Hypothalamic neuronal networks and feeding-related peptides involved in the regulation of feeding

The hypothalamus is a region of the brain that plays a critical role in feeding regulation. It has been revealed by various physiological experiments that the feeding-regulating center is confined to the ventromedial hypothalamus, lateral hypothalamus (LH) and arcuate nucleus (ARC). Many kinds of neurons in these areas of the hypothalamus express factors such as melanin-concentrating hormone (MCH), neuropeptide Y (NPY), proopiomelanocortin (POMC), orexin (OX) and ghrelin, which have been implicated in feeding regulation. In tissues of the periphery, two critical factors involved in feeding regulation, leptin and ghrelin, have been identified. Both hormone peptides are secreted mainly from adipose and stomach tissue, respectively, and are considered to function via their receptors mainly through several hypothalamic nuclei that play important roles in the regulation of appetite. The present review looks mainly at the functional significance of feeding-regulation factors, such as those described above, and the humoral and neuronal interactions among these compounds in the hypothalamus by drawing on published reports of morphological and physiological analyses. Immunohistochemical and in situ hybridization experiments indicate that both leptin and ghrelin receptors are distributed in the hypothalamus and that there are reciprocal interactions between MCH and OX neurons in the LH. Morphological and physiological studies on single living cells isolated from fresh rat hypothalamus or with receptor agonist and antagonist combined with immunohistochemisry clearly demonstrate that both leptin and OX reciprocally regulate NPY- and POMC-containing neurons in the ARC and that ghrelin may regulate feeding status independently through direct OX and NPY pathways. In this way, cross-talking systems in the hypothalamus play a role in determining feeding states.

[1]  P. Gross,et al.  Morphology and function of capillary networks in subregions of the rat tuber cinereum , 1992, Cell and Tissue Research.

[2]  D. Coleman Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice , 1978, Diabetologia.

[3]  S. Shioda,et al.  Co-existence of leptin- and orexin-receptors in feeding-regulating neurons in the hypothalamic arcuate nucleus—a triple labeling study , 2003, Peptides.

[4]  S. Shioda,et al.  Galanin-like peptide is target for regulation by orexin in the rat hypothalamus , 2003, Neuroscience Letters.

[5]  T. Sakurai,et al.  Ghrelin-induced food intake is mediated via the orexin pathway. , 2003, Endocrinology.

[6]  S. Shioda,et al.  Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation , 2002, International Journal of Obesity.

[7]  C. Lawrence,et al.  Centrally Administered Galanin‐Like Peptide Modifies Food Intake in the Rat: A Comparison with Galanin , 2002, Journal of neuroendocrinology.

[8]  S. Shioda,et al.  Galanin-like peptide is co-localized with α-melanocyte stimulating hormone but not with neuropeptide Y in the rat brain , 2002, Neuroscience Letters.

[9]  Noboru Murakami,et al.  The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. , 2002, Gastroenterology.

[10]  J Duhault,et al.  Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague–Dawley rats , 2002, International Journal of Obesity.

[11]  S. Shioda,et al.  Ultrastructural localization of orexin-1 receptor in pre- and post-synaptic neurons in the rat arcuate nucleus , 2002, Neuroscience Letters.

[12]  S. M. Robinson,et al.  Extent and Direction of Ghrelin Transport Across the Blood-Brain Barrier Is Determined by Its Unique Primary Structure , 2002, Journal of Pharmacology and Experimental Therapeutics.

[13]  S. Shioda,et al.  Orexin-1 receptor immunoreactivity in chemically identified target neurons in the rat hypothalamus , 2002, Neuroscience Letters.

[14]  Toshiharu Yamamoto,et al.  Centrifugal neurons of the octopus optic lobe cortex are immunopositive for calcitonin gene-related peptide , 2002, Neuroscience Letters.

[15]  M. Schwartz,et al.  Peptide signals regulating food intake and energy homeostasis. , 2002, Canadian journal of physiology and pharmacology.

[16]  A. Gundlach Galanin/GALP and galanin receptors: role in central control of feeding, body weight/obesity and reproduction? , 2002, European journal of pharmacology.

[17]  H. Onda,et al.  Galanin-like peptide stimulates food intake in the rat , 2002, Neuroscience Letters.

[18]  S. Shioda,et al.  Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus , 2002, Neuroscience Letters.

[19]  A. Yamanaka,et al.  Orexins activate histaminergic neurons via the orexin 2 receptor. , 2002, Biochemical and biophysical research communications.

[20]  C. Lawrence,et al.  Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. , 2002, Endocrinology.

[21]  T. Sakurai,et al.  Immunohistochemical characterization of localization of long-form leptin receptor (OB-Rb) in neurochemically defined cells in the ovine hypothalamus , 2001, Brain Research.

[22]  J. Kamegai,et al.  Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. , 2001, Diabetes.

[23]  R. Batterham,et al.  Ghrelin causes hyperphagia and obesity in rats. , 2001, Diabetes.

[24]  K. Hosoda,et al.  Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. , 2001, The Journal of clinical endocrinology and metabolism.

[25]  C. Saper,et al.  Differential expression of orexin receptors 1 and 2 in the rat brain , 2001, The Journal of comparative neurology.

[26]  E. Ravussin,et al.  Circulating ghrelin levels are decreased in human obesity. , 2001, Diabetes.

[27]  O. Nishimura,et al.  Distribution of galanin-like peptide in the rat brain. , 2001, Endocrinology.

[28]  J. Roberts,et al.  Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord , 2001, Neuroscience.

[29]  S. Shioda,et al.  Orexinergic innervation of POMC-containing neurons in the rat arcuate nucleus , 2001, Neuroreport.

[30]  M. Fujimiya,et al.  Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. , 2001, Gastroenterology.

[31]  B. Lowell,et al.  Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. , 2001, The Journal of clinical investigation.

[32]  K. Hosoda,et al.  Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. , 2001, Diabetes.

[33]  M. Nakazato,et al.  Ghrelin acts in the central nervous system to stimulate gastric acid secretion. , 2001, Biochemical and biophysical research communications.

[34]  S. Bouret,et al.  Comparative distribution of mRNA encoding the growth hormone secretagogue‐receptor (GHS‐R) in Microcebus murinus (Primate, Lemurian) and rat forebrain and pituitary , 2001 .

[35]  M. Nakazato,et al.  A role for ghrelin in the central regulation of feeding , 2001, Nature.

[36]  J. Arch,et al.  A selective orexin-1 receptor antagonist reduces food consumption in male and female rats , 2000, Regulatory Peptides.

[37]  Localization of long-form leptin receptor in the somatostatin-containing neurons in the sheep hypothalamus , 2000, Brain Research.

[38]  S. Bloom,et al.  The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. , 2000, Endocrinology.

[39]  M. Nakazato,et al.  Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. , 2000, Endocrinology.

[40]  M. Tschöp,et al.  Ghrelin induces adiposity in rodents , 2000, Nature.

[41]  M. Nakazato,et al.  Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. , 2000, Biochemical and biophysical research communications.

[42]  S. Shioda,et al.  Morphological evidence for neural interactions between leptin and orexin in the hypothalamus , 2000, Regulatory Peptides.

[43]  R. Steiner,et al.  Galanin-Like Peptide (GALP) Is a Target for Regulation by Leptin in the Hypothalamus of the Rat. , 2000, Endocrinology.

[44]  S. Woods,et al.  Central nervous system control of food intake , 2000, Nature.

[45]  A. Yamanaka,et al.  Orexin-induced food intake involves neuropeptide Y pathway , 2000, Brain Research.

[46]  M. Nakazato,et al.  Distribution of orexin/hypocretin in the rat median eminence and pituitary. , 2000, Brain Research. Molecular Brain Research.

[47]  C. Kitada,et al.  Isolation and cDNA Cloning of a Novel Galanin-like Peptide (GALP) from Porcine Hypothalamus* , 1999, The Journal of Biological Chemistry.

[48]  M. Nakazato,et al.  Ghrelin is a growth-hormone-releasing acylated peptide from stomach , 1999, Nature.

[49]  F. Casanueva,et al.  Neuroendocrine Regulation and Actions of Leptin , 1999, Frontiers in Neuroendocrinology.

[50]  Takeshi Sakurai,et al.  Distribution of orexin neurons in the adult rat brain 1 Published on the World Wide Web on 17 March 1999. 1 , 1999, Brain Research.

[51]  M. Takigawa,et al.  The effect of leptin on feeding-regulating neurons in the rat hypothalamus , 1999, Neuroscience Letters.

[52]  M. Takigawa,et al.  Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y , 1999, Neuroscience Letters.

[53]  S. Woods,et al.  Leptin Receptor Long-form Splice-variant Protein Expression in Neuron Cell Bodies of the Brain and Co-localization with Neuropeptide Y mRNA in the Arcuate Nucleus , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[54]  A. N. van den Pol,et al.  Synaptic Interaction between Hypocretin (Orexin) and Neuropeptide Y Cells in the Rodent and Primate Hypothalamus: A Novel Circuit Implicated in Metabolic and Endocrine Regulations , 1999, The Journal of Neuroscience.

[55]  C. Saper,et al.  From Lesions to Leptin Hypothalamic Control of Food Intake and Body Weight , 1999, Neuron.

[56]  T. Sakurai,et al.  Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[58]  B. Lowell,et al.  Mice lacking melanin-concentrating hormone are hypophagic and lean , 1998, Nature.

[59]  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.

[60]  C. Saper,et al.  Leptin Activates Hypothalamic CART Neurons Projecting to the Spinal Cord , 1998, Neuron.

[61]  K. McCowen,et al.  Leptin signaling in the hypothalamus of normal rats in vivo. , 1998, Endocrinology.

[62]  D. Macneil,et al.  Distribution of orexin receptor mRNA in the rat brain , 1998, FEBS letters.

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

[64]  K. Moar,et al.  Association of leptin receptor (OB-Rb), NPY and GLP-1 gene expression in the ovine and murine brainstem , 1998, Regulatory Peptides.

[65]  Robert C. Thompson,et al.  Evidence for GnRH Regulation by Leptin: Leptin Administration Prevents Reduced Pulsatile LH Secretion during Fasting , 1998, Neuroendocrinology.

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

[67]  J. Flier,et al.  Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus. , 1998, American journal of physiology. Endocrinology and metabolism.

[68]  K. Clément,et al.  A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction , 1998, Nature.

[69]  H Herzog,et al.  XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. , 1998, Pharmacological reviews.

[70]  S. Shioda,et al.  Immunohistochemical localization of leptin receptor in the rat brain , 1998, Neuroscience Letters.

[71]  K. Hamilton,et al.  Localization of leptin receptor immunoreactivity in the lean and obese Zucker rat brain , 1998, Brain Research.

[72]  S. Carr,et al.  Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior , 1998, Cell.

[73]  C. Saper,et al.  Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[74]  F E Bloom,et al.  The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[75]  R. Skoda,et al.  Leptin Receptor Immunoreactivity in Chemically Defined Target Neurons of the Hypothalamus , 1998, The Journal of Neuroscience.

[76]  K. Moar,et al.  Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. , 1998, Endocrinology.

[77]  S. Woods,et al.  Leptin Increases Hypothalamic Pro-opiomelanocortin mRNA Expression in the Rostral Arcuate Nucleus , 1997, Diabetes.

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

[79]  S. Grüninger,et al.  Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues. , 1997, Biochemical and biophysical research communications.

[80]  Roy G. Smith,et al.  Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. , 1997, Brain research. Molecular brain research.

[81]  A. Blomqvist,et al.  Y-receptor subtypes—how many more? , 1997, Trends in Neurosciences.

[82]  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.

[83]  R. Skoda,et al.  The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. , 1997, Molecular endocrinology.

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

[85]  Victor J. Hruby,et al.  Role of melanocortinergic neurons in feeding and the agouti obesity syndrome , 1997, Nature.

[86]  J. Parisi,et al.  Localization of leptin receptor in the human brain. , 1997, Neuroendocrinology.

[87]  T. Miyoshi,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Melanin-Concentrating Hormone Acutely Stimulates Feeding, But Chronic Administration Has No Effect on , 2022 .

[88]  W. Banks,et al.  Leptin enters the brain by a saturable system independent of insulin , 1996, Peptides.

[89]  P. Morgan,et al.  Coexpression of Leptin Receptor and Preproneuropeptide Y mRNA in Arcuate Nucleus of Mouse Hypothalamus , 1996, Journal of neuroendocrinology.

[90]  C. Christoffersen,et al.  Insulin and Cortisol Promote Leptin Production in Cultured Human Fat Cells , 1996, Diabetes.

[91]  J. Darnell,et al.  Leptin activation of Stat3 in the hypothalamus of wild–type and ob/ob mice but not db/db mice , 1996, Nature Genetics.

[92]  R. Skoda,et al.  Defective STAT signaling by the leptin receptor in diabetic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[93]  S. Woods,et al.  Specificity of Leptin Action on Elevated Blood Glucose Levels and Hypothalamic Neuropeptide Y Gene Expression in ob/ob Mice , 1996, Diabetes.

[94]  S. Gammeltoft,et al.  A role for melanin-concentrating hormone in the central regulation of feeding behaviour , 1996, Nature.

[95]  J. Friedman,et al.  Abnormal splicing of the leptin receptor in diabetic mice , 1996, Nature.

[96]  L. Tartaglia,et al.  Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice , 1996, Cell.

[97]  M. Dickie,et al.  Obese, a new mutation in the house mouse. , 1950, Obesity research.

[98]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[99]  T. Kawada,et al.  Augmented expression of the obese gene in the adipose tissue from rats fed high-fat diet. , 1995, Biochemical and biophysical research communications.

[100]  J. Bue-Valleskey,et al.  The role of neuropeptide Y in the antiobesity action of the obese gene product , 1995, Nature.

[101]  J. Auwerx,et al.  Transient increase in obese gene expression after food intake or insulin administration , 1995, Nature.

[102]  M. Deitel,et al.  Increased obese mRNA expression in omental fat cells from massively obese humans , 1995, Nature Medicine.

[103]  R. Devos,et al.  Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. , 1995, Science.

[104]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[105]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[106]  K. Nakao,et al.  Human Obese Gene Expression: Adipocyte-Specific Expression and Regional Differences in the Adipose Tissue , 1995, Diabetes.

[107]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[108]  E Stellar,et al.  The physiology of motivation. 1954. , 1994, Psychological review.

[109]  M. Jhanwar-Uniyal,et al.  Neuropeptide Y projection from arcuate nucleus to parvocellular division of paraventricular nucleus: specific relation to the ingestion of carbohydrate , 1993, Brain Research.

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

[111]  G. Koob,et al.  Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y , 1993, Brain Research.

[112]  N. Ling,et al.  Injection of anti-neuropeptide Y γ-globulin into the hypothalamic paraventricular nucleus decreases food intake in rats , 1993, Brain Research.

[113]  J. Vaughan,et al.  The melanin‐concentrating hormone system of the rat brain: An immuno‐ and hybridization histochemical characterization , 1992, The Journal of comparative neurology.

[114]  A. Fournier,et al.  Neurobehavioral profile of neuropeptide Y , 1991, Brain Research Bulletin.

[115]  A. Burlet,et al.  Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status , 1990, Brain Research.

[116]  G. Mcclearn,et al.  The body-mass index of twins who have been reared apart. , 1990, The New England journal of medicine.

[117]  C. Sladek,et al.  Neuropeptide Y, epinephrine and norepinephrine in the paraventricular nucleus: Stimulation of feeding and the release of corticosterone, vasopressin and glucose , 1988, Brain Research Bulletin.

[118]  J. Chahl,et al.  Substance P content in brain regions of the guinea-pig following morphine withdrawal , 1988, Regulatory Peptides.

[119]  M. G. Dube,et al.  Continuous intraventricular infusion of neuropeptide Y evokes episodic food intake in satiated female rats: Effects of adrenalectomy and cholecystokinin , 1988, Peptides.

[120]  J. Morley,et al.  Effect of neuropeptide Y on ingestive behaviors in the rat. , 1987, The American journal of physiology.

[121]  A. Vergoni,et al.  ACTH-(1–24) and α-MSH antagonize feeding behavior stimulated by kappa opiate agonists , 1986, Peptides.

[122]  D. Jacobowitz,et al.  Distribution of immunoreactive melanin-concentrating hormone in the central nervous system of the rat , 1986, Brain Research.

[123]  D. Jacobowitz,et al.  Melanin-concentrating hormone: unique peptide neuronal system in the rat brain and pituitary gland. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[124]  T. O'donohue,et al.  The anatomy of neuropeptide-y-containing neurons in rat brain , 1985, Neuroscience.

[125]  S. Leibowitz,et al.  Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[126]  P S Kalra,et al.  Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. , 1984, Endocrinology.

[127]  Y. Oomura,et al.  Neural network of glucose monitoring system. , 1984, Journal of the autonomic nervous system.

[128]  H. Kawauchi,et al.  Characterization of melanin-concentrating hormone in chum salmon pituitaries , 1983, Nature.

[129]  T. Crow,et al.  Neuropeptide Y distribution in the rat brain. , 1983, Science.

[130]  Stanley N Cohen,et al.  Characterization of the structural gene and putative 5′-regulatory sequences for human proopiomelanocortin , 1982, Nature.

[131]  V. Mutt,et al.  Neuropeptide Y—a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide , 1982, Nature.

[132]  T. O'donohue,et al.  alpha-Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[133]  M. Sugimori,et al.  Glucose Inhibition of the Glucose-sensitive Neurone in the Rat Lateral Hypothalamus , 1974, Nature.

[134]  R. M. Gold Hypothalamic Obesity: The Myth of the Ventromedial Nucleus , 1973, Science.

[135]  K. Hummel,et al.  Effects of parabiosis of normal with genetically diabetic mice. , 1969, The American journal of physiology.

[136]  J. Olney Brain Lesions, Obesity, and Other Disturbances in Mice Treated with Monosodium Glutamate , 1969, Science.

[137]  T. Ono,et al.  Glucose and Osmosensitive Neurones of the Rat Hypothalamus , 1969, Nature.

[138]  E. Stellar,et al.  The physiology of motivation. , 1954, Psychological review.

[139]  J. Brobeck,et al.  Localization of a “Feeding Center” in the Hypothalamus of the Rat , 1951, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.