major regulators of the hypothalamic-pituitary-adrenal (HPA) axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE). These effects are manifested in POMC neurons by a decrease in Pomc gene expression, a decrement in the levels of its derived peptide β-endorphin and a dysregulation of the stress response in the adult offspring. The HPA axis is a major neuroendocrine system with pivotal physiological functions and mode of regulation. This system has been shown to be perturbed by prenatal alcohol exposure. It has been demonstrated that the perturbation of the HPA axis by FAE is long-lasting and is linked to molecular, neurophysiological, and behavioral changes in exposed individuals. Recently, we showed that the dysregulation of the POMC system function by FAE is induced by epigenetic mechanisms such as hypermethylation of Pomc gene promoter and an alteration in histone marks in POMC neurons. This developmental programming of the POMC system by FAE altered the transcriptome in POMC neurons and induced a hyperresponse to stress in adulthood. These long-lasting epigenetic changes influenced subsequent generations via the male germline. We also demonstrated that the epigenetic programming of the POMC system by FAE was reversed in adulthood with the application of the inhibitors of DNA methylation or histone modifications. Thus, prenatal environmental influences, such as alcohol exposure, could epigenetically modulate POMC neuronal circuits and function to shape adult behavioral patterns. Identifying specific epigenetic factors in hypothalamic POMC neurons that are modulated by fetal alcohol and target Pomc gene could be potentially useful for the development of new therapeutic approaches to treat stress-related diseases in patients with fetal alcohol spectrum disorders. Copyright © 2014 by the Research Society on Alcoholism.
Radomska Katarzyna J
Full Text Available Abstract Background Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal. Results Deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. We found that 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. Moreover, ISH showed that FTO is present mainly in hunger-related sites and it shows a high degree of colocalization with anorexigenic oxytocin. Conclusion We conclude that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward. In line with that, neurons involved in feeding termination express FTO. Interestingly, baseline FTO expression appears linked not only with energy intake but also energy metabolism.
Shechter, Ravid; London, Anat; Kuperman, Yael; Ronen, Ayal; Rolls, Asya; Chen, Alon; Schwartz, Michal
Toll-like receptors (TLRs) are traditionally associated with immune-mediated host defense. Here, we ascribe a novel extra-immune, hypothalamic-associated function to TLR2, a TLR-family member known to recognize lipid components, in the protection against obesity. We found that TLR2-deficient mice exhibited mature-onset obesity and susceptibility to high-fat diet (HFD)-induced weight gain, via modulation of food intake. Age-related obesity was still evident in chimeric mice, carrying comparabl...
Jereme G. Spiers
Full Text Available Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA axis induce activity in the cellular reduction-oxidation (redox system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure.
Solov'eva, A D; Vorob'eva, O V; Loseva, M M; Khaspekova, N B; Fedorova, V I; Musaeva, Z A; Filatova, E G
The epidemiological survey covered 2000 city schoolchildren. They ranged in age from 7 to 15 years. Hypothalamic deficiency (HD) was detected in 5% of the examinees. Clinical and physiological findings on HD children are provided. They were found to have the history of hereditary or natal damage evidencing the acquired nature of the disease. Special emphasis is placed on HD manifestations in prepubertal and pubertal age. The authors show defective regulation of nonspecific brain systems in the form of predominant activation of the septohippocampal system and relative insufficiency of the brain stem mesencephalic reticular formation. Activation of cerebral ergotropic vegetative mechanisms combines with peripheral vegetative failure (sympathetic and parasympathetic), probably, of congenital origin.
Bleier, R; Albrecht, R; Cruce, J A
Cells lying on the ventricular surface of the hypothalamic ependyma of the tegu lizard exhibit the pseudopodial and flaplike processes characteristic of macrophages found elsewhere. Since they ingest latex beads, they may be considered a resident phagocytic system of the brain. The importance of ependyma and ventricular phagocytes as a first line of defense against viral invasion of the brain, as well as their role in the pathogenesis of certain virus-related diseases, is suggested by a number of experimental and clinical observations.
Stival, Alessia; Lucchesi, Maurizio; Farina, Silvia; Buccoliero, Anna Maria; Castiglione, Francesca; Genitori, Lorenzo; de Martino, Maurizio; Sardi, Iacopo
Diencephalic Syndrome is a rare clinical condition of failure to thrive despite a normal caloric intake, hyperalertness, hyperkinesis, and euphoria usually associated with low-grade hypothalamic astrocytomas. We reported an unusual case of diencephalic cachexia due to hypothalamic anaplastic astrocytoma (WHO-grade III). Baseline endocrine function evaluation was performed in this patient before surgery. After histological diagnosis, he enrolled to a chemotherapy program with sequential high-dose chemotherapy followed by hematopoietic stem cell rescue. The last MRI evaluation showed a good response. The patient is still alive with good visual function 21 months after starting chemotherapy. Diencephalic cachexia can rarely be due to high-grade hypothalamic astrocytoma. We suggest that a nutritional support with chemotherapy given to high doses without radiotherapy could be an effective strategy for treatment of a poor-prognosis disease.
Chun, Lauren E; Christensen, Jenny; Woodruff, Elizabeth R; Morton, Sarah J; Hinds, Laura R; Spencer, Robert L
Oscillating clock gene expression gives rise to a molecular clock that is present not only in the body's master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), but also in extra-SCN brain regions. These extra-SCN molecular clocks depend on the SCN for entrainment to a light:dark cycle. The SCN has limited neural efferents, so it may entrain extra-SCN molecular clocks through its well-established circadian control of glucocorticoid hormone secretion. Glucocorticoids can regulate the normal rhythmic expression of clock genes in some extra-SCN tissues. Untimely stress-induced glucocorticoid secretion may compromise extra-SCN molecular clock function. We examined whether acute restraint stress during the rat's inactive phase can rapidly (within 30 min) alter clock gene (Per1, Per2, Bmal1) and cFos mRNA (in situ hybridization) in the SCN, hypothalamic paraventricular nucleus (PVN), and prefrontal cortex (PFC) of male and female rats (6 rats per treatment group). Restraint stress increased Per1 and cFos mRNA in the PVN and PFC of both sexes. Stress also increased cFos mRNA in the SCN of male rats, but not when subsequently tested during their active phase. We also examined in male rats whether endogenous glucocorticoids are necessary for stress-induced Per1 mRNA (6-7 rats per treatment group). Adrenalectomy attenuated stress-induced Per1 mRNA in the PVN and ventral orbital cortex, but not in the medial PFC. These data indicate that increased Per1 mRNA may be a means by which extra-SCN molecular clocks adapt to environmental stimuli (e.g. stress), and in the PFC this effect is largely independent of glucocorticoids.
Takagi, Hironori; Shibutani, Makoto; Lee, Kyoung-Youl; Masutomi, Naoya; Fujita, Haruka; Inoue, Kaoru; Mitsumori, Kunitoshi; Hirose, Masao
We have previously examined the impact of perinatal exposure to ethinylestradiol (EE), methoxychlor (MXC), diisononyl phthalate (DINP), and genistein (GEN) in maternal diet on rat offspring, and found developmental and/or reproductive toxicity with 0.5 ppm EE, 1200 ppm MXC, and 20,000 ppm DINP. Although the toxicological profile with MXC was similar to the EE case, the population changes in pituitary hormone-producing cells totally differed between the two cases, changes being evident from 240 ppm with MXC. In the present study, to assess the impact of these agents on brain sexual differentiation, region-specific mRNA expression of estrogen receptors (ER) α and β, the progesterone receptor (PR), gonadotrophin-releasing hormone, steroid receptor coactivators (SRC)-1 and -2, and calbindin-D in microdissected hypothalamic medial preoptic areas (MPOAs) at postnatal day 10 was first analyzed in rats exposed to 0.5 ppm-EE from gestational day 15 by real-time RT-PCR. Sexually dimorphic expression of ERα and PR was noted with predominance in females and males, respectively, EE up-regulating SRC-1 in males and ERβ and PR in females. Next, we similarly examined expression changes of ERα and β, PR, and SRC-1 in animals exposed to MXC at 24, 240, and 1200 ppm, DINP at 4000 and 20,000 ppm, and GEN at 1000 ppm. MXC at 1200 ppm down- and up-regulated PR in males and females, respectively, and DINP at 20,000 ppm down-regulated PR in females, while GEN did not exert any clear effects. The results thus suggest that agents causing developmental and/or reproductive abnormalities in later life may affect hypothalamic PR expression during the exposure period in early life
Steele, C A; Powell, J L; Kemp, G J; Halford, J C G; Wilding, J P; Harrold, J A; Kumar, S V D; Cuthbertson, D J; Cross, A A; Javadpour, M; MacFarlane, I A; Stancak, A A; Daousi, C
Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.
Alkemade, Anneke; Yi, Chun-Xia; Pei, Lei; Harakalova, Magdalena; Swaab, Dick F.; la Fleur, Susanne E.; Fliers, Eric; Kalsbeek, Andries
Context: Rodent data show that altered hypothalamic signaling contributes to the development of obesity and insulin resistance. Objective: To determine differences in hypothalamic expression levels of neuropeptide Y (NPY), agouti-related peptide (AgRP), and alpha MSH in the infundibular nucleus, the
Full Text Available A 19-year-old man with cortical dysplasia and intractable focal seizures underwent a right temporal lobectomy. A hypothalamic hamartoma was subsequently recognized, and he then underwent MRI-guided stereotactic laser ablation. Unfortunately, he sustained damage to the bilateral medial mammillary bodies and suffered significant memory loss. We review laser ablation therapy for hypothalamic hamartomas and the anatomy of the memory network. We postulate that his persistent memory disorder resulted from a combination of the right temporal lobectomy and injury to the bilateral medial mammillary bodies.
Warren, M P; Fried, J L
Although the treatment of anovulation has become significantly more specialized and complex in the centuries since Hippocrates, a complete understanding of the causes and mechanisms of hypothalamic amenorrhea has not been achieved. Even the best research on hypothalamic amenorrhea is plagued by the lack of longitudinal studies, the use of different exercise models, the difficulty of controlling for caloric intake, and the fact that genetics may have a role in the disorder. Continuing research on metabolic rate, leptin, and other factors will ultimately answer many of the outstanding questions and will help to create better tools for treating this disorder.
Shrestha, P K; Tamrakar, P; Ibrahim, B A; Briski, K P
Cell-type compartmentation of glucose metabolism in the brain involves trafficking of the oxidizable glycolytic end product, l-lactate, by astrocytes to fuel neuronal mitochondrial aerobic respiration. Lactate availability within the hindbrain medulla is a monitored function that regulates systemic glucostasis as insulin-induced hypoglycemia (IIH) is exacerbated by lactate repletion of that brain region. A2 noradrenergic neurons are a plausible source of lactoprivic input to the neural gluco-regulatory circuit as caudal fourth ventricular (CV4) lactate infusion normalizes IIH-associated activation, e.g. phosphorylation of the high-sensitivity energy sensor, adenosine 5'-monophosphate-activated protein kinase (AMPK), in these cells. Here, we investigated the hypothesis that A2 neurons are unique among medullary catecholamine cells in directly screening lactate-derived energy. Adult male rats were injected with insulin or vehicle following initiation of continuous l-lactate infusion into the CV4. Two hours after injections, A1, C1, A2, and C2 neurons were collected by laser-microdissection for Western blot analysis of AMPKα1/2 and phosphoAMPKα1/2 proteins. Results show that AMPK is expressed in each cell group, but only a subset, e.g. A1, C1, and A2 neurons, exhibit increased sensor activity in response to IIH. Moreover, hindbrain lactate repletion reversed hypoglycemic augmentation of pAMPKα1/2 content in A2 and C1 but not A1 cells, and normalized hypothalamic norepinephrine and epinephrine content in a site-specific manner. The present evidence for discriminative reactivity of AMPK-expressing medullary catecholamine neurons to the screened energy substrate lactate implies that that lactoprivation is selectively signaled to the hypothalamus by A2 noradrenergic and C1 adrenergic cells. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
Erin Jane Campbell
Full Text Available Exposure to early life physiological stressors, such as infection, is thought to contribute to the onset of psychopathology in adulthood. In animal models, injections of the bacterial immune challenge, lipopolysaccharide (LPS, during the neonatal period has been shown to alter both neuroendocrine function and behavioural pain responses in adulthood. Interestingly, recent evidence suggests a role for the lateral hypothalamic peptide orexin in stress and nociceptive processing. However, whether neonatal LPS exposure affects the reactivity of the orexin system to formalin-induced inflammatory pain in later life remains to be determined. Male Wistar rats (n=13 were exposed to either LPS or saline (0.05mg/kg, i.p on postnatal days (PND 3 and 5. On PND 80-97, all rats were exposed to a subcutaneous hindpaw injection of 2.25% formalin. Following behavioural testing, animals were perfused and brains processed for Fos-protein and orexin immunohistochemistry. Rats treated with LPS during the neonatal period exhibited decreased licking behaviours during the interphase of the formalin test, the period typically associated with the active inhibition of pain, and increased grooming responses to formalin in adulthood. Interestingly, these behavioural changes were accompanied by an increase in the percentage of Fos-positive orexin cells in the dorsomedial and perifornical hypothalamus in LPS-exposed animals. Similar increases in Fos-protein were also observed in stress and pain sensitive brain regions that receive orexinergic inputs. These findings highlight a potential role for orexin in the behavioural responses to pain and provide further evidence that early life stress can prime the circuitry responsible for these responses in adulthood.
Krause, Eric G; Melhorn, Susan J; Davis, Jon F; Scott, Karen A; Ma, Li Y; de Kloet, Annette D; Benoit, Stephen C; Woods, Stephen C; Sakai, Randall R
Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind blood-borne ANGII and stimulate integrative and effector regions of the brain. The goal of these studies was to determine the contribution of AT1Rs within the SFO and OVLT to the water intake and HPA response to increased circulating ANGII. Antisense oligonucleotides directed against the AT1R [AT1R antisense (AT1R AS)] were administered into the OVLT or SFO. Quantitative receptor autoradiography confirmed that AT1R AS decreased ANGII binding in the SFO and OVLT compared with the scrambled sequence control but did not affect AT1R binding in other nuclei. Subsequently, water intake, ACTH, and corticosterone (CORT) were assessed after administration of isoproterenol, a beta-adrenergic agonist that decreases blood pressure and elevates circulating ANGII. Delivery of AT1R AS into the SFO attenuated water intake, ACTH, and CORT after isoproterenol, whereas similar treatment in the OVLT had no effect. To determine the specificity of this blunted drinking and HPA response, the same parameters were measured after treatment with hypertonic saline, a stimulus that induces drinking independently of ANGII. Delivery of AT1R AS into the SFO or OVLT had no effect on water intake, ACTH, or CORT after hypertonic saline. The results imply that AT1R within the SFO mediate drinking and HPA responses to stimuli that increase circulating ANGII.
Plotsky, P.M.; Neill, J.D.
Previous in situ voltammetric microelectrode measurements of median eminence dopamine release during mammary nerve stimulation of anesthetized lactating rats revealed a transient (1-3 min) 70% decline of dopamine concentrations. This dopamine was believed to be destined for secretion into the hypophysial portal circulation, but direct experimental support for this supposition was lacking. Thus, in the present study, [3H]dopamine release into brief sequential samples of hypophysial portal blood was compared with dopamine release in the median eminence measured by voltammetry. Lactating female rats were urethane anesthetized, and the median eminence pituitary region was exposed. [3H]Tyrosine was injected into a jugular cannula (100 microCi) followed by continuous infusion (5 microCi/min). In a preliminary experiment, this regimen produced a steady state level of [3H]dopamine in the portal blood within 45 min. In subsequent experiments, portal blood was collected as sequential 3-min samples, and electrochemical sampling from a microelectrode placed in the median eminence occurred at 1-min intervals. Electrochemical current resulting from the oxidation of dopamine in the medial median eminence was unvarying throughout the 75-min experiment in control rats (n . 4) and during the 30-min control period preceding mammary nerve stimulation in the other group (n . 4). These results were paralled by [3H] dopamine levels in portal blood during the same periods of time. All animals showed simultaneous decreases in oxidation current and [3H]dopamine levels within 1-4 min after initiation of mammary nerve stimulation. These and earlier results demonstrate that mammary nerve stimulation (and by extension, suckling) induces a momentary, but profound, decrease in hypothalamic dopamine secretion which precedes or accompanies the rise in PRL secretion evoked by the same stimulus
Israel, Jean-Marc; Oliet, Stéphane H; Ciofi, Philippe
Hypothalamic neurohormones are released in a pulsatile manner. The mechanisms of this pulsatility remain poorly understood and several hypotheses are available, depending upon the neuroendocrine system considered. Among these systems, hypothalamo-neurohypophyseal magnocellular neurons have been early-considered models, as they typically display an electrical activity consisting of bursts of action potentials that is optimal for the release of boluses of the neurohormones oxytocin and vasopressin. The cellular mechanisms underlying this bursting behavior have been studied in vitro, using either acute slices of the adult hypothalamus, or organotypic cultures of neonatal hypothalamic tissue. We have recently proposed, from experiments in organotypic cultures, that specific central pattern generator networks, upstream of magnocellular neurons, determine their bursting activity. Here, we have tested whether a similar hypothesis can be derived from in vitro experiments in acute slices of the adult hypothalamus. To this aim we have screened our electrophysiological recordings of the magnocellular neurons, previously obtained from acute slices, with an analysis of autocorrelation of action potentials to detect a rhythmic drive as we recently did for organotypic cultures. This confirmed that the bursting behavior of magnocellular neurons is governed by central pattern generator networks whose rhythmic drive, and thus probably integrity, is however less satisfactorily preserved in the acute slices from adult brains.
Full Text Available Hypothalamic neurohormones are released in a pulsatile manner. The mechanisms of this pulsatility remain poorly understood and several hypotheses are available, depending upon the neuroendocrine system considered. Among these systems, hypothalamo-neurohypophyseal magnocellular neurons have been early-considered models, as they typically display an electrical activity consisting of bursts of action potentials that is optimal for the release of boluses of the neurohormones oxytocin and vasopressin. The cellular mechanisms underlying this bursting behavior have been studied in vitro, using either acute slices of the adult hypothalamus, or organotypic cultures of neonatal hypothalamic tissue. We have recently proposed, from experiments in organotypic cultures, that specific central pattern generator networks, upstream of magnocellular neurons, determine their bursting activity. Here, we have tested whether a similar hypothesis can be derived from in vitro experiments in acute slices of the adult hypothalamus. To this aim we have screened our electrophysiological recordings of the magnocellular neurons, previously obtained from acute slices, with an analysis of autocorrelation of action potentials to detect a rhythmic drive as we recently did for organotypic cultures. This confirmed that the bursting behavior of magnocellular neurons is governed by central pattern generator networks whose rhythmic drive, and thus probably integrity, is however less satisfactorily preserved in the acute slices from adult brains.
Da Young Yoon
Full Text Available Central precocious puberty (CPP is caused by premature activation of the hypothalamic-gonadal axis, and must be treated adequately. In particular, CPP that occurs at a relatively young age or in boys is likely to be caused by an organic lesion. Hypothalamic hamartoma (HH is the most common organic cause of CPP. The present case report describes an 11-month-old female infant who presented with vaginal bleeding and rapidly progressive secondary sex characteristics from the age of 6 months. She was diagnosed with CPP following the detection of HH via magnetic resonance imaging. The infant girl was successfully treated with gonadotropin-releasing hormone agonist. After 6 months, her breast had regressed and clinical and radiological follow-up demonstrated stable findings with no evidence of tumor growth or secondary sexual characteristics until the fourth year after the initiation of treatment. This patient is the one of the youngest infants presenting with CPP and HH in Korea; treatment was successful over a relatively long follow-up period.
Full Text Available The response of a thickness shear mode biosensor to immortalized murine hypothalamic neurons (mHypoE-38 and -46 cells under a variety of conditions and stimuli is discussed. Cellular studies which lead to the production of detectable neuronal responses include neuronal deposition, adhesion and proliferation, alteration in the extent of specific cell-surface interactions, actin filament and microtubule cytoskeletal disruptions, effects of cell depolarization, inhibition of the Na+-K+ pump via ouabain, effects of neuronal synchronization and the effects ligand-receptor interaction (glucagon. In the presence of cells, fs shifts are largely influenced by the damping of the TSM resonator. The formation of cell-surface interactions and hence the increase in coupling and acoustic energy dissipation can be modeled as an additional resistor in the BVD model. Further sensor and cellular changes can be obtained by negating the effects of damping from fs via the use of Rm and θmax. Keywords: Acoustic wave sensor, Hypothalamic neurons, Neuron cell-surface interaction
Anastasia N Zink
Full Text Available There is a rising medical need for novel therapeutic targets of physical activity. Physical activity spans from spontaneous, low intensity movements to voluntary, high-intensity exercise. Regulation of spontaneous and voluntary movement is distributed over many brain areas and neural substrates, but the specific cellular and molecular mechanisms responsible for mediating overall activity levels are not well understood. The hypothalamus plays a central role in the control of physical activity, which is executed through coordination of multiple signaling systems, including the orexin neuropeptides. Orexin producing neurons integrate physiological and metabolic information to coordinate multiple behavioral states and modulate physical activity in response to the environment. This review is organized around three questions: (1 How do orexin peptides modulate physical activity? (2 What are the effects of aging and lifestyle choices on physical activity? (3 What are the effects of aging on hypothalamic function and the orexin peptides? Discussion of these questions will provide a summary of the current state of knowledge regarding hypothalamic orexin regulation of physical activity during aging and provide a platform on which to develop improved clinical outcomes in age-associated obesity and metabolic syndromes.
Baskind, N Ellissa; Balen, Adam H
Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous disorder linked with disturbances of reproductive, endocrine and metabolic function. The definition and aetiological hypotheses of PCOS are continually developing to incorporate evolving evidence of the syndrome, which appears to be both multifactorial and polygenic. The pathophysiology of PCOS encompasses inherent ovarian dysfunction that is strongly influenced by external factors including the hypothalamic-pituitary axis and hyperinsulinaemia. Neuroendocrine abnormalities including increased gonadotrophin-releasing hormone (GnRH) pulse frequency with consequent hypersecretion of luteinising hormone (LH) affects ovarian androgen synthesis, folliculogenesis and oocyte development. Disturbed ovarian-pituitary and hypothalamic feedback accentuates the gonadotrophin abnormalities, and there is emerging evidence putatively implicating dysfunction of the Kiss 1 system. Within the follicle subunit itself, there are intra-ovarian paracrine modulators, cytokines and growth factors, which appear to play a role. Adrenally derived androgens may also contribute to the pathogenesis of PCOS, but their role is less defined. Copyright Â© 2016. Published by Elsevier Ltd.
Kamali, Arash; Karbasian, Niloofar; Rabiei, Pejman; Cano, Andres; Riascos, Roy F; Tandon, Nitin; Arevalo, Octavio; Ocasio, Laura; Younes, Kyan; Khayat-Khoei, Mahsa; Mirbagheri, Saeedeh; Hasan, Khader M
The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain. Copyright © 2018. Published by Elsevier B.V.
Potapenko, Evgeniy S.; Biancardi, Vinicia C.; Zhou, Yiqiang
A dynamic balance between the excitatory and inhibitory neurotransmitters glutamate and GABA is critical for maintaining proper neuronal activity in the brain. This balance is partly achieved via presynaptic interactions between glutamatergic and GABAAergic synapses converging into the same targets. Here, we show that in hypothalamic magnocellular neurosecretory neurons (MNCs), a direct crosstalk between postsynaptic NMDA receptors (NMDARs) and GABAA receptors (GABAARs) contributes to the excitatory/inhibitory balance in this system. We found that activation of NMDARs by endogenous glutamate levels controlled by astrocyte glutamate transporters, evokes a transient and reversible potentiation of postsynaptic GABAARs. This inter-receptor crosstalk is calcium-dependent and involves a kinase-dependent phosphorylation mechanism, but does not require nitric oxide as an intermediary signal. Finally, we found the NMDAR–GABAAR crosstalk to be blunted in rats with heart failure, a pathological condition in which the hypothalamic glutamate–GABA balance is tipped toward an excitatory predominance. Together, our findings support a novel form of glutamate–GABA interactions in MNCs, which involves crosstalk between NMDA and GABAA postsynaptic receptors, whose strength is controlled by the activity of local astrocytes. We propose this inter-receptor crosstalk to act as a compensatory, counterbalancing mechanism to dampen glutamate-mediated overexcitation. Finally, we propose that an uncoupling between NMDARs and GABAARs may contribute to exacerbated neuronal activity and, consequently, sympathohumoral activation in such disease conditions as heart failure. PMID:23303942
Rezg, Raja; Mornagui, Bessem; Benahmed, Malika; Chouchane, Sonia Gharsalla; Belhajhmida, Nadia; Abdeladhim, Maha; Kamoun, Abdelaziz; El-fazaa, Saloua; Gharbi, Najoua
Exposure to organophosphate (OP) pesticides is virtually ubiquitous. These inevitable agents are neurotoxicants, but recent evidence also points to lasting effects on carbohydrate metabolism. The aim of this study was to investigate the effects of 32 repeated treatment days with malathion, an OP insecticide, on some molecular and metabolic parameters. Malathion at 100 mg/kg was administered by gavage in Wistar rats. Results of this study indicate a significant decrease in hypothalamic corticotropin-releasing hormone mRNA, of malathion-treated rats. This result, in accordance with that of diabetic type 2 rat model, may be due to very potent negative feedback effects of glucocorticoids on hypothalamo-pituitary-adrenal (HPA) axis activity. In addition, we have recorded a significant increase in hypothalamic inducible NO synthase mRNA which probably enhances the negative feedback. These alterations are accompanied with hypertriglyceridemia that may be a favourable condition to insulin resistance. Thus, results of the present study suggest that malathion can be considered as an important risk factor in the development of diabetes type 2, which prevalence increased substantially in our country and around the world. Clearly, we need to focus further research on the specific incidences of hazardous food chemical contaminant that might be contributing to epidemic health perspectives. Crown Copyright 2010. Published by Elsevier Ltd. All rights reserved.
Full Text Available High-fat diets (HFDs lead to obesity and inflammation in the central nervous system (CNS. Estrogens and estrogen receptor α (ERα protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way.
Morselli, Eugenia; Fuente-Martin, Esther; Finan, Brian; Kim, Min; Frank, Aaron; Garcia-Caceres, Cristina; Navas, Carlos Rodriguez; Gordillo, Ruth; Neinast, Michael; Kalainayakan, Sarada P; Li, Dan L; Gao, Yuanqing; Yi, Chun-Xia; Hahner, Lisa; Palmer, Biff F; Tschöp, Matthias H; Clegg, Deborah J
High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor α (ERα) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA) and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way.
Addictive drugs (opiates, ethanol, cannabinoids (CBs), nicotine, cocaine, amphetamines) induce activation of the hypothalamic-pituitary-adrenal (HPA) axis, with the subsequent release of adrenocorticotropic hormone and glucocorticoids. The sequence of events leading to HPA activation appears to start within the brain, suggesting that activation is not secondary to peripheral homeostatic alterations. The precise neurochemical mechanisms and brain pathways involved are markedly dependent on the particular drug, although it is assumed that information eventually converges into the hypothalamic paraventricular nucleus (PVN). Whereas some drugs may act on the hypothalamus or directly within PVN neurons (i.e. ethanol), others exert their primary action outside the PVN (i.e. CBs, nicotine, cocaine). Corticotropin-releasing hormone (CRH) has a critical role in most cases, but the changes in c-fos and CRH gene expression in the PVN also reveal differences among drugs. More studies are needed to understand how addictive drugs act on this important neuroendocrine system and their functional consequences. Copyright 2010 Elsevier Ltd. All rights reserved.
Gigante, Eduardo D; Benaliouad, Faiza; Zamora-Olivencia, Veronica; Wise, Roy A
Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates.
Schmidt, M.; Theissen, P.; Dietlein, M.; Schicha, H.; Jackenhoevel, F.; Krone, W.
The following article reviews nuclear medicine techniques which can be used for assessment of endocrine disorders of the hypothalamic-pituitary axis. For planar and SPECT imaging somatostatin-receptor- and dopamine-D2-receptor-scintigraphy are the most widely distributed techniques. These nuclear medicine techniques may be indicated in selected cases to answer differential diagnostic problems. They can be helpful to search for presence and localization of receptor positive tissue. Furthermore they can detect metastasis in the rare cases of a pituitary carcinoma. Scintigraphy with Gallium-67 is suitable for further diagnostic evaluation in suspected hypophysitis. Other SPECT radiopharmaca do not have relevant clinical significance. F-18-FDG as PET radiopharmacon is not ideal because obvious pituitary adenomas could not be visualized. Other PET radiopharmaca including C-11-methionine, C-11-tyrosine, F-18-fluoroethylspiperone, C-11-methylspiperone, and C-11-raclopride are available in specialized centers only. Overall indications for nuclear medicine in studies for the assessment of endocrine disorders of the hypothalamic-pituitary-axis are rare. Original studies often report only about a small number of patients. According to the authors' opinion the relevance of nuclear medicine in studies of clinically important endocrinologic fields, e. g. localization of small ACTH-producing pituitary adenomas, tumor localization in ectopic ACTH syndrome, localization of recurrent pituitary tissue, assessment of small incidentalomas, can not be definitely given yet. (orig.) [de
Jeong, Joo Yeon; Lee, Dong Hoon; Kang, Sang Soo
Stress affects body weight and food intake, but the underlying mechanisms are not well understood. We evaluated the changes in body weight and food intake of ICR male mice subjected to daily 2 hours restraint stress for 15 days. Hypothalamic gene expression profiling was analyzed by cDNA microarray. Daily body weight and food intake measurements revealed that both parameters decreased rapidly after initiating daily restraint stress. Body weights of stressed mice then remained significantly lower than the control body weights, even though food intake slowly recovered to 90% of the control intake at the end of the experiment. cDNA microarray analysis revealed that chronic restraint stress affects the expression of hypothalamic genes possibly related to body weight control. Since decreases of daily food intake and body weight were remarkable in days 1 to 4 of restraint, we examined the expression of food intake-related genes in the hypothalamus. During these periods, the expressions of ghrelin and pro-opiomelanocortin mRNA were significantly changed in mice undergoing restraint stress. Moreover, daily serum corticosterone levels gradually increased, while leptin levels significantly decreased. The present study demonstrates that restraint stress affects body weight and food intake by initially modifying canonical food intake-related genes and then later modifying other genes involved in energy metabolism. These genetic changes appear to be mediated, at least in part, by corticosterone.
Maria Julia Scerbo
Full Text Available The organizational action of testosterone during critical periods of development is the cause of numerous sex differences in the brain. However, sex differences in neuritogenesis have been detected in primary neuronal hypothalamic cultures prepared before the peak of testosterone production by fetal testis. In the present study we assessed the hypothesis of that cell-autonomous action of sex chromosomes can differentially regulate the expression of the neuritogenic gene neurogenin 3 (Ngn3 in male and female hypothalamic neurons, generating sex differences in neuronal development. Neuronal cultures were prepared from male and female E14 mouse hypothalami, before the fetal peak of testosterone. Female neurons showed enhanced neuritogenesis and higher expression of Ngn3 than male neurons. The silencing of Ngn3 abolished sex differences in neuritogenesis, decreasing the differentiation of female neurons. The sex difference in Ngn3 expression was determined by sex chromosomes, as demonstrated using the four core genotypes mouse model, in which a spontaneous deletion of the testis-determining gene Sry from the Y chromosome was combined with the insertion of the Sry gene onto an autosome. In addition, the expression of Ngn3, which is also known to mediate the neuritogenic actions of estradiol, was increased in the cultures treated with the hormone, but only in those from male embryos. Furthermore, the hormone reversed the sex differences in neuritogenesis promoting the differentiation of male neurons. These findings indicate that Ngn3 mediates both cell-autonomous actions of sex chromosomes and hormonal effects on neuritogenesis.
Bomba, Monica; Corbetta, Fabiola; Bonini, Luisa; Gambera, Alessandro; Tremolizzo, Lucio; Neri, Francesca; Nacinovich, Renata
Functional hypothalamic amenorrhea (FHA) is a form of anovulation, due to the suppression of hypothalamic-pituitary-ovarian axis, not related to identifiable organic causes. Like adolescents with anorexia nervosa (AN), subjects with FHA show dysfunctional attitudes, low self-esteem, depressive mood, anxiety and inability to cope with daily stress. The aim of the study is to examine similarities and differences between FHA and AN in terms of clinical profiles and psychological variables. 21 adolescents with FHA, 21 adolescents with anorexia nervosa, and 21 healthy adolescents were included in the study. All the teenagers completed a battery of self-administered psychological tests for the detection of behaviors and symptoms attributable to the presence of an eating disorder (EDI-2), depression (CDI), and alexithymia (TAS-20). Different from healthy controls, subjects with FHA and with AN shared common psychopathological aspects, such as maturity issues, social insecurity and introversion, a tendency to depression, excessive concerns with dieting, and fear of gaining weight. Nevertheless, adolescents with AN presented a more profound psychopathological disorder as observed at test comparisons with subjects with FHA. Results show a clinical spectrum that includes AN and FHA and suggest the necessity to treat FHA with a multidisciplinary approach for both organic and psychological aspects.
Schneider, Lisa F; Warren, Michelle P
To determine whether ghrelin, an orexigen released by the stomach, is elevated in women with hypothalamic amenorrhea who are of normal weight and whether this is associated with abnormal eating behaviors. Controlled clinical study. Healthy volunteers in an academic research environment. Twenty-seven women with functional hypothalamic amenorrhea (FHA) and 42 normally menstruating women. None. Ghrelin and eating behavior. Ghrelin was significantly elevated in FHA (648.4 +/- 92.0 pg/mL vs. controls 596.7 +/- 79.0 pg/mL), while leptin, although lower, was not significantly so (FHA 5.4 +/- 2.8 ng/mL vs. controls 6.4 +/- 3 ng/mL). Eating Attitudes Test (EAT) scores were also significantly elevated in FHA (15.3 +/- 10.6 vs. controls 10.3 +/- 8.4), particularly on the subscale that measured bulimic behaviors. However, FHA patients consumed significantly more kilocalories (1,930 kcal/day vs. 1,588 kcal/day). High ghrelin in women with FHA may be linked to abnormal dietary behaviors, as reflected in high EAT scores yet characterized by normal caloric intake. Ghrelin may act as a restraining metabolic signal preventing a return to cyclicity in women with both disordered eating and FHA, prolonging amenorrhea when leptin has returned to normal.
Bomba, Monica; Gambera, Alessandro; Bonini, Luisa; Peroni, Maria; Neri, Francesca; Scagliola, Pasquale; Nacinovich, Renata
To determine trigger factors and neuropsychologic correlates of functional hypothalamic amenorrhea (FHA) in adolescence and to evaluate the correlations with the endocrine-metabolic profile. Cross-sectional comparison of adolescents with FHA and eumenorrheic controls Academic medical institution Twenty adolescent girls with FHA (aged <18 years) and 20 normal cycling girls All subjects underwent endocrine-gynecologic (hormone) and neuropsychiatric (tests and interview) investigations. A separate semistructured interview was also used to investigate parents. Gonadotropins, leptin, prolactin, androgens, estrogens, cortisol, carrier proteins (SHBG, insulin-like growth factor-binding protein 1), and metabolic parameters (insulin, insulin-like growth factor 1, thyroid hormones) were assayed in FHA and control subjects. All girls were evaluated using a test for depression, a test for disordered eating, and a psychodynamic semistructured interview. Adolescents with FHA showed a particular susceptibility to common life events, restrictive disordered eating, depressive traits, and psychosomatic disorders. The endocrine-metabolic profile was strictly correlated to the severity of the psychopathology. Functional hypothalamic amenorrhea in adolescence is due to a particular neuropsychologic vulnerability to stress, probably related to familial relationship styles, expressed by a proportional endocrine impairment.
Drakopoulos, Panagiotis; Casarosa, Elena; Bucci, Fiorella; Piccinino, Manuela; Wenger, Jean-Marie; Nappi, Rossella Elena; Polyzos, Nicholas; Genazzani, Andrea Riccardo; Pluchino, Nicola
Brain-derived neurotrophic factor (BDNF) is strongly related to hormonal networks and is modulated by hypothalamic activity. To evaluate plasma BDNF concentration in patients with functional hypothalamic amenorrhea (FHA), with reference to the BDNF circadian rhythm and its relation with the cortisol (F) rhythm, and to assess whether the duration of amenorrhea might influence the BDNF:F ratio in FHA. This was an observational study evaluating 36 amenorrheic and 30 eumenorrheic women. Basal values of BDNF and hormones were examined in blood samples collected from 7:00 to 9:00 h in all the women. Basal BDNF and F levels were determined in blood samples collected in 12 subjects from each group at 8:00, 12:00, 16:00, 20:00, and 24:00 h. BDNF plasma levels are significantly lower in amenorrheic women (p 0.05), sex steroids, and F in FHA. Low plasma BDNF levels in FHA are not significantly correlated with duration of amenorrhea. The 24-hour variation of BDNF in amenorrheic women is significantly lower when compared to the control group, and normal daily variations of BDNF disappeared in FHA patients. F preserved its circadian rhythm in both groups. Interactions between BDNF, the hypothalamus-pituitary-adrenal axis, and sex steroids might be critical in clinical conditions of modified homeostasis/adaptation, such as FHA. © 2015 S. Karger AG, Basel.
Borges, Lavinia Estrela; Morgante, Giuseppe; Musacchio, Maria Concetta; Petraglia, Felice; De Leo, Vincenzo
To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. This was an open-label study. Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.
Reis, Wagner L; Yi, Chun-Xia; Gao, Yuanqing; Tschöp, Mathias H; Stern, Javier E
Hypothalamic inflammation, involving microglia activation in the arcuate nucleus (ARC), is proposed as a novel underlying mechanism in obesity, insulin and leptin resistance. However, whether activated microglia affects ARC neuronal activity, and consequently basal and hormonal-induced food intake, is unknown. We show that lipopolysaccharide, an agonist of the toll-like receptor-4 (TLR4), which we found to be expressed in ARC microglia, inhibited the firing activity of the majority of orexigenic agouti gene-related protein/neuropeptide Y neurons, whereas it increased the activity of the majority of anorexigenic proopiomelanocortin neurons. Lipopolysaccharide effects in agouti gene-related protein/neuropeptide Y (but not in proopiomelanocortin) neurons were occluded by inhibiting microglia function or by blocking TLR4 receptors. Finally, we report that inhibition of hypothalamic microglia altered basal food intake, also preventing central orexigenic responses to ghrelin. Our studies support a major role for a TLR4-mediated microglia signaling pathway in the control of ARC neuronal activity and feeding behavior.
Varela, Luis; Martínez-Sánchez, Noelia; Gallego, Rosalía; Vázquez, María J; Roa, Juan; Gándara, Marina; Schoenmakers, Erik; Nogueiras, Rubén; Chatterjee, Krishna; Tena-Sempere, Manuel; Diéguez, Carlos; López, Miguel
Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Gomes, J R; Freitas, J R; Grassiolli, S
The small intestine plays a role in obesity as well as in satiation. However, the effect of physical exercise on the morphology and function of the small intestine during obesity has not been reported to date. This study aimed to evaluate the effects of physical exercise on morphological aspects of the rat small intestine during hypothalamic monosodium glutamate (MSG)-induced obesity. The rats were divided into four groups: Sedentary (S), Monosodium Glutamate (MSG), Exercised (E), and Exercised Monosodium Glutamate (EMSG). The MSG and EMSG groups received a daily injection of monosodium glutamate (4 g/kg) during the 5 first days after birth. The S and E groups were considered as control groups and received injections of saline. At weaning, at 21 days after birth, the EMSG and E groups were submitted to swimming practice 3 times a week until the 90th day, when all groups were sacrificed and the parameters studied recorded. Exercise significantly reduced fat deposits and the Lee Index in MSG-treated animals, and also reduced the thickness of the intestinal wall, the number of goblet cells and intestinal alkaline phosphatase activity. However, physical activity alone increased the thickness and height of villi, and the depth of the crypts. In conclusion, regular physical exercise may alter the morphology or/and functions of the small intestine, reducing the prejudicial effects of hypothalamic obesity. Anat Rec, 299:1389-1396, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Burfeind, Kevin G; Michaelis, Katherine A; Marks, Daniel L
When challenged with a variety of inflammatory threats, multiple systems across the body undergo physiological responses to promote defense and survival. The constellation of fever, anorexia, and fatigue is known as the acute illness response, and represents an adaptive behavioral and physiological reaction to stimuli such as infection. On the other end of the spectrum, cachexia is a deadly and clinically challenging syndrome involving anorexia, fatigue, and muscle wasting. Both of these processes are governed by inflammatory mediators including cytokines, chemokines, and immune cells. Though the effects of cachexia can be partially explained by direct effects of disease processes on wasting tissues, a growing body of evidence shows the central nervous system (CNS) also plays an essential mechanistic role in cachexia. In the context of inflammatory stress, the hypothalamus integrates signals from peripheral systems, which it translates into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements. Therefore, we will discuss how hypothalamic inflammation is an essential driver of both the acute illness response and cachexia, and why this organ is uniquely equipped to generate and maintain chronic inflammation. First, we will focus on the role of the hypothalamus in acute responses to dietary and infectious stimuli. Next, we will discuss the role of cytokines in driving homeostatic disequilibrium, resulting in muscle wasting, anorexia, and weight loss. Finally, we will address mechanisms and mediators of chronic hypothalamic inflammation, including endothelial cells, chemokines, and peripheral leukocytes. Copyright © 2015 Elsevier Ltd. All rights reserved.
Xiao, Yuzhong; Deng, Yalan; Yuan, Feixiang; Xia, Tingting; Liu, Hao; Li, Zhigang; Chen, Shanghai; Liu, Zhixue; Ying, Hao; Liu, Yi; Zhai, Qiwei; Guo, Feifan
ATF4 (activating transcription factor 4) is an important transcription factor that has many biological functions, while its role in hypothalamic POMC (pro-opiomelanocortin-α) neurons in the regulation of energy homeostasis has not been explored. We recently discovered that mice with an Atf4 deletion specific to POMC neurons (PAKO mice) are lean and have higher energy expenditure. Furthermore, these mice are resistant to high-fat diet (HFD)-induced obesity and obesity-related metabolic disorders. Mechanistically, we found the expression of ATG5 (autophagy-related 5) is upregulated in POMC neurons of PAKO mice, and ATF4 regulates ATG5 expression by binding directly to its promoter. Mice with Atf4 and Atg5 double knockout in POMC neurons have reduced energy expenditure and gain more fat mass compared with PAKO mice under a HFD. Finally, the effect of Atf4 knockout in POMC neurons is possibly mediated by enhanced ATG5-dependent macroautophagy/autophagy and α-melanocyte-stimulating hormone (α-MSH) production in the hypothalamus. Together, this work not only identifies a beneficial role for ATF4 in hypothalamic POMC neurons in the regulation of obesity, but also provides a new potential therapeutic target for obesity and obesity-related metabolic diseases.
Zhou, Chunxue; Teegala, Suraj B; Khan, Bilal A; Gonzalez, Christina; Routh, Vanessa H
Hypoglycemia is a profound threat to the brain since glucose is its primary fuel. As a result, glucose sensors are widely located in the central nervous system and periphery. In this perspective we will focus on the role of hypothalamic glucose-inhibited (GI) neurons in sensing and correcting hypoglycemia. In particular, we will discuss GI neurons in the ventromedial hypothalamus (VMH) which express neuronal nitric oxide synthase (nNOS) and in the perifornical hypothalamus (PFH) which express orexin. The ability of VMH nNOS-GI neurons to depolarize in low glucose closely parallels the hormonal response to hypoglycemia which stimulates gluconeogenesis. We have found that nitric oxide (NO) production in low glucose is dependent on oxidative status. In this perspective we will discuss the potential relevance of our work showing that enhancing the glutathione antioxidant system prevents hypoglycemia associated autonomic failure (HAAF) in non-diabetic rats whereas VMH overexpression of the thioredoxin antioxidant system restores hypoglycemia counterregulation in rats with type 1 diabetes.We will also address the potential role of the orexin-GI neurons in the arousal response needed for hypoglycemia awareness which leads to behavioral correction (e.g., food intake, glucose administration). The potential relationship between the hypothalamic sensors and the neurocircuitry in the hindbrain and portal mesenteric vein which is critical for hypoglycemia correction will then be discussed.
Full Text Available Hypoglycemia is a profound threat to the brain since glucose is its primary fuel. As a result, glucose sensors are widely located in the central nervous system and periphery. In this perspective we will focus on the role of hypothalamic glucose-inhibited (GI neurons in sensing and correcting hypoglycemia. In particular, we will discuss GI neurons in the ventromedial hypothalamus (VMH which express neuronal nitric oxide synthase (nNOS and in the perifornical hypothalamus (PFH which express orexin. The ability of VMH nNOS-GI neurons to depolarize in low glucose closely parallels the hormonal response to hypoglycemia which stimulates gluconeogenesis. We have found that nitric oxide (NO production in low glucose is dependent on oxidative status. In this perspective we will discuss the potential relevance of our work showing that enhancing the glutathione antioxidant system prevents hypoglycemia associated autonomic failure (HAAF in non-diabetic rats whereas VMH overexpression of the thioredoxin antioxidant system restores hypoglycemia counterregulation in rats with type 1 diabetes.We will also address the potential role of the orexin-GI neurons in the arousal response needed for hypoglycemia awareness which leads to behavioral correction (e.g., food intake, glucose administration. The potential relationship between the hypothalamic sensors and the neurocircuitry in the hindbrain and portal mesenteric vein which is critical for hypoglycemia correction will then be discussed.
Full Text Available Sigma-1 receptor knockout (σ1R-KO mice exhibit a depressive-like phenotype. Because σ1R is highly expressed in the neuronal cells of hypothalamic paraventricular nuclei (PVN, this study investigated the influence of σ1R deficiency on the regulation of the hypothalamic-pituitary-adrenocortical (HPA axis. Here, we show that the levels of basal serum corticosterone (CORT, adrenocorticotropic hormone (ACTH and corticotrophin releasing factor (CRF as well as the level of CRF mRNA in PVN did not significantly differ between adult male σ1R-KO mice and wild-type (WT mice. Acute mild restraint stress (AMRS induced a higher and more sustainable increase in activity of HPA axis and CRF expression in σ1R-KO mice. Percentage of dexamethasone (Dex-induced reduction in level of CORT was markedly attenuated in σ1R−/− mice. The levels of glucocorticoid receptor (GR and protein kinase C (PKC phosphorylation were reduced in the PVN of σ1R-KO mice and σ1R antagonist NE100-treated WT mice. The exposure to AMRS in σ1R-KO mice induced a stronger phosphorylation of cAMP-response element binding protein (CREB in PVN than that in WT mice. Intracerebroventricular (i.c.v. injection of PKC activator PMA for 3 days in σ1R-KO mice not only recovered the GR phosphorylation and the percentage of Dex-reduced CORT but also corrected the AMRS-induced hyperactivity of HPA axis and enhancement of CRF mRNA and CREB phosphorylation. Furthermore, the injection (i.c.v. of PMA in σ1R-KO mice corrected the prolongation of immobility time in forced swim test (FST and tail suspension test (TST. These results indicate that σ1R deficiency causes down-regulation of GR by reducing PKC phosphorylation, which attenuates GR-mediated feedback inhibition of HPA axis and facilitates the stress response of HPA axis leading to the production of depressive-like behaviors.
... in the brain to reduce spinal fluid pressure. Risks of radiation therapy include damage to healthy brain cells when tumor cells are destroyed. Common side effects from chemotherapy include loss of appetite, nausea and vomiting, and fatigue.
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Increased anti-Mullerian hormone levels and ovarian size in a subgroup of women with functional hypothalamic amenorrhea: further identification of the link between polycystic ovary syndrome and functional hypothalamic amenorrhea.
Carmina, Enrico; Fruzzetti, Franca; Lobo, Roger A
Functional hypothalamic amenorrhea is a disorder characterized by cessation of menstrual cycles in the absence of organic disease. In most patients, it occurs in adult life after a stressful event and may be related to a condition of mild chronic energy deprivation. The endocrine pattern is characterized by low estrogen levels with an absent response to a progestogen challenge test and low-normal gonadotropin levels. A few studies have shown that some of these women may have some features of polycystic ovary syndrome; these features include an increased androgen response to gonadotropins, increased anti-Mullerian hormone levels, and altered ovarian morphology or increased ovarian size. These findings suggest a link between these 2 completely different disorders: functional hypothalamic amenorrhea and polycystic ovary syndrome. The importance of the possible coexistence of these disorders in some women is important for follow-up of these women and in their treatment if they desire to become pregnant. To determine whether a subgroup of well-characterized women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. Retrospective analysis of women with functional hypothalamic amenorrhea. Forty consecutive patients and 28 normal age-matched control patients were studied. Blood was obtained for serum anti-Mullerian hormone, androgens, and other hormone levels and all women had ovarian ultrasonographic measurements. In the entire group of women with functional hypothalamic amenorrhea, anti-Mullerian hormone and ovarian volume were greater than in control patients. In 13 patients (32.5%), anti-Mullerian hormone was elevated (>4.7 ng/mL, levels consistent with polycystic ovary syndrome) and in this group, ovarian volume was significantly greater than in the remaining patients with functional hypothalamic amenorrhea. Four of the 13 women with functional hypothalamic amenorrhea who had elevated anti-Mullerian hormone levels (10%), also
G.A.C. van Haasteren (Goedele)
textabstractThyrotrophin-releasing-hormone (TRH), a tripeptide, is produced by hypothalamic neurons and transported along their axons to the median eminence (ME). From there it is released at nerve terminals into hypophyseal portal blood. It is then transported to the anterior pituitary gland where
Chandrakantan, Arvind; Poulton, Thomas J
Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction is an increasingly common diagnosis in patients who are being seen at tertiary care children's hospitals. We present two cases of anesthetics from the authors' own experience in addition to a comprehensive review of the disorder and anesthetic implications. © 2012 Blackwell Publishing Ltd.
The transcription factor steroidogenic factor 1 (SF-1) is exclusively expressed in the brain in the ventral medial hypothalamic nucleus (VMH) and is required for the development of this nucleus. However, the physiological importance of transcriptional programs regulated by SF-1 in the VMH is not wel...
Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-a (ERa) stimulates neural firing of VMH neurons expressing ERa, and these ...
Imbernon, Monica; Sanchez-Rebordelo, Estrella; Romero-Picó, Amparo; Kalló, Imre; Chee, Melissa J; Porteiro, Begoña; Al-Massadi, Omar; Contreras, Cristina; Fernø, Johan; Senra, Ana; Gallego, Rosalia; Folgueira, Cintia; Seoane, Luisa M; van Gestel, Margriet; Adan, Roger A; Liposits, Zsolt; Dieguez, Carlos; Lopez, Miguel; Nogueiras, Ruben
The opioid system is widely known to modulate the brain reward system and thus affect human and animal behaviour, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and
Miller, Gregory E.; Chen, Edith; Zhou, Eric S.
The notion that chronic stress fosters disease by activating the hypothalamic-pituitary adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed…
Laurent, Heidemarie K.; Leve, Leslie D.; Neiderhiser, Jenae M.; Natsuaki, Misaki N.; Shaw, Daniel S.; Fisher, Philip A.; Marceau, Kristine; Harold, Gordon T.; Reiss, David
Child hypothalamic pituitary adrenal (HPA) activity was investigated as a moderator of parental depressive symptom effects on child behavior in an adoption sample ("n" = 210 families). Adoptive parents' depressive symptoms and child internalizing and externalizing were assessed at 18, 27, and 54 months, and child morning and evening HPA…
Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict doseresponse and time-course (...
Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course ...
Exposure to endocrine disrupting chemicals can affect reproduction and development in both humans and wildlife. We are developing a mechanistic mathematical model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (...
Gordijn, Maartje S.; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.
Background Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress
Gordijn, Maartje S.; Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.
Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate
Palmieri, G.; Stefani, S.; Gridelli, C.; Conte, A.; Airoma, G.; Contegiacomo, A.; Bianco, A.R.
We report on a 54-year-old woman with disseminated histiocytosis X who had a complete regression of all mucocutaneous lesions within 1 month from the completion of radiation therapy (4500 cGy) to the hypothalamic-hypophyseal (H-H) area. This response lasted 12 months, after which new cutaneous and bone lesions appeared
Rensen, Niki; Gemke, Reinoud J. B. J.; van Dalen, Elvira C.; Rotteveel, Joost; Kaspers, Gertjan J. L.
Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate
Kamatchi, Ganesan L; Rathanaswami, Palaniswami
The role of gamma amino butyric acid A receptors/neurons of the hypothalamic, endocrine and alimentary systems in the food intake seen in hunger was studied in 20 h food-deprived rats. Food deprivation decreased blood glucose, serum insulin and produced hyperphagia. The hyperphagia was inhibited by subcutaneous or ventromedial hypothalamic administration of gamma amino butyric acid A antagonists picrotoxin or bicuculline. Although results of blood glucose was variable, insulin level was increased by picrotoxin or bicuculline. In contrast, lateral hypothalamic administration of these agents failed to reproduce the above changes. Subcutaneous administration of picrotoxin or bicuculline increased gastric content, decreased gastric motility and small bowel transit. In contrast, ventromedial or lateral hypothalamic administration of picrotoxin or bicuculline failed to alter the gastric content but decreased the small bowel transit. The results of alimentary studies suggest that gamma amino butyric acid neurons of both ventromedial and lateral hypothalamus selectively regulate small bowel transit but not the gastric content. It may be concluded that ventromedial hypothalamus plays a dominant role in the regulation of food intake and that picrotoxin or bicuculline inhibited food intake by inhibiting gamma amino butyric acid receptors of the ventromedial hypothalamus, increasing insulin level and decreasing the gut motility.
Norren, van Klaske; Dwarkasing, Jvalini T.; Witkamp, Renger F.
PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia–cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key
van Santen, Hanneke M.; Schouten-Meeteren, Antoinette Y.; Serlie, Mireille; Meijneke, Ruud W. H.; van Trotsenburg, A. S.; Verberne, Hein; Holleman, Frits; Fliers, Eric
Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all
van Iersel, Laura; Meijneke, Ruud W. H.; Schouten-van Meeteren, Antoinette Y. N.; Reneman, Liesbeth; de Win, Maartje M.; van Trotsenburg, A. S. Paul; Bisschop, Peter H.; Finken, Martijn J. J.; Vandertop, W. Peter; van Furth, Wouter R.; van Santen, Hanneke M.
Hypothalamic obesity (HO) is a major concern in patients treated for craniopharyngioma (CP). The influence of degree of resection on development of HO, event-free survival (EFS), and neuroendocrine sequelae is an issue of debate. A retrospective cohort consisting of all CP patients treated between
de Vetten, L.; Bocca, Gianni
Objective With this case report, we aim to improve recognition of the systemic effects of hypothermia due to hypothalamic dysfunctioning. We present a patient who developed temperature dysregulation after surgery for craniopharyngioma. He suffered from several episodes of hypothermia associated with
Gardner, M.P.; Lightman, S.; Sayer, A.A.; Cooper, C.; Cooper, R.; Deeg, D.J.H.; Ebrahim, S.; Gallacher, J.; Kivimaki, M.; Kumari, M.; Kuh, D; Martin, R.M.; Peeters, G.; Ben-Shlomoa, Y.
The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is
Carter, R. N.; Paterson, J. M.; Tworowska, U.; Stenvers, D. J.; Mullins, J. J.; Seckl, J. R.; Holmes, M. C.
Inter-individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity underlie differential vulnerability to neuropsychiatric and metabolic disorders, although the basis of this variation is poorly understood. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has previously been
Evans, B.E.; Greaves-Lord, K.; Euser, A.S.; Franken, I.H.A.; Huizink, A.C.
Aims: Hypothalamic-pituitary-adrenal (HPA) axis activity may prove a viable biomarker for identifying those susceptible to alcohol use disorders. The purpose of this study was to examine the relation of the age at which adolescents begin drinking with diurnal and stress cortisol. Design:
Arrieta-Cruz, Isabel; Su, Ya; Knight, Colette M; Lam, Tony K T; Gutiérrez-Juárez, Roger
The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyte-neuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline's action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA-mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.
Bank, Jonathan H H; Cubuk, Ceyda; Wilson, Dana; Rijntjes, Eddy; Kemmling, Julia; Markovsky, Hanna; Barrett, Perry; Herwig, Annika
Thyroid hormones play an important role in regulating seasonal adaptations of mammals. Several studies suggested that reduced availability of 3,3',5-triiodothyronine (T3) in the hypothalamus is required for the physiological adaptation to winter in Djungarian hamsters. We have previously shown that T3 is involved in the regulation of daily torpor, but it remains unclear, whether T3 affects torpor by central or peripheral mechanisms. To determine the effect of T3 concentrations within the hypothalamus in regulating daily torpor, we tested the hypothesis that low hypothalamic T3 metabolism would favour torpor and high T3 concentrations would not. In experiment 1 gene expression in torpid hamsters was assessed for transporters carrying thyroid hormones between cerebrospinal fluid and hypothalamic cells and for deiodinases enzymes, activating or inactivating T3 within hypothalamic cells. Gene expression analysis suggests reduced T3 in hypothalamic cells during torpor. In experiment 2, hypothalamic T3 concentrations were altered via microdialysis and torpor behaviour was continuously monitored by implanted body temperature transmitters. Increased T3 concentrations in the hypothalamus reduced expression of torpor as well as torpor bout duration and depth. Subsequent analysis of gene expression in the ependymal layer of the third ventricle showed clear up-regulation of T3 inactivating deiodinase 3 but no changes in several other genes related to photoperiodic adaptations in hamsters. Finally, serum analysis revealed that increased total T3 serum concentrations were not necessary to inhibit torpor expression. Taken together, our results are consistent with the hypothesis that T3 availability within the hypothalamus significantly contributes to the regulation of daily torpor via a central pathway.
Meczekalski, B; Tonetti, A; Monteleone, P; Bernardi, F; Luisi, S; Stomati, M; Luisi, M; Petraglia, F; Genazzani, A R
Hypothalamic amenorrhea (HA) is a functional disorder caused by disturbances in gonadotropin-releasing hormone (GnRH) pulsatility. The mechanism by which stress alters GnRH release is not well known. Recently, the role of corticotropin-releasing hormone (CRH) and neurosteroids in the pathophysiology of HA has been considered. The aim of the present study was to explore further the role of the hypothalamic-pituitary-adrenal axis in HA. We included 8 patients (aged 23.16+/-1.72 years) suffering from hypothalamic stress-related amenorrhea with normal body weight and 8 age-matched healthy controls in the follicular phase of the menstrual cycle. We measured basal serum levels of FSH, LH, and estradiol and evaluated ACTH, allopregnanolone and cortisol responses to CRH test in both HA patients and healthy women. Serum basal levels of FSH, LH, and estradiol as well as basal levels of allopregnanolone were significantly lower in HA patients than in controls (P<0.001) while basal ACTH and cortisol levels were significantly higher in amenorrheic patients with respect to controls (P<0.001). The response (area under the curve) of ACTH, allopregnanolone and cortisol to CRH was significantly lower in amenorrheic women compared with controls (P<0.001, P<0.05, P<0.05 respectively). In conclusion, women with HA, despite the high ACTH and cortisol levels and, therefore, hypothalamus-pituitary-adrenal axis hyperactivity, are characterized by low allopregnanolone basal levels, deriving from an impairment of both adrenal and ovarian synthesis. The blunted ACTH, allopregnanolone and cortisol responses to CRH indicate that, in hypothalamic amenorrhea, there is a reduced sensitivity and expression of CRH receptor. These results open new perspectives on the role of neurosteroids in the pathogenesis of hypothalamic amenorrhea.
Sawchenko, P. E.; Arias, C.; Krasnov, I.; Grindeland, R. E.; Vale, W.
Possible effects of reduced gravity on central hypophysiotropic systems controlling growth hormone (GH) secretion were investigated in rats flown on Cosmos 1887 and 2044 biosatellites. Immunohistochemical (IHC)staining for the growth hormone-releasing factor (GRF), somatostatin (SS), and other hypothalamic hormones was performed on hypothalami obtained from rats. IHC analysis was complemented by quantitative in situ assessments of mRNAs encoding the precursors for these hormones. Data obtained suggest that exposure to microgravity causes a preferential reduction in GRF peptide and mRNA levels in hypophysiotropic neurons, which may contribute to impared GH secretion in animals subjected to spaceflight. Effects of weightlessness are not mimicked by hindlimb suspension in this system.
Layé, S; Gheusi, G; Cremona, S; Combe, C; Kelley, K; Dantzer, R; Parnet, P
The present study was designed to determine the role of endogenous brain interleukin (IL)-1 in the anorexic response to lipopolysaccharide (LPS). Intraperitoneal administration of LPS (5-10 microgram/mouse) induced a dramatic, but transient, decrease in food intake, associated with an enhanced expression of proinflammatory cytokine mRNA (IL-1beta, IL-6, and tumor necrosis factor-alpha) in the hypothalamus. This dose of LPS also increased plasma levels of IL-1beta. Intracerebroventricular pretreatment with IL-1 receptor antagonist (4 microgram/mouse) attenuated LPS-induced depression of food intake and totally blocked the LPS-induced enhanced expression of proinflammatory cytokine mRNA measured in the hypothalamus 1 h after treatment. In contrast, LPS-induced increases in plasma levels of IL-1beta were not altered. These findings indicate that endogenous brain IL-1 plays a pivotal role in the development of the hypothalamic cytokine response to a systemic inflammatory stimulus.
Do-Young, Kim; Fenoglio, Kristina A.; Kerrigan, John F.; Rho, Jong M.
SUMMARY The role of bicarbonate (HCO3-) in GABAA receptor-mediated depolarization of human hypothalamic hamartoma (HH) neurons was investigated using cellular electrophysiological and calcium imaging techniques. Activation of GABAA receptors with muscimol (30 μM) provoked neuronal excitation in over 70% of large (18-22 μM) HH neurons in HCO3- buffer. Subsequent perfusion of HCO3--free HEPES buffer produced partial suppression of muscimol-induced excitation. Additionally, 53% of large HH neurons under HCO3--free conditions exhibited reduced intracellular calcium accumulation by muscimol. These results suggest that HCO3- efflux through GABAA receptors on a subpopulation of large HH neurons may contribute to membrane depolarization and subsequent activation of L-type calcium channels. PMID:19022626
Jansen, Steffy W; Roelfsema, Ferdinand; Akintola, Abimbola A
OBJECTIVE: The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched...... for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation...... of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls. DESIGN: Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls...
Slavnov, V.N.; Luchitskij, E.V.
The corticotropic, thyrotropic and somatotropic functions of the adenohypophysis of patients with Cushing syndrome were examined radioimmunologically. Blood corticotropine and thyrotropine of these patients was characterized by a disturbed 24 hour rhythm. The release of corticotropine and somatotropine was but little increased as response to insulin hypoglycemia. The adenohypophysis responded weakly to the stimulation by thyroliberine. With the clinical remission of Cushing syndrome following treatment with chloditane or with a combined method an increased concentration of adenohypophyseal hormones in the blood could be demonstrated. The response to insulin hypoglycemic stress and to the thyroliberine stimulation was not normalized just as the 24-hour rhythm of the blood level of corticotropine and thyreotropine. Thus it can be concluded that these disturbances are caused by injuries of the central regulatory mechanisms of the hypothalamic-hypophyseal system, and pathogenetic therapeutic methods for the Cushing syndrome must be elaborated
Mello Andrea de Abreu Feijó de
Full Text Available Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology
Lin, Eleanor; Grinspoon, Steven; Wang, Thomas; Miller, Karen K
Natriuretic peptides, which are important regulators of salt handling and blood pressure, are 60%-75% higher in healthy young women than in men, consistent with a gender dimorphism. In this randomized, placebo-controlled study in women with functional hypothalamic amenorrhea, we show that administration of oral contraceptives (OC) increases natriuretic peptide levels and that end-of-study free T levels are inversely associated with amino-terminal pro-B-type natriuretic peptide levels, consistent with the hypothesis that natriuretic peptide levels may be mediated by differences in gonadal steroid concentrations-estrogens (E) or androgens. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Bomba, Monica; Corbetta, Fabiola; Gambera, Alessandro; Nicosia, Franco; Bonini, Luisa; Neri, Francesca; Tremolizzo, Lucio; Nacinovich, Renata
Aim of this study consisted in assessing the 24-h heart rate variability (HRV), a measure of autonomic nervous system (ANS) imbalance, in 21 adolescents with functional hypothalamic amenorrhea (FHA, 11 normogonadotropic, N-FHA, and 10 hypogonadotropic, Hy-FHA) compared to 21 patients with anorexia nervosa (AN) and 21 controls. As expected, subjects with AN showed a significant dysregulation in multiple HRV parameters, while Hy-FHA patients presented with a dysregulation in a few domains (SDNN, HFr), which was not present in girls with N-FHA, who showed values largely similar to controls. FHA might represent part of the AN biological spectrum, and a link between these two conditions might exist, possibly related to the degree of psychological and/or hormonal dysfunction. © 2013 Published by Elsevier Ireland Ltd.
Dundon, Carolyn M; Rellini, Alessandra H; Tonani, Silvia; Santamaria, Valentina; Nappi, Rosella
To investigate the sexual function of women with functional hypothalamic amenorrhea (FHA) and to test the mediating effects of depression and anxiety on the sexual functioning of women with FHA. In this cross-sectional study, participants completed questionnaires on sexual function, depression, and anxiety. Tertiary care university hospital. Women with (n=41) and without (n=39) FHA recruited from a gynecologic endocrinology unit. None. The McCoy Female Sexuality Questionnaire assessed sexual function, and the Zung Scale measured depression and anxiety. Women with FHA experienced more sexual function problems and significantly higher depression and anxiety compared to women without menstrual dysfunction. In addition, depression offered a significant explanation for the sexual problems experienced by women with FHA. The psychologic symptoms that contribute to the onset of FHA partially mediate the relationship between FHA and sexual dysfunction. Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Xiong, Fuxia; Zhang, Lubo
Adverse environments during the fetal and neonatal development period may permanently program physiology and metabolism, and lead to increased risk of diseases in later life. Programming of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key mechanisms that contribute to altered metabolism and response to stress. Programming of the HPA axis often involves epigenetic modification of the glucocorticoid receptor (GR) gene promoter, which influences tissue-specific GR expression patterns and response to stimuli. This review summarizes the current state of research on the HPA axis and programming of health and disease in the adult, focusing on the epigenetic regulation of GR gene expression patterns in response to fetal and neonatal stress. Aberrant GR gene expression patterns in the developing brain may have a significant negative impact on protection of the immature brain against hypoxic-ischemic encephalopathy in the critical period of development during and immediately after birth. PMID:23200813
Full Text Available Potassium iodide (KI is recommended as an emergency treatment for exposure to radioiodines, most commonly associated with nuclear detonation or mishaps at nuclear power plants. Protecting the thyroid gland of infants and children remains a priority because of increased incidence of thyroid cancer in the young exposed to radioiodines (such as 131I and 133I. There is a lack of clinical studies for KI and radioiodines in children or infants to draw definitive conclusions about the effectiveness and safety of KI administration in the young. In this paper, we compare functional aspects of the hypothalamic-pituitary-thyroid (HPT axis in the young and adults and review the limited studies of KI in children. The HPT axis in the infant and child is hyperactive and therefore will respond less effectively to KI treatment compared to adults. Research on the safety and efficacy of KI in infants and children is needed.
Varela, Luis; Suyama, Shigetomo; Huang, Yan; Shanabrough, Marya; Tschöp, Matthias H; Gao, Xiao-Bing; Giordano, Frank J; Horvath, Tamas L
Glucose is the primary driver of hypothalamic proopiomelanocortin (POMC) neurons. We show that endothelial hypoxia-inducible factor 1α (HIF-1α) controls glucose uptake in the hypothalamus and that it is upregulated in conditions of undernourishment, during which POMC neuronal activity is decreased. Endothelium-specific knockdown of HIF-1α impairs the ability of POMC neurons to adapt to the changing metabolic environment in vivo, resulting in overeating after food deprivation in mice. The impaired functioning of POMC neurons was reversed ex vivo or by parenchymal glucose administration. These observations indicate an active role for endothelial cells in the central control of metabolism and suggest that central vascular impairments may cause metabolic disorders. © 2017 by the American Diabetes Association.
The hypothalamic arcuate nucleus (ARC) and the area postrema (AP) represent targets for hormonal and metabolic signals involved in energy homoeostasis, e.g. glucose, amylin, insulin, leptin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and ghrelin. Orexigenic neuropeptide Y expressing ARC neurons are activated by food deprivation and inhibited by feeding in a nutrient-dependent manner. PYY and leptin also reverse or prevent fasting-induced activation of the ARC. Interestingly, hypothalamic responses to fasting are blunted in different models of obesity (e.g. diet-induced obesity (DIO) or late-onset obesity). The AP also responds to feeding-related signals. The pancreatic hormone amylin acts via the AP to control energy intake. Amylin-sensitive AP neurons are also glucose-responsive. Furthermore, diet-derived protein attenuates amylin responsiveness suggesting a modulation of AP sensitivity by macronutrient supply. This review gives an overview of the receptive function of the ARC and the AP to hormonal and nutritional stimuli involved in the control of energy balance and the possible implications in the context of obesity. Collectively, there is consistency between the neurophysiological actions of these stimuli and their effects on energy homoeostasis under experimental conditions. However, surprisingly little progress has been made in the development of effective pharmacological approaches against obesity. A promising way to improve effectiveness involves combination treatments (e.g. amylin/leptin agonists). Hormonal alterations (e.g. GLP-1 and PYY) are also considered to mediate body weight loss observed in obese patients receiving bariatric surgery. The effects of hormonal and nutritional signals and their interactions might hold the potential to develop poly-mechanistic therapeutic strategies against obesity.
Xiong, Xiaolu; Zhong, Anyuan; Xu, Huajun
Microcystins LR (MC-LR) are hepatotoxic cyanotoxins that have been shown to induce reproductive toxicity, and Hypothalamic-Pituitary-Gonadal Axis (HPG) is responsible for the control of reproductive functions. However, few studies have been performed to evaluate the effects of MC-LR on HPG axis. This study aimed to investigate the MC-LR-induced toxicity in the reproductive system of mouse and focus on the HPG axis. Adult male C57BL/6 mice were exposed to various concentrations of MC-LR (0, 3.75, 7.50, 15.00 and 30.00 µg/kg body weight per day) for 1 to 14 days, and it was found that exposure to different concentrations of MC-LR significantly disturbed sperm production in the mice testes in a dose- and time-dependent manner. To elucidate the associated possible mechanisms, the serum levels of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assessed. Meanwhile, PCR assays were employed to detect alterations in a series of genes involved in HPG axis, such as FSH, LH, gonadotropin-releasing hormone (GnRH) and their complement receptors. Furthermore, the effect of MC-LR on the viability and testosterone production of Leydig cells were tested in vitro. MC-LR significantly impaired the spermatogenesis of mice possibly through the direct or indirect inhibition of GnRH synthesis at the hypothalamic level, which resulted in reduction of serum levels of LH that lead to suppression of testosterone production in the testis of mice. MC-LR may be a GnRH toxin that would disrupt the reproductive system of mice.
Full Text Available Microcystins LR (MC-LR are hepatotoxic cyanotoxins that have been shown to induce reproductive toxicity, and Hypothalamic-Pituitary-Gonadal Axis (HPG is responsible for the control of reproductive functions. However, few studies have been performed to evaluate the effects of MC-LR on HPG axis. This study aimed to investigate the MC-LR-induced toxicity in the reproductive system of mouse and focus on the HPG axis.Adult male C57BL/6 mice were exposed to various concentrations of MC-LR (0, 3.75, 7.50, 15.00 and 30.00 µg/kg body weight per day for 1 to 14 days, and it was found that exposure to different concentrations of MC-LR significantly disturbed sperm production in the mice testes in a dose- and time-dependent manner. To elucidate the associated possible mechanisms, the serum levels of testosterone, follicle-stimulating hormone (FSH and luteinizing hormone (LH were assessed. Meanwhile, PCR assays were employed to detect alterations in a series of genes involved in HPG axis, such as FSH, LH, gonadotropin-releasing hormone (GnRH and their complement receptors. Furthermore, the effect of MC-LR on the viability and testosterone production of Leydig cells were tested in vitro.MC-LR significantly impaired the spermatogenesis of mice possibly through the direct or indirect inhibition of GnRH synthesis at the hypothalamic level, which resulted in reduction of serum levels of LH that lead to suppression of testosterone production in the testis of mice.MC-LR may be a GnRH toxin that would disrupt the reproductive system of mice.
It is shown that the model of the hypothalamic-pituitary-adrenal gland axis is a differentially flat one and this permits to transform it to the so-called linear canonical form. For the new description of the system's dynamics the transformed control inputs contain unknown terms which depend on the system's parameters. To identify these terms an adaptive fuzzy approximator is used in the control loop. Thus an adaptive fuzzy control scheme is implemented in which the unknown or unmodeled system dynamics is approximated by neurofuzzy networks and next this information is used by a feedback controller that makes the state variables (CRH - corticotropin releasing hormone, adenocortocotropic hormone - ACTH, cortisol) of the hypothalamic-pituitary-adrenal gland axis model converge to the desirable levels (setpoints). This adaptive control scheme is exclusively implemented with the use of output feedback, while the state vector elements which are not directly measured are estimated with the use of a state observer that operates in the control loop. The learning rate of the adaptive fuzzy system is suitably computed from Lyapunov analysis, so as to assure that both the learning procedure for the unknown system's parameters, the dynamics of the observer and the dynamics of the control loop will remain stable. The performed Lyapunov stability analysis depends on two Riccati equations, one associated with the feedback controller and one associated with the state observer. Finally, it is proven that for the control scheme that comprises the feedback controller, the state observer and the neurofuzzy approximator, an H-infinity tracking performance can be succeeded.
Fernandez, Marina O; Bourguignon, Nadia S; Arocena, Paula; Rosa, Matías; Libertun, Carlos; Lux-Lantos, Victoria
Bisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins and polystyrene found in many common products. Several reports revealed potent in vivo and in vitro effects. In this study we analyzed the effects of the exposure to BPA in the hypothalamic-pituitary-thyroid axis in female rats, both in vivo and in vitro. Female Sprague-Dawley rats were injected sc from postnatal day 1 (PND1) to PND10 with BPA: 500 μg 50 μl -1 oil (B500), or 50 μg 50 μl -1 (B50), or 5 μg 50 μl -1 (B5). Controls were injected with 50 μl vehicle during the same period. Neonatal exposure to BPA did not modify TSH levels in PND13 females, but it increased them in adults in estrus. Serum T4 was lower in B5 and B500 with regards to Control, whereas no difference was seen in T3. No significant differences were observed in TRH, TSHβ and TRH receptor expression between groups. TSH release from PPC obtained from adults in estrus was also higher in B50 with regard to Control. In vitro 24 h pre-treatment with BPA or E 2 increased basal TSH as well as prolactin release. On the other hand, both BPA and E 2 lowered the response to TRH. The results presented here show that the neonatal exposure to BPA alters the hypothalamic pituitary-thyroid axis in adult rats in estrus, possibly with effects on the pituitary and thyroid. They also show that BPA alters TSH release from rat PPC through direct actions on the pituitary. Copyright © 2018 Elsevier B.V. All rights reserved.
Vries, H.P. de; Wiener, J.D.; Vrije Universiteit, Amsterdam
The aim of this study was to develop a test which could be used as a complement to the assay of serum TSH and the TRH test in the evaluation of hypothalamic-pituitary-thyroid adequacy. When T 3 , 75 μg per day, was given to healthy subjects for 7 days (days 1-7), a significant rebound of serum TSH over the basal value was found on at least two of days 15-17 in nine of ten cases, provided potassium iodide, 10 mg per day, was also given on days 6-16. A much more pronounced rebound of TSH was obtained when thyroid hormone release was more rigorously blocked with the following medication: 125 μg T 3 on days 1-7, 500 mg KI on days 1-16, and 400 mg of a slowly resorbed lithium carbonate preparation on days 1-16. In the latter case TSH rose from an average basal value of 0.96 μU/ml to a mean of 3.41 μU/ml on day 17 in 10 healthy subjects. In a subsequent experiment a similar TSH rebound was obtained with 125 μg T 3 (days 1-7) and 500 mg KI (days 1-16) only. The mechanism whereby the TSH rebound is brought about remains to be established. One possibility is a transhypothalamic action. In this case the procedure may prove useful as a clinical test for the detection of slight degrees of hypothalamic insufficiency which cannot be diagnosed with certainty by the TRH test. The present experiments provide indirect evidence for a suppressive action of comparatively small doses (10 mg per day) of KI on thyroid hormone release in healthy subjects. (orig.) [de
Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David
Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested ( n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present in the presence of tetrodotoxin and 4-aminopyridine, suggesting a monosynaptic connection between orexin neurons and SPNs. In addition to generating postsynaptic responses, photostimulation facilitated action potential firing in SPNs (current clamp configuration). Glutamatergic, but not GABAergic, postsynaptic currents were diminished by application of the orexin receptor antagonist almorexant, indicating orexin release facilitates glutamatergic neurotransmission in this pathway. This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function. NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not
Osterstock, Guillaume; El Yandouzi, Taoufik; Romanò, Nicola; Carmignac, Danielle; Langlet, Fanny; Coutry, Nathalie; Guillou, Anne; Schaeffer, Marie; Chauvet, Norbert; Vanacker, Charlotte; Galibert, Evelyne; Dehouck, Bénédicte; Robinson, Iain C A F; Prévot, Vincent; Mollard, Patrice; Plesnila, Nikolaus; Méry, Pierre-François
Traumatic brain injury is a leading cause of hypopituitarism, which compromises patients' recovery, quality of life, and life span. To date, there are no means other than standardized animal studies to provide insights into the mechanisms of posttraumatic hypopituitarism. We have found that GH levels were impaired after inducing a controlled cortical impact (CCI) in mice. Furthermore, GHRH stimulation enhanced GH to lower level in injured than in control or sham mice. Because many characteristics were unchanged in the pituitary glands of CCI mice, we looked for changes at the hypothalamic level. Hypertrophied astrocytes were seen both within the arcuate nucleus and the median eminence, two pivotal structures of the GH axis, spatially remote to the injury site. In the arcuate nucleus, GHRH neurons were unaltered. In the median eminence, injured mice exhibited unexpected alterations. First, the distributions of claudin-1 and zonula occludens-1 between tanycytes were disorganized, suggesting tight junction disruptions. Second, endogenous IgG was increased in the vicinity of the third ventricle, suggesting abnormal barrier properties after CCI. Third, intracerebroventricular injection of a fluorescent-dextran derivative highly stained the hypothalamic parenchyma only after CCI, demonstrating an increased permeability of the third ventricle edges. This alteration of the third ventricle might jeopardize the communication between the hypothalamus and the pituitary gland. In conclusion, the phenotype of CCI mice had similarities to the posttraumatic hypopituitarism seen in humans with intact pituitary gland and pituitary stalk. It is the first report of a pathological status in which tanycyte dysfunctions appear as a major acquired syndrome.
Full Text Available ABSTRACT The objective of this study was to evaluate the effect of high or low energy intake on carcass composition and expression of hypothalamic genes related to the onset of puberty. Twenty-four prepubertal Nellore heifers, 18-20- months-old, with 275.3±18.0 kg body weight (BW, and 4.9±0.2 (1-9 scale body condition score (BCS were randomly assigned to two treatments: high-energy diet (HE and low-energy diet (LE. Heifers were housed in two collective pens and fed diets formulated to promote average daily gain of 0.4 (LE or 1.2 kg (HE BW/day. Eight heifers from each treatment were slaughtered after the first corpus luteum detection - considered as age of puberty. The 9-10-11th rib section was taken and prepared for carcass composition analyses. Samples from hypothalamus were collected, frozen in liquid nitrogen, and stored at −80 °C. Specific primers for targets (NPY, NPY1R, NPY4R, SOCS3, OXT, ARRB1, and IGFPB2 and control (RPL19 and RN18S1 genes were designed for real-time PCR and then the relative quantification of target gene expression was performed. High-energy diets increased body condition score, cold carcass weight, and Longissimus lumborum muscle area and decreased age at slaughter. High-energy diets decreased the expression of NPY1R and ARRB1 at 4.4-fold and 1.5-fold, respectively. In conclusion, the hastening of puberty with high energy intake is related with greater body fatness and lesser hypothalamic expression of NPY1 receptor and of β-arrestin1, suggesting a less sensitive hypothalamus to the negative effects of NPY signaling.
Khatlab, A.S.; Vesco, A.P. DEL; Goes, E.R.; Neto, A.R.O.; Soares, M.A.M.; Gasparino, E.
Our study aims to evaluate gender and heat stress effects on animal performance and on the expression of five hypothalamic genes related to feed consumption: neuropeptide Y (NPY), ghrelin (GHRL), pro-opiomelanocortin (POMC), AMP-activated protein kinase (AMPKα-1), and liver kinase B1 (LKB1). To assay these effects, 42-day-old male and female broilers were maintained in thermal comfort or were subjected to heat stress (HS, 38°C for 24 hours). All animals were fed with diets formulated to meet their nutritional requirements. Broilers subjected to HS showed lower weight gain (p=0.0065) and tended to have lower feed intake (p=0.0687) than broilers kept in comfortable conditions. We observed gender and heat stress interaction effects on NPY (p=0.0225), AMPKα-1 (p=0.0398), and POMC expression (p=0.0072). The highest NPY gene expression was observed in male broilers from the thermal comfort group. Male broilers exposed to HS showed the highest AMPKα-1 gene expression levels. Comparing POMC expression between males and females at the comfortable temperature, we observed that females showed higher POMC expression levels than male broilers. A gender effect was also observed on LKB1 and AMPKα-1 gene expression (p=0.0256 and p=0.0001, respectively); increased expression was observed in male broilers. Our results indicate that the expression of some hypothalamic genes related to food consumption may contribute to the observed differences in voluntary feed intake between animals of different gender exposed to different environmental conditions.
Pearlman, S.H.; Rubin, P.; White, H.C.; Wiegand, S.J.; Gash, D.M.
This study was designed to test the hypothesis that neural implants can ameliorate or prevent some of the long-term changes associated with CNS irradiation. Using a rat model, the initial study focused on establishing motor, regulatory, and morphological changes associated with brain radiation treatments. Secondly, fetal hypothalamic tissue grafts were placed into the third ventricle of rats which had been previously irradiated. Adult male Long Evans rats received one of three radiation doses (15, 22.5, ampersand 30 Gy) or no radiation. Three days after irradiation, 7 animals in each dose group received an embryonic day 17 hypothalamic graft into the third ventricle while the remaining 8-9 animals in each group received injections of vehicle solution (sham). Few changes were observed in the 15 and 22.5 Gy animals, however rats in the 30 Gy treatment group showed stereotypic and ambulatory behavioral hyperactivity 32 weeks after irradiation. Regulatory changes in the high dose group included decreased growth rate and decreased urine osmolalities, but these measures were extremely variable among animals. Morphological results demonstrated that 30 Gy irradiated animals showed extensive necrosis primarily in the fimbria, which extended into the internal capsule, optic nerve, hippocampus, and thalamus. Hemorrhages were found in the hippocampus, thalamus, and fimbria. Defects in the blood-brain barrier also were evident by entry of intravascularly injected horseradish peroxidase into the parenchyma of the brain. Animals in the 30 Gy grafted group showed fewer behavioral changes and less brain damage than their sham grafted counterparts. Specifically, activity measures were comparable to normal levels, and a dilute urine was not found in the 30 Gy implanted rats. Morphological changes support these behavioral results since only two 30 Gy implanted rats showed necrosis
Perkins, R B; Hall, J E; Martin, K A
To characterize the neuroendocrine patterns of abnormal GnRH secretion in hypothalamic amenorrhea (HA), 49 women with primary and secondary HA underwent frequent sampling of LH in a total of 72 baseline studies over 12-24 h. A subset of women participated in more than one study to address 1) the variability of LH pulse patterns over time; and 2) the impact of modulating opioid, dopaminergic, and adrenergic tone on LH secretory patterns. The frequency and amplitude of LH secretion was compared with that seen in the early follicular phase (EFP) of normally cycling women. The spectrum of abnormalities of LH pulses was 8% apulsatile, 27% low frequency/low amplitude, 8% low amplitude/normal frequency, 43% low frequency/normal amplitude, 14% normal frequency/normal amplitude. Of patients studied overnight, 45% demonstrated a pubertal pattern of augmented LH secretion during sleep. Of patients studied repeatedly, 75% demonstrated at least 2 different patterns of LH secretion, and 33% reverted at least once to a normal pattern of secretion. An increase in LH pulse frequency was seen in 12 of 15 subjects in response to naloxone (opioid receptor antagonist). Clonidine (alpha-2 adrenergic agonist) was associated with a decrease in mean LH in 3 of 3 subjects. An increase in LH pulse frequency was seen in 4 of 8 subjects in response to metoclopramide (dopamine receptor antagonist), but the response was not statistically significant. Baseline abnormalities in LH secretion did not appear to influence response to neurotransmitter modulation. 1) HA represents a spectrum of disordered GnRH secretion that can vary over time; 2) LH pulse patterns at baseline do not appear to influence the ability to respond to neurotransmitter modulation; 3) Opioid and adrenergic tone appear to influence the hypothalamic GnRH pulse generator in some individuals with HA.
Dembele, Korami; Yao, Xing-Hai; Chen, Li; Nyomba, B L Grégoire
Prenatal ethanol (EtOH) exposure is associated with low birth weight, followed by increased appetite, catch-up growth, insulin resistance, and impaired glucose tolerance in the rat offspring. Because EtOH can induce oxidative stress, which is a putative mechanism of insulin resistance, and because of the central role of the hypothalamus in the regulation of energy homeostasis and insulin action, we investigated whether prenatal EtOH exposure causes oxidative damage to the hypothalamus, which may alter its function. Female rats were given EtOH by gavage throughout pregnancy. At birth, their offspring were smaller than those of non-EtOH rats. Markers of oxidative stress and expression of neuropeptide Y and proopiomelanocortin (POMC) were determined in hypothalami of postnatal day 7 (PD7) and 3-mo-old (adult) rat offspring. In both PD7 and adult rats, prenatal EtOH exposure was associated with decreased levels of glutathione and increased expression of MnSOD. The concentrations of lipid peroxides and protein carbonyls were normal in PD7 EtOH-exposed offspring, but were increased in adult EtOH-exposed offspring. Both PD7 and adult EtOH-exposed offspring had normal neuropeptide Y and POMC mRNA levels, but the adult offspring had reduced POMC protein concentration. Thus only adult offspring preexposed to EtOH had increased hypothalamic tissue damage and decreased levels of POMC, which could impair melanocortin signaling. We conclude that prenatal EtOH exposure causes hypothalamic oxidative stress, which persists into adult life and alters melanocortin action during adulthood. These neuroendocrine alterations may explain weight gain and insulin resistance in rats exposed to EtOH early in life.
Full Text Available Maternal consumption of a high fat diet during early development has been shown to impact the formation of hypothalamic neurocircuitry, thereby contributing to imbalances in appetite and energy homeostasis and increasing the risk of obesity in subsequent generations. Early in postnatal life, the neuronal projections responsible for energy homeostasis develop in response to appetite-related peptides such as leptin. To date, no study characterises the genome-wide transcriptional changes that occur in response to exposure to high fat diet during this critical window. We explored the effects of maternal high fat diet consumption on hypothalamic gene expression in Sprague Dawley rat offspring at postnatal day 10. RNA-sequencing enabled discovery of differentially expressed genes between offspring of dams fed a high fat diet and offspring of control diet fed dams. Female high fat diet offspring displayed altered expression of 86 genes (adjusted P-value<0.05, including genes coding for proteins of the extra cellular matrix, particularly Collagen 1a1 (Col1a1, Col1a2, Col3a1, and the imprinted Insulin-like growth factor 2 (Igf2 gene. Male high fat diet offspring showed significant changes in collagen genes (Col1a1 and Col3a1 and significant upregulation of two genes involved in regulation of dopamine availability in the brain, tyrosine hydroxylase (Th and dopamine reuptake transporter Slc6a3 (also known as Dat1. Transcriptional changes were accompanied by increased body weight, body fat and body length in the high fat diet offspring, as well as altered blood glucose and plasma leptin. Transcriptional changes identified in the hypothalamus of offspring of high fat diet mothers could alter neuronal projection formation during early development leading to abnormalities in the neuronal circuitry controlling appetite in later life, hence priming offspring to the development of obesity.
McEwen, Hayden J L; Inglis, Megan A; Quennell, Janette H; Grattan, David R; Anderson, Greg M
The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction. Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the
Naderi, Fatemeh; Hernández-Pérez, Juan; Chivite, Mauro; Soengas, José L; Míguez, Jesús M; López-Patiño, Marcos A
Stress is conditioning animal welfare by negatively affecting a wide range of physiological and behavioral functions. This may be applied to circadian physiology and food intake. Cortisol, the stress-related hormone, may mediate such effect of stress, but other indirect mediators might be considered, such as sirtuin1. Then, either the independent modulatory effect or the existence of any interaction between mediators may be responsible. The circadian system is the main modulator of several integrative mechanisms at both central and peripheral levels that are rhythmically presented, thus influencing different processes such as food intake. In this way, food intake is controlled by the circadian system, as demonstrated by the persistence of such rhythms of food intake in the absence of environmental external cues. Our study aimed to evaluate the daily profile of hypothalamic mRNA abundance of circadian clock genes (clock1a, bmal1, per1 and rev-erbβ-like), and food intake regulators (crf, pomc-a1, cart, and npy) in rainbow trout (Oncorhynchus mykiss), the impact of stress on such rhythms, and the involvement of cortisol and sirtuin1 as mediators. Four cohorts of trout were subjected to 1) normal stocking density (control group), 2) high stocking density for 72 hours (stress group), 3) normal stocking density and implanted with mifepristone, a glucocorticoid receptors antagonist, and 4) mifepristone administered and stressed for 72 hours. Fish from each group were sampled every 4-h along the 24-h LD cycle, and cortisol, glucose and lactate plasma levels were evaluated. Hypothalamic mRNA abundance of clock genes, food intake regulators, glucocorticoid receptors and sirtuin1 were qPCR assayed. Our results reveal the impact of stress on most of the genes assayed, but different mechanisms appear to be involved. The rhythm of clock genes displayed decreased amplitude and averaged levels in stressed trout, with no changes of the acrophase being observed. This effect was
Horst, G.J. ter; Luiten, P.G.M.
Intrahypothalamic connections of the lateral (LHA), ventromedial (VMH), dorsomedial (DMH) and paraventricular (PVN) hypothalamic nuclei were studied with anterograde transport of iontophoretically injected Phaseolus vulgaris leuco-agglutinin and the immunocytochemical detection of labeled
To identify transcription factors (TFs), members of hypothalamic-pituitary- gonadal axis (HPG-axis), TF networks and signaling pathways underlying generalized effects of 3-beta hydroxysteroid dehydrogenase (HSD3B) inhibition, reproductively mature zebrafish (Danio rerio) were exp...
The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazo...
The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazo...
Sorgdrager, F. J. H.; Doornbos, B.; Penninx, B. W. J. H.; de Jonge, P.; Kema, I. P.
Objectives: Persistent changes in serotonergic and hypothalamic pituitary adrenal (HPA) axis functioning are implicated in recurrent types of major depressive disorder (MDD). Systemic tryptophan levels, which influence the rate of serotonin synthesis, are regulated by glucocorticoids produced along
Full Text Available response to endotoxin (LPS). Derijk RH, van Rooijen N, Berkenbosch F. Res Immunol. 1992 Feb;143(2):224-9. (....e hypothalamic-pituitary-adrenal activation inresponse to endotoxin (LPS). Authors Derijk RH, van Rooijen N, Berk
U.S. Environmental Protection Agency — The aim of this study was to investigate temporal changes in the hypothalamic-pituitary-gonadal axis of fathead minnow treated with the model androgen receptor (AR)...
Sugiyama, Mariko; Banno, Ryoichi; Mizoguchi, Akira; Tominaga, Takashi; Tsunekawa, Taku; Onoue, Takeshi; Hagiwara, Daisuke; Ito, Yoshihiro; Morishita, Yoshiaki; Iwama, Shintaro; Goto, Motomitsu; Suga, Hidetaka; Arima, Hiroshi
Hypothalamic insulin receptor signaling regulates energy balance and glucose homeostasis via agouti-related protein (AgRP). While protein tyrosine phosphatase 1B (PTP1B) is classically known to be a negative regulator of peripheral insulin signaling by dephosphorylating both insulin receptor β (IRβ) and insulin receptor substrate, the role of PTP1B in hypothalamic insulin signaling remains to be fully elucidated. In the present study, we investigated the role of PTP1B in hypothalamic insulin signaling using PTP1B deficient (KO) mice in vivo and ex vivo. For the in vivo study, hypothalamic insulin resistance induced by a high-fat diet (HFD) improved in KO mice compared to wild-type (WT) mice. Hypothalamic AgRP mRNA expression levels were also significantly decreased in KO mice independent of body weight changes. In an ex vivo study using hypothalamic organotypic cultures, insulin treatment significantly increased the phosphorylation of both IRβ and Akt in the hypothalamus of KO mice compared to WT mice, and also significantly decreased AgRP mRNA expression levels in KO mice. While incubation with inhibitors of phosphatidylinositol-3 kinase (PI3K) had no effect on basal levels of Akt phosphorylation, these suppressed insulin induction of Akt phosphorylation to almost basal levels in WT and KO mice. The inhibition of the PI3K-Akt pathway blocked the downregulation of AgRP mRNA expression in KO mice treated with insulin. These data suggest that PTP1B acts on the hypothalamic insulin signaling via the PI3K-Akt pathway. Together, our results suggest a deficiency of PTP1B improves hypothalamic insulin sensitivity resulting in the attenuation of AgRP mRNA expression under HFD conditions. Copyright © 2017 Elsevier Inc. All rights reserved.
Lindahl, Magnus S; Olovsson, Matts; Nyberg, Sigrid; Thorsen, Kim; Olsson, Tommy; Sundström Poromaa, Inger
To assess the hypothalamic-pituitary-adrenal (HPA) axis at all levels, to determine the origin of the previously reported hypercortisolism in patients with functional hypothalamic amenorrhea. A secondary aim was to evaluate factors outside the central nervous system which are known to affect the HPA axis, i.e., circulating levels of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and fat mass-adjusted leptin levels, in patients with functional hypothalamic amenorrhea and healthy controls. Cross-sectional study. Umeå University Hospital, Umeå, Sweden. Fifteen subjects with hypothalamic amenorrhea, and 14 age- and weight-matched controls. None. We collected blood samples four times during a 24-hour interval for analysis of cortisol, leptin, IL-1Ra, and IL-6 levels. We performed a low-dose oral dexamethasone test and a low-dose ACTH test. We measured body-fat percentage using a dual-energy X-ray absorptiometer. Patients with hypothalamic amenorrhea had increased diurnal cortisol levels (P<.001). The cortisol response to intravenous low-dose ACTH was increased in functional hypothalamic amenorrhea patients compared to control subjects (P<.01), but they had similar rates of dexamethasone suppression. Patients with hypothalamic amenorrhea also had decreased diurnal leptin (P<.05), and decreased diurnal IL-1Ra levels (P<.05), compared to controls. Body-fat percentage was the main predictor of leptin levels. The present study suggests novel links for the development of functional hypothalamic amenorrhea, including increased adrenal responsiveness and impairments in proinflammatory cytokine pathways.
Xu, Tao-Tao; Jin, Hong-Ting; Tong, Pei-Jian
As a traditional concept of Chinese medicine (CM), the theory of "Shen (Kidney) controlling bones" has been gradually proven. And in modern allopathic medicine, the multiple mechanisms of bone growth, development and regeneration align with the theory. Shen defifi ciency as a pathological condition has a negative effect on the skeleton of body, specififi cally the disorder of bone homeostasis. Present studies indicate that Shen defifi ciency shares a common disorder characterized by dysfunction of hypothalamic-pituitary-adrenal (HPA) axis. HPA axis may be an important regulator of bone diseases with abnormal homeostasis. Therefore, we posit the existence of hypothalamic-pituitary-adrenal-osteo-related cells axis: cells that comprise bone tissue (osteo-related cells) are targets under the regulation of HPA axis in disorder of bone homeostasis. Chinese herbs for nourishing Shen have potential in the development of treatments for disorder of bone homeostasis.
Gerstenberg, Marina Kjærgaard; Nilsson, C; Secher, A
Background/objective: Intake of high-energy foods and maternal nutrient overload increases the risk of metabolic diseases in the progeny such as obesity and diabetes. We hypothesized that maternal and postnatal intake of chocolate and soft drink will affect leptin sensitivity and hypothalamic...... for the metabolic phenotype in the offspring if they continued on the S diet in postnatal life. These offspring displayed obesity despite lowered energy intake associated with alterations in hypothalamic leptin signalling....... assigned to either S or C diet, giving four groups until the end of the experiment at 26 weeks of age. Results: As expected, adult offspring fed the S diet post weaning became obese (body weight: P
Allaway, Heather C M; Southmayd, Emily A; De Souza, Mary Jane
An energy deficiency is the result of inadequate energy intake relative to high energy expenditure. Often observed with the development of an energy deficiency is a high drive for thinness, dietary restraint, and weight and shape concerns in association with eating behaviors. At a basic physiologic level, a chronic energy deficiency promotes compensatory mechanisms to conserve fuel for vital physiologic function. Alterations have been documented in resting energy expenditure (REE) and metabolic hormones. Observed metabolic alterations include nutritionally acquired growth hormone resistance and reduced insulin-like growth factor-1 (IGF-1) concentrations; hypercortisolemia; increased ghrelin, peptide YY, and adiponectin; and decreased leptin, triiodothyronine, and kisspeptin. The cumulative effect of the energetic and metabolic alterations is a suppression of the hypothalamic-pituitary-ovarian axis. Gonadotropin releasing hormone secretion is decreased with consequent suppression of luteinizing hormone and follicle stimulating hormone release. Alterations in hypothalamic-pituitary secretion alters the production of estrogen and progesterone resulting in subclinical or clinical menstrual dysfunction.
Full Text Available The hypothalamus is a forebrain structure critically involved in the organization of defensive responses to aversive stimuli. Gamma-aminobutyric acid (GABAergic dysfunction in dorsomedial and posterior hypothalamic nuclei is implicated in the origin of panic-like defensive behavior, as well as in pain modulation. The present study was conducted to test the difference between these two hypothalamic nuclei regarding defensive and antinociceptive mechanisms. Thus, the GABA A antagonist bicuculline (40 ng/0.2 µL or saline (0.9% NaCl was microinjected into the dorsomedial or posterior hypothalamus in independent groups. Innate fear-induced responses characterized by defensive attention, defensive immobility and elaborate escape behavior were evoked by hypothalamic blockade of GABA A receptors. Fear-induced defensive behavior organized by the posterior hypothalamus was more intense than that organized by dorsomedial hypothalamic nuclei. Escape behavior elicited by GABA A receptor blockade in both the dorsomedial and posterior hypothalamus was followed by an increase in nociceptive threshold. Interestingly, there was no difference in the intensity or in the duration of fear-induced antinociception shown by each hypothalamic division presently investigated. The present study showed that GABAergic dysfunction in nuclei of both the dorsomedial and posterior hypothalamus elicit panic attack-like defensive responses followed by fear-induced antinociception, although the innate fear-induced behavior originates differently in the posterior hypothalamus in comparison to the activity of medial hypothalamic subdivisions.
Aljabban, Lama; Kassab, Lina; Bakoura, Nour Alhuda; Alsalka, Mohammad Fayez; Maksoud, Ismaeil
Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome is a rare pediatric disorder with a variable sequence of clinical presentations, undefined etiology, and high risk of mortality. Our patient presented an unusual course of the disease accompanied by a homogenous mild enlargement of her pituitary gland with an intact pituitary-endocrine axis which, to the best of our knowledge, represents a new finding in rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome. We present a documented case of a 4 years and 8-month-old Syrian Arabic girl with a distinctive course of signs and symptoms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome accompanied by mature ganglioneuroma in her chest, a homogenous mild enlargement of her pituitary gland, generalized cortical brain atrophy, and seizures. Three months after her first marked symptoms were noted she had a sudden progression of severe respiratory distress that ended with her death. The findings of this case could increase our understanding of the pathogenetic mechanisms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation, and place more emphases on pediatricians to consider rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome whenever early rapid onset of obesity, associated with any malfunction, is observed in children. This knowledge could be lifesaving for children with rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome.
Patisaul Heather B
Full Text Available Abstract Background It is well established that sexual differentiation of the rodent hypothalamic-pituitary-gonadal (HPG axis is principally orchestrated by estrogen during the perinatal period. Here we sought to better characterize the mechanistic role the beta form of the estrogen receptor (ERβ plays in this process. Methods To achieve this, we exposed neonatal female rats to three doses (0.5, 1 and 2 mg/kg of the ERβ selective agonist diarylpropionitrile (DPN using estradiol benzoate (EB as a positive control. Measures included day of vaginal opening, estrous cycle quality, GnRH and Fos co-localization following ovariectomy and hormone priming, circulating luteinizing hormone (LH levels and quantification of hypothalamic kisspeptin immunoreactivity. A second set of females was then neonatally exposed to DPN, the ERα agonist propyl-pyrazole-triol (PPT, DPN+PPT, or EB to compare the impact of ERα and ERβ selective agonism on kisspeptin gene expression in pre- and post-pubescent females. Results All three DPN doses significantly advanced the day of vaginal opening and induced premature anestrus. GnRH and Fos co-labeling, a marker of GnRH activation, following ovariectomy and hormone priming was reduced by approximately half at all doses; the magnitude of which was not as large as with EB or what we have previously observed with the ERα agonist PPT. LH levels were also correspondingly lower, compared to control females. No impact of DPN was observed on the density of kisspeptin immunoreactive (-ir fibers or cell bodies in the arcuate (ARC nucleus, and kisspeptin-ir was only significantly reduced by the middle (1 mg/kg DPN dose in the preoptic region. The second experiment revealed that EB, PPT and the combination of DPN+PPT significantly abrogated preoptic Kiss1 expression at both ages but ARC expression was only reduced by EB. Conclusion Our results indicate that selective agonism of ERβ is not sufficient to completely achieve male
Hypothalamic-Pituitary-Adrenal Function in Posttraumatic Stress PRINCIPAL INVESTIGATOR: Sabra Inslicht, Ph.D. RECIPIENT: Northern California Institute...Posttraumatic Stress 5b. GRANT NUMBER W81XWH-16-1-0313 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sabra Inslicht, PhD 5d. PROJECT NUMBER 5e. TASK NUMBER...ABSTRACT Post-traumatic stress (PTS) is a common psychiatric condition that may result after combat exposure and can have a profound effect on sleep
Barclay, Sarah F.; Rand, Casey M.; Borch, Lauren A.; Nguyen, Lisa; Gray, Paul A.; Gibson, William T.; Wilson, Richard J. A.; Gordon, Paul M. K.; Aung, Zaw; Berry-Kravis, Elizabeth M.; Ize-Ludlow, Diego; Weese-Mayer, Debra E.; Bech-Hansen, N. Torben
Background Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients. Methods We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin ...
White, Christy L.; Whittington, Amy; Barnes, Maria J.; Wang, Zhong; Bray, George A.; Morrison, Christopher D.
Protein tyrosine phosphatase 1B (PTP1B) contributes to leptin resistance by inhibiting intracellular leptin receptor signaling. Mice with whole body or neuron-specific deletion of PTP1B are hypersensitive to leptin and resistant to diet-induced obesity. Here we report a significant increase in PTP1B protein levels in the mediobasal hypothalamus (P = 0.003) and a concomitant reduction in leptin sensitivity following 28 days of high-fat (HF) feeding in rats. A significant increase in PTP1B mRNA levels was also observed in rats chronically infused with leptin (3 μg/day icv) for 14 days (P = 0.01) and in leptin-deficient ob/ob mice infused with leptin (5 μg/day sc for 14 days; P = 0.003). When saline-infused ob/ob mice were placed on a HF diet for 14 days, an increase in hypothalamic PTP1B mRNA expression was detected (P = 0.001) despite the absence of circulating leptin. In addition, although ob/ob mice were much more sensitive to leptin on a low-fat (LF) diet, a reduction in this sensitivity was still observed following exposure to a HF diet. Taken together, these data indicate that hypothalamic PTP1B is specifically increased during HF diet-induced leptin resistance. This increase in PTP1B is due in part to chronic hyperleptinemia, suggesting that hyperleptinemia is one mechanism contributing to the development of leptin resistance. However, these data also indicate that leptin is not required for the increase in hypothalamic PTP1B or the development of leptin resistance. Therefore, additional, leptin-independent mechanisms must exist that increase hypothalamic PTP1B and contribute to leptin resistance. PMID:19017730
Lucassen, Eliane A.; Cizza, Giovanni
Obesity, exposure to stress and inadequate sleep are prevalent phenomena in modern society. In this review we focus on their relationships and critically evaluate causality. In obese individuals, one of the main stress systems, the hypothalamic-pituitary-adrenal axis, is altered, and concentrations of cortisol are elevated in adipose tissue due to elevated local activity of 11β-hydroxysteroid dehydrogenase (HSD) type 1. Short sleep and decreased sleep quality are also associated with obesity....
Harrell, Constance S.; Burgado, Jillybeth; Kelly, Sean D.; Johnson, Zachary P.; Neigh, Gretchen N.
Fructose consumption, which promotes insulin resistance, hypertension, and dyslipidemia, has increased by over 25% since the 1970s. In addition to metabolic dysregulation, fructose ingestion stimulates the hypothalamic-pituitary-adrenal (HPA) axis leading to elevations in glucocorticoids. Adolescents are the greatest consumers of fructose, and adolescence is a critical period for maturation of the HPA axis. Repeated consumption of high levels of fructose during adolescence has the potential to promote long-term dysregulation of the stress response. Therefore, we determined the extent to which consumption of a diet high in fructose affected behavior, serum corticosterone, and hypothalamic gene expression using a whole-transcriptomics approach. In addition, we examined the potential of a high-fructose diet to interact with exposure to chronic adolescent stress. Male Wistar rats fed the periadolescent high-fructose diet showed increased anxiety-like behavior in the elevated plus maze and depressive-like behavior in the forced swim test in adulthood, irrespective of stress history. Periadolescent fructose-fed rats also exhibited elevated basal corticosterone concentrations relative to their chow-fed peers. These behavioral and hormonal responses to the high-fructose diet did not occur in rats fed fructose during adulthood only. Finally, rats fed the high-fructose diet throughout development underwent marked hypothalamic transcript expression remodeling, with 966 genes (5.6%) significantly altered and a pronounced enrichment of significantly altered transcripts in several pathways relating to regulation of the HPA axis. Collectively, the data presented herein indicate that diet, specifically one high in fructose, has the potential to alter behavior, HPA axis function, and the hypothalamic transcriptome in male rats. PMID:26356038
Nakamoto, Kazuo; Nishinaka, Takashi; Sato, Naoya; Mankura, Mitsumasa; Koyama, Yutaka; Kasuya, Fumiyo; Tokuyama, Shogo
GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently inc...
Ghaffari, Firouzeh; Keikha, Fatemeh; Arabipoor, Arezoo
We reported a rare case of hypothalamic amenorrhea and transverse vaginal septum. A 28-year-old woman presented with primary amenorrhea and no complaint of abdominal pain. Laparoscopy revealed a small rudimentary uterus with streak ovaries and a vaginal pouch. The patient with diagnosis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome was subjected to a vaginoplasty in another fertility center. In our institute, after two courses of estrogen and progesterone, sonography revealed hematocolpos...
D’Anna-Hernandez, Kimberly L.; Ross, Randal G.; Natvig, Crystal L.; Laudenslager, Mark L.
Maternal stress during pregnancy is associated with negative maternal/child outcomes. One potential biomarker of the maternal stress response is cortisol, a product of activity of the hypothalamic-pituitary-adrenal axis. This study evaluated cortisol levels in hair throughout pregnancy as a marker of total cortisol release. Cortisol levels in hair have been shown to be easily quantifiable and may be representative of total cortisol release more than single saliva or serum measures. Hair corti...
Hsu, Chuan-Chih; Chen, Sheng-Hsien; Lin, Cheng-Hsien; Yung, Ming-Chi
Intolerance to heat exposure is believed to be associated with hypothalamo-pituitary-adrenocortical (HPA) axis impairment [reflected by decreases in blood concentrations of both adrenocorticotrophic-hormone (ACTH) and corticosterone]. The purpose of this study was to determine the effect of human recombinant factor VIIa (rfVIIa) on heat intolerance, HPA axis impairment, and hypothalamic inflammation, ischemic and oxidative damage, and apoptosis in mice under heat stress. Immediately after heat stress (41.2 °C for 1 h), mice were treated with vehicle (1 mL/kg of body weight) or rfVIIa (65-270 µg/kg of body weight) and then returned to room temperature (26 °C). Mice still alive on day 4 of heat exposure were considered survivors. Cellular ischemia markers (e.g., glutamate, lactate-to-pyruvate ratio), oxidative damage markers (e.g., nitric oxide metabolite, hydroxyl radials), and pro-inflammatory cytokines (e.g., interleukin-6, interleukin-1β, tumor necrosis factor-α) in hypothalamus were determined. In addition, blood concentrations of both ACTH and corticosterone were measured. Hypothalamic cell damage was assessed by determing the neuronal damage scores, whereas the hypothalamic cell apoptosis was determined by assessing the numbers of cells stained with terminal deoxynucleotidyl transferase-mediated αUTP nick-end labeling, caspase-3-positive cells, and platelet endothelial cell adhesion molecula-1-positive cells in hypothalamus. Compared with vehicle-treated heated mice, rfVIIa-treated heated mice had significantly higher fractional survival (8/10 vs 1/10), lesser thermoregulatory deficit (34.1 vs 24.8 °C), lesser extents of ischemic, oxidative, and inflammatory markers in hypothalamus, lesser neuronal damage scores and apoptosis in hypothalamus, and lesser HPA axis impairment. Human recombinant factor VIIa appears to exert a protective effect against heatstroke by attenuating hypothalamic cell apoptosis (due to ischemic, inflammatory, and oxidative damage
Dadak, Selma; Beall, Craig; Vlachaki Walker, Julia M; Soutar, Marc P M; McCrimmon, Rory J; Ashford, Michael L J
The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose-excited (GE) neurons) and mouse arcuate nucleus (ARC) neurons. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate- and glucose-sensing properties of mouse hypothalamic neurons. Oleate or lowered glucose concentration caused hyperpolarization and inhibition of firing of GT1-7 cells by the activation of ATP-sensitive K + channels (K ATP ). This effect of oleate was not dependent on fatty acid oxidation or raised AMP-activated protein kinase activity or prevented by the presence of the UCP2 inhibitor genipin. Oleate did not alter intracellular calcium, indicating that CD36/fatty acid translocase may not play a role. However, oleate activation of K ATP may require ATP metabolism. The short-chain fatty acid octanoate was unable to replicate the actions of oleate on GT1-7 cells. Although oleate decreased GT1-7 cell mitochondrial membrane potential there was no change in total cellular ATP or ATP/ADP ratios. Perforated patch and whole-cell recordings from mouse hypothalamic slices demonstrated that oleate hyperpolarized a subpopulation of ARC GE neurons by K ATP activation. Additionally, in a separate small population of ARC neurons, oleate application or lowered glucose concentration caused membrane depolarization. In conclusion, oleate induces K ATP- dependent hyperpolarization and inhibition of firing of a subgroup of GE hypothalamic neurons without altering cellular energy charge. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Haythorne, Elizabeth; Hamilton, D Lee; Findlay, John A; Beall, Craig; McCrimmon, Rory J; Ashford, Michael L J
Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (K ATP ) activity, with K ATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7 cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and K ATP activity. GT1-7 cells exposed to 3 or 24 h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished K ATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic K ATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. K ATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains K ATP closure. Single channel recordings indicate that NN414 alters K ATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to K ATP , probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.