Hypothalamic regulation of energy homeostasis.

The co-ordinated regulation of food intake and energy expenditure takes place in the hypothalamic regions of the brain. Current understanding of the systems involved in this regulation suggests that, in the hypothalamus, there are two major groups of neuropeptides involved in orexigenic and anorexic processes. The orexigenic neuropeptides are neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the anorexic neuropeptides are alpha-melanocyte-stimulating hormone (alpha-MSH) and cocaine and amphetamine-related transcript (CART). Theneurons expressing these neuropeptides interact with each other and with signals from the periphery (such as leptin, insulin, ghrelin and glucocorticoids) to regulate feeding behaviour, energy expenditure and various endocrine axes. Although direct evidence is limited, there are examples of genetic obesity in humans which suggest that the balance between orexigenic and anorexic pathways in the hypothalamus is also pivotally important in the maintenance of energy homeostasis in humans.

[1]  D. Porte,et al.  Localization of insulin receptor mRNA in rat brain by in situ hybridization. , 1990, Endocrinology.

[2]  M. Herkenham,et al.  Arcuate nucleus neurons that project to the hypothalamic paraventricular nucleus: Neuropeptidergic identity and consequences of adrenalectomy on mRNA levels in the rat , 1995, The Journal of comparative neurology.

[3]  C. Saper,et al.  Distributions of leptin receptor mRNA isoforms in the rat brain , 1998, The Journal of comparative neurology.

[4]  R. Broadwell,et al.  Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood , 1976, The Journal of comparative neurology.

[5]  H. Herzog,et al.  Regional distribution of Y‐receptor subtype mRNAs in rat brain , 1999, The European journal of neuroscience.

[6]  J. Falk Physiology and Behavior. , 1973 .

[7]  J. Mcdonald,et al.  Neuropeptide Y Actions on Reproductive and Endocrine Functions , 1993 .

[8]  R. Boston,et al.  Metabolic Consequences of Prolonged Hyperinsulinemia in Humans: Evidence for Induction of Insulin Insensitivity , 1986, Diabetes.

[9]  R. Rizza,et al.  Effects of glucocorticoids on carbohydrate metabolism. , 1988, Diabetes/metabolism reviews.

[10]  F. Assimacopoulos-Jeannet,et al.  The hormonal and metabolic basis of experimental obesity. , 1976, Clinics in endocrinology and metabolism.

[11]  G. Thomas,et al.  Hypothalamic Y2 receptors regulate bone formation. , 2002, The Journal of clinical investigation.

[12]  F. Rohner-Jeanrenaud,et al.  Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. , 1993, Endocrinology.

[13]  R. Emsley,et al.  Serotonergic agents in the treatment of hypothalamic obesity syndrome: a case report. , 1996, International Journal of Eating Disorders.

[14]  M. Ghatei,et al.  Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse. , 1993, Endocrinology.

[15]  E. Arenas,et al.  Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor , 1999, Nature Medicine.

[16]  R. Palmiter,et al.  Role of the Y5 neuropeptide Y receptor in feeding and obesity , 1998, Nature Medicine.

[17]  T. Pedrazzini,et al.  Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor , 1998, Nature Medicine.

[18]  Rachel L. Batterham,et al.  Gut hormone PYY3-36 physiologically inhibits food intake , 2002, Nature.

[19]  G. Bray,et al.  Sympathetic activity following paraventricular or ventromedial hypothalamic lesions in rats , 1988, Brain Research Bulletin.

[20]  M. Zemel,et al.  Diazoxide down‐regulates leptin and lipid metabolizing enzymes in adipose tissue of Zucker rats , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  Allen S Levine,et al.  Divergence of the feeding and thermogenic pathways influenced by NPY in the hypothalamic PVN of the rat. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[22]  A. Sclafani Neural pathways involved in the ventromedial hypothalamic lesion syndrome in the rat. , 1971, Journal of comparative and physiological psychology.

[23]  S. Corbett,et al.  Thermogenesis after lateral hypothalamic lesions: contributions of brown adipose tissue. , 1988, The American journal of physiology.

[24]  M. Kasuga,et al.  Cocaine-Amphetamine-Regulated Transcript Influences Energy Metabolism, Anxiety and Gastric Emptying in Mice , 2001, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[25]  J. Ronan,et al.  Centrally administered MTII affects feeding, drinking, temperature, and activity in the Sprague-Dawley rat. , 2000, Journal of applied physiology.

[26]  A. Pontiroli,et al.  Patients with insulinoma show insulin resistance in the absence of arterial hypertension , 1992, Diabetologia.

[27]  L. Vécsei,et al.  Opposite effects of centrally administered neuropeptide Y (NPY) on locomotor activity of spontaneously hypertensive (SH) and normal rats. , 1989, Acta physiologica Scandinavica.

[28]  C. Wahlestedt,et al.  The Biology of Neuropeptide Y and Related Peptides , 1993, Contemporary Neuroscience.

[29]  W. Rand,et al.  a-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression , 2000 .

[30]  S. Bloom,et al.  Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals. , 2001, Diabetes.

[31]  D. Smith,et al.  Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone. , 2000, Diabetes.

[32]  G. Cooney,et al.  Central but not peripheral glucocorticoid infusion in adrenalectomized male rats increases basal and substrate-induced insulinemia through a parasympathetic pathway. , 2001, Obesity research.

[33]  R. Lechan,et al.  Agouti-Related Protein Containing Nerve Terminals Innervate Thyrotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus. , 1999, Endocrinology.

[34]  F. Assimacopoulos-Jeannet,et al.  Hyperinsulinemia increases the amount of GLUT4 mRNA in white adipose tissue and decreases that of muscles: a clue for increased fat depot and insulin resistance. , 1990, Endocrinology.

[35]  D. Coscina,et al.  Dissociated feeding and hypothermic effects of neuropeptide Y in the paraventricular and perifornical hypothalamus , 1995, Peptides.

[36]  S. Bloom,et al.  Printed in U.S.A. Copyright © 2001 by The Endocrine Society Evidence of an Orexigenic Role for Cocaine- and Amphetamine-Regulated Transcript after Administration into Discrete Hypothalamic Nuclei , 2022 .

[37]  I. Baird Progress in Obesity Research 1990 , 1992 .

[38]  C. Wahlestedt,et al.  Evidence for different pre- and post-junctional receptors for neuropeptide Y and related peptides , 1986, Regulatory Peptides.

[39]  R. Lechan,et al.  Printed in U.S.A. Copyright © 1998 by The Endocrine Society The Arcuate Nucleus Is the Major Source for Neuropeptide Y-Innervation of Thyrotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus* , 2022 .

[40]  S. Woods,et al.  Intraventricular corticosterone increases the rate of body weight gain in underweight adrenalectomized rats. , 1992, Endocrinology.

[41]  C. Strader,et al.  Activation of the NPY Y5 receptor regulates both feeding and energy expenditure. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[42]  S. Joseph,et al.  Arcuate nucleus projections to brainstem regions which modulate nociception , 1991, Journal of Chemical Neuroanatomy.

[43]  P. J. Larsen,et al.  Hypothalamic CART is a new anorectic peptide regulated by leptin , 1998, Nature.

[44]  G. Barsh,et al.  Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area , 1998, The Journal of comparative neurology.

[45]  T. Hori,et al.  Thermoregulatory effect of intracerebral injections of neuropeptide Y in rats at different environmental temperatures. , 1994, General pharmacology.

[46]  J. Roberts,et al.  Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice. , 2000, Diabetes.

[47]  R. Palmiter,et al.  Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y , 1996, Nature.

[48]  M. Kuhar,et al.  Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference. , 2000, The Journal of pharmacology and experimental therapeutics.

[49]  T. Hökfelt,et al.  Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[50]  S. Bloom,et al.  The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. , 2000, The Journal of clinical investigation.

[51]  Michael W. Schwartz,et al.  Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons , 1998, Nature Neuroscience.

[52]  T. Hökfelt,et al.  Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. , 1997, Neuroendocrinology.

[53]  R. Cone,et al.  Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice , 1997, Cell.

[54]  J. Halaas,et al.  Leptin and the regulation of body weight in mammals , 1998, Nature.

[55]  P. J. Larsen,et al.  Chronic Intracerebroventricular Administration of Recombinant CART(42–89) Peptide Inhibits Food Intake and Causes Weight Loss in Lean and Obese Zucker (fa/fa) Rats , 2000 .

[56]  W. Rand,et al.  Printed in U.S.A. Copyright © 2001 by The Endocrine Society Neuropeptide Y Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid Axis* , 2022 .

[57]  Katherine S Brown,et al.  Central injection in rats of α-melanocyte-stimulating hormone analog: effects on food intake and brain Fos , 1998, Regulatory Peptides.

[58]  G. Barsh,et al.  Obesity, diabetes, and neoplasia in yellow Avy/‐ mice: ectopic expression of the agouti gene , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[59]  D. Johnson,et al.  Expression cloning of a human brain neuropeptide Y Y2 receptor , 1996, Regulatory Peptides.

[60]  R. Cone,et al.  Knockout models resulting in the development of obesity. , 2001, Trends in genetics : TIG.

[61]  G. Cooney,et al.  Chronic central melanocortin-4 receptor antagonism and central neuropeptide-Y infusion in rats produce increased adiposity by divergent pathways. , 2002, Diabetes.

[62]  I. McGregor,et al.  Metabolic effects of neuropeptide Y injections into the paraventricular nucleus of the hypothalamus , 1990, Brain Research.

[63]  S. Leibowitz,et al.  The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s) , 1993, Brain Research.

[64]  J. Wikberg,et al.  Long-term administration of MC4 receptor antagonist HS014 causes hyperphagia and obesity in rats. , 1999, Neuroreport.

[65]  H. Herzog,et al.  Inhibitory effects of central neuropeptide Y on the somatotropic and gonadotropic axes in male rats are independent of adrenal hormones , 2001, Peptides.

[66]  Y. Deshaies,et al.  Effects of corticotropin-releasing factor on energy balance in rats are sex dependent. , 1989, American Journal of Physiology.

[67]  R. Palmiter,et al.  Attenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y , 1996, Science.

[68]  S. O’Rahilly,et al.  Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. , 2000, The Journal of clinical investigation.

[69]  M. Aubert,et al.  Chronic blockade of the melanocortin 4 receptor subtype leads to obesity independently of neuropeptide Y action, with no adverse effects on the gonadotropic and somatotropic axes. , 2000, Endocrinology.

[70]  M. Kuhar,et al.  Actions of cocaine- and amphetamine-regulated transcript (CART) peptide on regulation of appetite and hypothalamo–pituitary axes in vitro and in vivo in male rats , 2001, Brain Research.

[71]  S. Leibowitz,et al.  Neuropeptide Y chronically injected into the hypothalamus: A powerful neurochemical inducer of hyperphagia and obesity , 1986, Peptides.

[72]  D. Macneil,et al.  Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice , 2002, Molecular and Cellular Biology.

[73]  G. Barsh,et al.  Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. , 1997, Science.

[74]  A. N. van den Pol,et al.  Multiple NPY Receptors Coexist in Pre- and Postsynaptic Sites: Inhibition of GABA Release in Isolated Self-Innervating SCN Neurons , 1996, The Journal of Neuroscience.

[75]  T. Kowalski,et al.  Neuropeptide Y Overexpression in the Preweanling Zucker (fa/fa) Rat , 1999, Physiology & Behavior.

[76]  R. Cone,et al.  Independent and additive effects of central POMC and leptin pathways on murine obesity. , 1997, Science.

[77]  A. Levine,et al.  Effect of CART in the hypothalamic paraventricular nucleus on feeding and uncoupling protein gene expression , 2000, Neuroreport.

[78]  R. Cone,et al.  Genetic models of obesity and energy balance in the mouse. , 2000, Annual review of genetics.

[79]  T. Horvath,et al.  Segregation of the intra- and extrahypothalamic neuropeptide Y and catecholaminergic inputs on paraventricular neurons, including those producing thyrotropin-releasing hormone , 1998, Regulatory Peptides.

[80]  J. Peters,et al.  Environmental contributions to the obesity epidemic. , 1998, Science.

[81]  S. Kalra,et al.  c-fos expression in the rat brain following central administration of neuropeptide Y and effects of food consumption , 1994, Brain Research.

[82]  S. O’Rahilly,et al.  Congenital leptin deficiency is associated with severe early-onset obesity in humans , 1997, Nature.

[83]  F. Rohner-Jeanrenaud A neuroendocrine reappraisal of the dual-centre hypothesis: its implications for obesity and insulin resistance. , 1995, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[84]  A. Debons,et al.  Gold thioglucose-induced hypothalamic damage, hyperphagia, and obesity: dependence on the adrenal gland. , 1982, Endocrinology.

[85]  R. Palmiter,et al.  A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[86]  G. Bray,et al.  Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. , 1991, The American journal of physiology.

[87]  R. Seeley,et al.  Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[88]  F. Rohner-Jeanrenaud,et al.  The Leptin-Like Effects of 3-d Peripheral Administration of a Melanocortin Agonist Are More Marked in Genetically Obese Zucker (fa/fa) than in Lean Rats. , 2002, Endocrinology.

[89]  Motonao Nakamura,et al.  Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[90]  O. Boss,et al.  Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. , 1999, Diabetes.

[91]  J. Rodin,et al.  Effect of chronic stress and exogenous glucocorticoids on regional fat distribution and metabolism , 1992, Physiology & Behavior.

[92]  M. Dallman,et al.  Feast and Famine: Critical Role of Glucocorticoids with Insulin in Daily Energy Flow , 1993, Frontiers in Neuroendocrinology.

[93]  L. Yaswen,et al.  Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin , 1999, Nature Medicine.

[94]  E. Ravussin,et al.  Chronic central infusion of cocaine- and amphetamine-regulated transcript (CART 55-102): effects on body weight homeostasis in lean and high-fat-fed obese rats , 2002, International Journal of Obesity.

[95]  B. Hamilton,et al.  Chronic application of MTII in a rat model of obesity results in sustained weight loss. , 2002, Obesity research.

[96]  Gareth Williams,et al.  The hypothalamus and the control of energy homeostasis Different circuits, different purposes , 2001, Physiology & Behavior.

[97]  L. Pénicaud,et al.  In vivo metabolic changes as studied longitudinally after ventromedial hypothalamic lesions. , 1986, The American journal of physiology.

[98]  M. Brownstein,et al.  Distribution of α-melanocyte-stimulating hormone in the rat brain: Evidence that α-MSH-containing cells in the arcuate region send projections to extrahypothalamic areas , 1979, Brain Research.

[99]  S. Woods,et al.  Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[100]  J. Shutter,et al.  Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. , 1997, Genes & development.

[101]  S. Hisano,et al.  Localization of glucocorticoid receptor in neuropeptide Y-containing neurons in the arcuate nucleus of the rat hypothalamus , 1988, Neuroscience Letters.

[102]  M. Hudson,et al.  Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. , 1999, The Journal of pediatrics.

[103]  T. Hökfelt,et al.  The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[104]  K. Hall,et al.  Physiology and behaviour , 1965 .

[105]  T. Hökfelt,et al.  Neuropeptide Y Innervation and Neuropeptide-Y-Y1-Receptor-Expressing Neurons in the Paraventricular Hypothalamic Nucleus of the Mouse , 1999, Neuroendocrinology.