Hypothalamic Centers Research Articles

Orexins and the regulation of the hypothalamic‐pituitary‐testicular axis

Orexins (OX), OX-A and OX-B, were initially identified as hypothalamic neuropeptides primarily involved in the control of food intake and states of arousal. Thereafter, orexins have been substantiated as putative pleiotropic regulators of a wide diversity of biological systems, including different neuroendocrine axes. Among the latter, compelling experimental evidence has recently been documented that orexins, mainly OX-A, may act at different levels of the hypothalamic-pituitary-gonadal (HPG) axis to modulate reproductive function. These actions are likely to include regulatory effects on the hypothalamic centres governing the HPG axis, as well as direct actions at the gonadal level. We review herein the experimental evidence, gathered in recent years, supporting a reproductive 'facet' of orexins, with special emphasis on our current knowledge of their patterns of expression and potential functional roles in the testis. Overall, the available data strongly suggest that, by acting at different levels of the HPG axis, orexins may operate as putative neuroendocrine and autocrine/paracrine regulators of gonadal function.

Anorexigenic and orexigenic factors regulation in the rat dorsal vagal complex during stress-induced anorexia

Event Abstract Back to Event Anorexigenic and orexigenic factors regulation in the rat dorsal vagal complex during stress-induced anorexia Fatiha Chigr1*, Mohamed Najimi1, Fatima Rachidi1, Catherine Tardivel2, Jérôme Trouslard2 and Emmanuel Moyse2 1 Université Sultan Moulay Slimane, Laboratoire “Génie Biologique”, Morocco 2 Université Aix Marseille 3, CRN2M, Labo PNV, France Food intake regulation in adult mammals is integrated mainly by two brain structures: the hypothalamus and the dorsal vagal complex (DVC), which involves a diversified array of neuroendocrine communications. Short-term regulation, which consists in reflex arrest of food intake under stomac filling or satiety reflex, is triggered by vagus nerve afferents to the DVC. Long-term regulation consists essentially in satiety reflex threshold modulation by “adiposity signals”, which involve the hypothalamus and its reciprocal connections with the DVC. Stressful situations are well known to alter food intake and factors involved in its control. We showed recently that anorexia-inducing immobilization stress (IS) triggers different crain-derived neurotrophic factor (BDNF) recruitment patterns between DVC and hypothalamus. In the context of food intake, many other gut hormones and factors act on hypothalamic and brainstem centres of appetite control, among them neuropeptide Y (NPY) and cocaine- and amphetamine- regulated transcript (CART). In order to investigate the involvement of the signalling of these peptides in the food control, notably in the context of food intake alterations (anorexia caused by stress), we analysed the hypothalamic and DVC expression of NPY and CART mRNAs. We showed, by using RT-PCR that the mRNAs of the two peptides display significant increases in stressed rats compared to controls, although with differential peaks. In hypothalamus, NPY and CART transcript up-regulation is observed at the end of IS and persists until 48-72h after IS. In the DVC, expression of the two transcripts peaks significantly at 24h post-stress and decline afterwards; NPY mRNA remains then significantly higher than in controls, whereas CART mRNA is down-regulated after 48h post-stress. The persistence of alteration of the expression of anorexigenic and orexigenic factors during the post-stress period could be highly related to the slow recovery of the hypothalamo-hypophyseo-adrenal (HPA) axis in IS and points to stress-induced plasticity in both nervous centres of food intake regulation. Acknowledgment: GDRI Neuro (CNRS-CNRST, France – Maroc), PICS CNRS-CNRST (France Maroc), Université Aix Marseille 3, TWAS Conference: 2nd NEUROMED Workshop, Fez, Morocco, 10 Jun - 12 Jun, 2010. Presentation Type: Poster Presentation Topic: Poster Session 3: Adaptation to environmental stress Citation: Chigr F, Najimi M, Rachidi F, Tardivel C, Trouslard J and Moyse E (2010). Anorexigenic and orexigenic factors regulation in the rat dorsal vagal complex during stress-induced anorexia. Front. Neurosci. Conference Abstract: 2nd NEUROMED Workshop. doi: 10.3389/conf.fnins.2010.12.00019 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Jun 2010; Published Online: 03 Jun 2010. * Correspondence: Fatiha Chigr, Université Sultan Moulay Slimane, Laboratoire “Génie Biologique”, Beni-Mellal, Morocco, fchigr@voila.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Fatiha Chigr Mohamed Najimi Fatima Rachidi Catherine Tardivel Jérôme Trouslard Emmanuel Moyse Google Fatiha Chigr Mohamed Najimi Fatima Rachidi Catherine Tardivel Jérôme Trouslard Emmanuel Moyse Google Scholar Fatiha Chigr Mohamed Najimi Fatima Rachidi Catherine Tardivel Jérôme Trouslard Emmanuel Moyse PubMed Fatiha Chigr Mohamed Najimi Fatima Rachidi Catherine Tardivel Jérôme Trouslard Emmanuel Moyse Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

P02-230 - “Psychogenic” polidipsia and its biological correlates: a case report

ObjectivePrimary polydipsia is a clinical disorder characterized by excessive fluid intake (polydipsia) and consequent excessive fluid excretion (polyuria). The underlying pathophysiology of Primary polydipsia is still unclear. We present a case of a 26 year-old man without any previous psychiatric or neurological history who was thoroughly investigated for severe symptoms of polydipsia and polyuria. The only finding consisted of a probable micro-adenoma on the left side of the sella turcica.MethodsThe patient was thoroughly assessed by psychiatrists and psychologists through clinical and diagnostic interviews and was administered a wide range of psychometric tools including MMPI-2, SCID, YBOCS, BDI, HAM-17 and SCL-90. Moreover, he underwent a comprehensive physical and neurological examination, blood tests, renal function tests, endocrinological assessment including hormone assays, water deprivation test and desmopressin trial and brain Magnetic Resonance Imaging (MRI).ResultsNo major psychiatric disorder was detected apart from the presence of mild depressive symptoms. A brain MRI revealed a 4-5 mm diameter lesion on the left side of the sella turcica with lower contrast enhancement than the rest of the gland, which was suggestive of pituitary micro-adenoma.ConclusionWe considered the patient's depressive symptomatology as secondary to his condition. There is no other report of pituitary microadenoma in patients with symptoms of polydipsia and polyuria. We hypothesize that the location of the lesion may be related to the hypothalamic centre of thirst.

Metabolic control of puberty onset: New players, new mechanisms

Puberty, as the end-point of a complex series of maturational events affecting the components of the hypothalamic-pituitary-gonadal (HPG) axis, is gated by the state of body energy reserves and sensitive to different metabolic cues; conditions of severe metabolic stress and energy unbalance (from anorexia to morbid obesity) being commonly linked to perturbation of the onset of puberty. In the last two decades, the neuroendocrine mechanisms responsible for the tight coupling between energy homeostasis and puberty onset have begun to be deciphered. These seemingly involve a plethora of metabolic hormones and neuropeptides, which impinge and integrate (mostly) at the hypothalamic centers governing reproduction. Yet, characterization of the mechanisms of action of such regulators (and even their nature and physiological relevance) still remains incomplete. In this review, we will summarize some recent developments in our knowledge of the effects and mechanisms of action of two key metabolic hormones, leptin and ghrelin, in the control of puberty onset. In addition, the roles of the hypothalamic Kiss1 system in the metabolic gating of puberty will be reviewed, with special attention to its regulation by leptin and the recent identification of the putative roles of Crtc1 and mTOR signaling as molecular conduits for the metabolic control of Kiss1 expression. Elucidation of these novel players and regulatory mechanisms will help for a better understanding of the determinants of the timing of puberty, and its eventual alterations in adverse metabolic conditions.

Neuroendocrine dysfunction in fibromyalgia and migraine

Fibromyalgia (FM) and migraine are common chronic disorders that predominantly affect women. The prevalence of headache in patients with FM is high (35%-88%), with migraine being the most frequent type. A particular subgroup of patients with FM (approximately half) presents with a combined clinical form of these two painful disorders, which may exhibit a different manner of progression regarding symptomatology and impact on daily activities. This article reviews several common aspects of the pathophysiology regarding pain control mechanisms and neuroendocrine dysfunction occurring in FM and migraine, particularly in the chronic form of the latter. We also discuss the participation of hypothalamic and brainstem centers of pain control, the putative role played by neurotransmitters or neuromodulators on central sensitization, and changes in their levels in the cerebrospinal fluid. Understanding their mechanisms will help to establish new treatment strategies for treating these disabling brain disorders.

PI3K integrates the effects of insulin and leptin on large-conductance Ca2+-activated K+ channels in neuropeptide Y neurons of the hypothalamic arcuate nucleus

The adipocyte-derived hormone leptin and the pancreatic beta-cell-derived hormone insulin function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. They act in hypothalamic centers to modulate the function of specific neuronal subtypes, such as neuropeptide Y (NPY) neurons, by modifying neuronal electrical activity. To investigate the intrinsic activity of these neurons and their responses to insulin and leptin, we used a combination of morphological features and immunocytochemical technique to identify the NPY neurons of hypothalamic arcuate nucleus (ARC) and record whole cell large-conductance Ca(2+)-activated potassium (BK) currents on them. We found that both of the hormones increase the peak amplitude of BK currents, shifting the steady-state activation curve to the left. The effect of both insulin and leptin can be prevented by pretreatment with inhibitors of tyrosine kinase and phosphatidylinositol 3-kinase (PI3K) but not MAPK. These data indicate that PI3K-mediated signals are the common regulators of BK channels by insulin and leptin and mediated the two hormones' identical activatory effects on ARC NPY neurons. The effect of insulin and leptin together was similar to that of insulin or leptin alone, and leptin or insulin pretreatment did not lead to insulin- or leptin-sensitizing effects, respectively. These intracellular signaling mechanisms may play key roles in regulating ARC NPY neuron activity and physiological processes such as the control of food intake and body weight, which are under the combined control of insulin and leptin.

Schizophrenia as a possible dysfunction of the suprachiasmatic nucleus

Psychosis and dreaming have many similarities, including delusions, hallucinations, bizarre thinking and perceptual distortions. This clinical observation has lead us to hypothesize that the suprachiasmatic nucleus (SCN), a hypothalamic center regulating sleep and wakefulness, is involved in the pathogenesis of schizophrenia. Schizophrenic patients have certain sleep architecture characteristics, and distinctive biological markers suggesting abnormity of the SCN, including irregular pattern of melatonin secretion, abnormal actigraphyic studies, D1-dopamine receptors involvement in the process of entraining the SCN and vulnerability to psychotic exacerbation due to jet lag. In addition, SCN lesions in rodents are associated with pathologic day-time sleep pattern, very similar to the sleeping pattern in patients with schizophrenia. We introduce the concept of REM sleep abnormity as a possible etiological factor in development of psychosis. We hypothesize that the proposed dysfunction of the SCN may contribute to schizophrenia through several different, not necessarily mutually exclusive, mechanisms, including "REM sleep (dream) rebound" phenomenon, damaged neuronal pathways connecting SCN to the brain regions affected by schizophrenia, and the SCN dysfunction induced dysregulation of gene expression in different parts of the body, including the brain. Moreover, the influenza virus, which has been implicated in the etiology of schizophrenia, is capable of resetting the SCN, the ultimate processor of light signals, suggesting the explanation for chronological variability of incidence of schizophrenia. Future investigation of the proposed mechanisms will provide the ultimate test of our hypothesis that lesions of the suprachiasmatic nucleus play an important role in the etiology of schizophrenia.

Symposium Overview

Symposium Overview

Management of Atypical Antipsychotic Drug‐Induced Weight Gain: Focus on Metformin

Many patients taking atypical antipsychotic drugs will experience weight gain. Evidence suggests that long-term treatment with these agents decreases glucose effectiveness, alters satiety signals, creates hormonal resistance to satiety control, and may have a direct effect on hypothalamic appetite centers. The serotonin(2c-) and histamine(1)-receptor antagonism of atypical antipsychotics may also lead to weight gain. Several nonpharmacologic and pharmacologic methods have been used to address this adverse effect, with varying success. Metformin is an antidiabetic drug that has been shown to cause weight loss in patients with diabetes mellitus, as well as in some individuals without diabetes. To evaluate whether metformin can decrease weight gain induced by atypical antipsychotics in patients without diabetes, we conducted a literature search using the MEDLINE database (1970-October 2008) and clinicaltrials.gov Web site for relevant trials. Overall, 14 articles were identified for inclusion; review articles, case reports, and open-label studies were excluded. Thus, eight double-blind, placebo-controlled studies were reviewed; both pediatric and adult trials were included. Metformin has several advantages, including ease of use and a favorable safety profile. Although lactic acidosis was not reported in any of the studies reviewed, this potentially rare but severe adverse effect must be considered when prescribing this agent. Limited data suggest that metformin may attenuate weight gain in both adult and adolescent patients taking atypical antipsychotics. However, most of the trials included foreign populations, were only 12-16 weeks in duration, and the dosage of metformin may not have been adequately titrated. Although the study results do not provide clear substantial evidence that metformin, as an adjuvant to atypical antipsychotic use, will decrease weight gain and improve metabolic effects, they are encouraging. Additional studies of longer duration that include behavioral therapy and special diets should be conducted in patients from the United States. Currently, the drug is being used as a secondary or tertiary intervention, and its use may be considered in patients with a personal and/or family history of obesity or metabolic dysfunction, and in subjects who have rapid weight gain early in antipsychotic treatment.

Euthanasia in Endocrinology: The Choices Get More Complex

In 1927, the German physicist Werner Heisenberg published a paper that developed the principle of imprecision or uncertainty in measuring the position and momentum of subatomic particles; simply stated, “the more precisely the position is determined, the less precisely the momentum is known, . . . and vice versa.” This principle reflects a fact of life that most scientists learn at an early age:preciseexperimentalmeasurementsmayonlybepossibleunder conditions in which the properties of the system can no longer be completely defined. For endocrinologists, the problems are particularly acute because of the sensitivity of endocrine systems to metabolic, sensory, or pharmacologically induced perturbation. This makes itdifficult tostudythese systems invivo,without introducing the potential for experimentally induced error. The challenge is to develop procedures that induce as little disturbance of normal hormonal interactions as possible. Experiments involving euthanasia present a particular problem because of the need to balance ethical concerns in the treatment of animals with avoidance of procedures that might alter the experimental results. Most countries have now adopted guidelines for research that stress the principle that animals should not be unnecessarily exposed to pain and suffering. In the euthanasia guidelines of the American Veterinary Medical Association, for example, euthanasia isdefinedastheactof inducinghumanedeathinananimal, “with an emphasis on making the death as painless and distress free as possible” (1). Ensuring that death is distress free, however, may be possible only by depressing consciousness, through modulation of neuronal activity in the central nervous system. This is hard to do without also affecting the hypothalamic and limbic brain centers that normally regulate neuroendocrine function. Measures to achieve painless euthanasia may, therefore, themselves alter the endocrine endpoints under study, particularly if those endpoints are sensitive to changes in neuroendocrine hormone secretion. The demonstration in the mid-1970s that neural activity may continue in the brain for 13–14 sec after decapitation (2) resulted in adoption of policies encouraging sedation or complete anesthesia beforephysicalmethodsofeuthanasia,basedonthehypothesis that continued brain activity might reflect a perception of pain. Because many inhalant and noninhalant anesthetic drugs themselves induce stress responses and changes in hormone levels, their usefulness is limited (3,4). Several studies, however, indicated that sedationwith CO2 gas might provide a nonstressful alternative. Exposure to CO2 concentrations as low as 7.5% in air increases pain thresholds, whereas30–100%CO2 canproducerapid lossofconsciousness (5, 6). Importantly, brief exposure to CO2 ( 30 sec) did not seem to increase the levelsofACTH,ahormone that isnotoriously sensitive tostress (7).Forthisreason,CO2sedationhasbecomeawidelyused method to limit pain and distress before euthanasia. In the current issue of Endocrinology, however, Reed et al. (8) report that only 20–25 sec exposure of male rats to CO2 gas, sufficient to render them recumbent and unresponsive but still alive, results in a dramatic elevation in the levels of vasopressin and oxytocin in the circulation. Using methods based on a combination of RIA with liquid capillary chromatography-mass spectrometry to achieve definitive identification of the peptides, Reed et al. (8) show that plasma levels of vasopressin and oxytocin increase at least 10fold after brief CO2 exposure. The authors speculate that these findings may explain previous observations of CO2 induced analgesia, because of the reported ability of iv vasopressin to induce non-opioidergic analgesic effects (9) as well as observations on induction of ACTH release after longer periods (2 min) of CO2 exposure (7). The mechanisms of these effects remain unclear. Reed et al. (8) speculate that it may involve changes in a number of neurotransmitter systems in the brain, perhaps secondary to changes in blood pressure triggered by CO2 exposure, but additional work will be required to define the underlying mechanisms, given that the systems in the brain that control the posterior pituitary may also influence other aspects of endocrine function. The data also have ramifications for studies that may not appear to have a direct neuroendocrine connection, because of the powerful effects of the posteriorpituitaryhormonesaroundthebody. Inadditionto itsactions as an ACTH secretagogue, vasopressin increases blood pressure by increasing peripheral vascular resistance (10), stimulates water resorption in the kidney (11), and influences aggressive and social

BLOOD GLUCOSE AND HYPOTHALAMIC FEEDING CENTERS

Blood Glucose and Hypothalamic Feeding Centers Nutrition Reviews, Volume 20, Issue 10, October 1962, Pages 308–310, https://doi.org/10.1111/j.1753-4887.1962.tb04509.x Published: 01 October 1962

THE STOMACH AND HYPOTHALAMIC FEEDING CENTERS

The Stomach and Hypothalamic Feeding Centers Get access Nutrition Reviews, Volume 20, Issue 11, November 1962, Pages 344–346, https://doi.org/10.1111/j.1753-4887.1962.tb04529.x Published: 01 November 1962

Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond

Given the multiple differences between mice and men, it was once thought that mice could not be used to model atherosclerosis, principally a human disease. Apolipoprotein E-deficient (apoEKO) mice have convincingly changed this view, and the ability to model human-like plaques in these mice has provided scientists a platform to study multiple facets of atherogenesis and to explore potential therapeutic interventions. In addition to its well-established role in lipoprotein metabolism, recent observations of reduced adiposity and improved glucose homeostasis in apoEKO mice suggest that apoE may also play a key role in energy metabolism in peripheral organs, including adipose tissue. Finally, along with apoEKO mice, knockin mice expressing human apoE isoforms in place of endogenous mouse apoE have provided insights into how quantitative and qualitative genetic alterations interact with the environment in the pathogenesis of complex human diseases.

The organization of feedback projections in a pathway important for processing pheromonal signals

In most of the mammalian sensory systems there are massive cortical feedback projections to early processing stations. The mammalian accessory olfactory system is considered unique in several aspects. It is specialized for processing pheromonal signals and plays a critical role in regulating sociosexual behaviors. Furthermore, pheromonal signals are believed to bypass cortex and reach the hypothalamic behavioral centers after merely three forward projections. Because the organization of the feedback projections in the accessory olfactory system remains largely unclear, the importance of the feedback projections in the processing of pheromonal signals has been ignored. Here we show that in mice the feedback projections from the bed nucleus of stria terminalis (BST) and the vomeronasal amygdala to the accessory olfactory bulb (AOB) are topographically organized and use different neurotransmitters. By retrograde and anterograde tracing, we find that the feedback projection from the BST terminates in the AOB mitral cell layer, whereas that from the amygdala terminates in the AOB granule cell layer. By combining tracing, genetic labeling of GABAergic neurons, and immunostaining against a marker of glutamatergic synapses, we observe that the BST-to-AOB projection is GABAergic whereas the amygdala-to-AOB projection is glutamatergic. In addition, a substantial number of feedback neurons in the amygdala and BST express estrogen receptors. Thus, the accessory olfactory system, like other sensory systems, possesses extensive feedback projections. Moreover, our results suggest that central hormonal cues may modulate the processing of pheromonal signals at early stations through the precisely organized feedback projections.

Observation of Sympathomimetic Effect of Ear Acupuncture Stimulation for Body Weight Reduction

Ear acupuncture stimulation has been used for body weight reduction as early as the 1970s. Several hypotheses have been proposed in literature regarding its mechanism of action, among which are the effects of the stimulation of the hypothalamic satiety center on decreased neuropeptide Y production. Here, we present another possible mechanism to account for the temporary and short-term effects of ear acupuncture stimulation in the treatment of obesity, the sympathetic effects of the autonomic nervous system. 14 female volunteers underwent a randomized clinical trial of the ear acupuncture stimulation. A prospective, sham-point control, crossover study was performed with two sequential four-week stimulation periods separated by a two-week washout interval. The clinical features of and effects on the autonomic nervous system were recorded and analyzed. Decreased body weight was observed in both the experimental and the control groups in the first 4 weeks of stimulation. Sympathomimetic effects were also noted in both groups. Whereas the sympathomimetic effects and body weight reduction were sustained in the experimental group in the second 4 weeks of stimulation, such effects were not observed in the control group. Some sympathomimetic effects were noted in both the experimental and the control groups initially. This effect remained apparent in the experimental group in sequential stimulation but was lost in the control group. Consequently, we believe that sympathomimetic effects may account for the reduction in body weight by temporarily increasing basal metabolic rate and decreasing appetite, but the body may regain weight after the termination of such effects. Accordingly, the combination of an optimal exercise and diet program with repeated acupoint therapy may be necessary to maintain a healthy body weight.

Mecanismo fisiopatológico de los sofocos-sudores inducidos por deprivación androgénica en el carcinoma prostático

Hot flushes and perspiration are common problems during androgen deprivation therapy for prostate carcinoma, and largely contribute to worsen patient quality of life.Different hypotheses have been proposed to explain the underlying physiopathological mechanisms, though all are very complex, basically because of the multiple causal factors involved.The present review offers a pondered and updated perspective of the origin of hot flushes-perspiration in such patients.Negative feedback of the plasma sexual hormones upon the hypothalamic secretion of noradrenalin and serotonin appears to be the main cause. Likewise, the direct action of such mechanisms upon the LH-RH producing hypothalamic center located close to the thermoregulatory center, together with shortening of the thermoneutral interval, would also play a role.Improved understanding of the causal mechanism may help improve the treatment of such symptoms.

Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI)

We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.

Metabolic sensing and regulation by the hypothalamus

EDITORIAL FOCUSMetabolic sensing and regulation by the hypothalamusMartin G. Myers Jr.Martin G. Myers Jr.Published Online:01 May 2008https://doi.org/10.1152/ajpendo.90282.2008This is the final version - click for previous versionMoreSectionsPDF (25 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations this issue of the American Journal of Physiology-Endocrinology and Metabolism contains the first three in a series of review articles dealing with metabolic sensing in the hypothalamus and the regulation of physiological processes. The convergence of molecular genetic techniques with intracellular signaling and neuroanatomical approaches in recent years has revealed mechanisms of hypothalamic regulation and physiology not previously possible utilizing any one of these methodologies alone. Building upon insights made possible by recent studies, the series examines the mechanisms by which hypothalamic centers sense the metabolic state and thereby regulate energy balance, glycemic control, reproduction, and other neuroendocrine and autonomic end points. Each of these reviews is written by a leader in this field of inquiry, in collaboration with up-and-coming young investigators.Drs. Jens Brüning, Eva Rother, and A. Christine Könner discuss the substantial recent work regarding hypothalamic insulin and leptin action in the regulation of glucose and nutrient partitioning in the liver and other peripheral tissues. In particular, this analysis extends the early work of Dr. Brüning, which revealed the metabolic and reproductive function of insulin receptors in the central nervous system. Subsequent work has elucidated the role for the phosphatidylinositol 3′-kinase (PI3K) pathway in the regulation of ATP-sensitive potassium (KATP) channels and the control of membrane potential in the function of the “classic” proopiomelanocortin (POMC) and neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC). Specifically, stimulation of PI3K activates KATP channels to hyperpolarize these neurons, with important consequences for the regulation of hepatic nutrient handling and glucose homeostasis.Drs. Tamas Horvath and Qian Gao trace the overlapping and divergent functions of leptin and estrogen in the hypothalamus: both modulate reproductive function and each participates in the regulation of energy homeostasis (although the hormones are clearly produced and regulated by different mechanisms). In addition to examining the hypothalamic functions of leptin and estrogen, the authors focus on the regulation of the latent transcription factor STAT3 by these hormones and discuss how STAT3 mediates common and distinct responses to these hormones in the regulation of energy balance and the hypothalamic control of reproduction.The review by Drs. Joel Elmquist, Carol Elias, and Jennifer Hill also deals with the metabolic control of reproduction, but at the level of the neural substrate (as opposed to the intracellular signaling pathways) by which metabolic signals such as leptin mediate permissive effects upon the neuroendocrine reproductive axis. This timely review examines recent findings suggesting important roles for NPY, as well as neuronal populations outside of the ARC, in the regulation of reproduction by metabolic and nutritional cues from the periphery. Additionally, the likely role for kisspeptin in the regulation of neuroendocrine reproductive function features prominently in this discussion.Overall, these reviews exemplify the kind of exciting research and important insights that have been generated recently into the metabolic regulation of hypothalamic processes and the role of metabolic sensing in the hypothalamus in the regulation of metabolic and endocrine physiology.AUTHOR NOTESAddress for reprint requests and other correspondence: M. G. Myers, Jr., Division of Metabolism, Endocrinology and Diabetes, Dept. of Medicine, Univ. of Michigan Medical School, 5560 MSRB II/0678, 1150 W. Medical Center Dr., Ann Arbor, MI 48109 (e-mail: [email protected])This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformation Cited BySensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation29 July 2021 | Metabolites, Vol. 11, No. 8Cyclin-dependent kinase 4/6 inhibitors require an arcuate-to-paraventricular hypothalamus melanocortin circuit to treat diet-induced obesityNiloy Jafar Iqbal, Gary J. 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Circadian rest‐activity rhythm is altered in Parkinson's disease patients with hallucinations

The sleep-wake cycle in Parkinson's Disease (PD) is profoundly disrupted, but less is known about circadian rhythm in PD and its relationship to other important clinical features. This study compared rest-activity rhythms in healthy older adults and PD patients with and without hallucinations. Twenty-nine older adults and 50 PD patients (27 with hallucinations, 23 without) were assessed using wrist-worn actigraphy for 5 days. Disease-related and cognitive data were also collected. PD patients demonstrated reduced amplitude of activity (F = 12.719, P < 0.01) and increased intradaily variability (F = 22.005, P < 0.001), compared to healthy older adults, independently of age, and cognitive status. Hallucinators showed lower interdaily stability (F = 7.493, P < 0.01) significantly greater activity during "night-time" (F = 6.080, P < 0.05) and significantly reduced relative amplitude of activity (F = 5.804, P < 0.05) compared to nonhallucinators, independently of clinical factors including motor fluctuations. PD patients with hallucinations display altered rest-activity rhythm characterized by an unpredictable circadian pattern across days, likely arising from damage to brainstem and hypothalamic sleep centers. Treatment of sleep and rest-activity rhythm disturbance is an important target in Parkinson's Disease.

Effects of selective Bcl-2 inhibitor HA14-1 treatments on functional activity of magnocellular vasopressinergic neurons of rat hypothalamus

In this study we examined whether in vivo treatments with Bcl-2 inhibitor HA14-1 can affect the function of vasopressinergic system of rat. HA14-1 is a novel organic compound that has micromolar affinity for Bcl-2 and Bcl-xL and acts as a mimetic of BH3-only proteins by antagonizing the anti-apoptotic Bcl-2 proteins and triggering Bax-dependent apoptosis. We found that intrahypothalamic injections of HA14-1 did not induce apoptosis of vasopressin (VP) cells of supraoptic nucleus, but led to activation of VP synthesis and release, resulting in decreased diuresis. Our data has also demonstrated that injections of HA14-1 increased phospho-MEK1/2, phospho-CREB and phospho-Elk-1 levels in magnocellular neurons. Thus we propose that injections of HA14-1 into the hypothalamus do not lead to neuronal death, but change the functional activity of VP neurons of hypothalamus centres.