The Distribution and Mechanism of Action of Ghrelin in the CNS Demonstrates a Novel Hypothalamic Circuit Regulating Energy Homeostasis

The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and humans via hypothalamic actions. We discovered expression of ghrelin in a previously uncharacterized group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These neurons send efferents onto key hypothalamic circuits, including those producing neuropeptide Y (NPY), Agouti-related protein (AGRP), proopiomelanocortin (POMC) products, and corticotropin-releasing hormone (CRH). Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Using electrophysiological recordings, we found that ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH). We propose that at these sites, release of ghrelin may stimulate the release of orexigenic peptides and neurotransmitters, thus representing a novel regulatory circuit controlling energy homeostasis.

[1]  M. Papotti,et al.  Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans , 2000, Journal of endocrinological investigation.

[2]  Roy G. Smith,et al.  Peptidomimetic regulation of growth hormone secretion. , 1997, Endocrine reviews.

[3]  T. Horvath,et al.  Minireview: Ghrelin and the Regulation of Energy Balance-A Hypothalamic Perspective. , 2001, Endocrinology.

[4]  M. Bednarek,et al.  Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. , 2000, Journal of medicinal chemistry.

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

[6]  T. Horvath.  Suprachiasmatic efferents avoid phenestrated capillaries but innervate neuroendocrine cells, including those producing dopamine. , 1997, Endocrinology.

[7]  J. Friedman,et al.  Virus-Assisted Mapping of Neural Inputs to a Feeding Center in the Hypothalamus , 2001, Science.

[8]  M. Korbonits,et al.  The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. , 2001, The Journal of clinical endocrinology and metabolism.

[9]  B. Wisse,et al.  A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. , 2001, Diabetes.

[10]  M. Tschöp,et al.  Post-prandial decrease of circulating human ghrelin levels , 2001, Journal of endocrinological investigation.

[11]  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.

[12]  W. Colmers,et al.  Multiple NPY Receptors Inhibit GABAA Synaptic Responses of Rat Medial Parvocellular Effector Neurons in the Hypothalamic Paraventricular Nucleus. , 2002, Endocrinology.

[13]  M. Tschöp,et al.  GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. , 2002, Endocrinology.

[14]  C. Oliver,et al.  Distribution, characterization, and subcellular localization of MSH in the brain. , 1977, Frontiers of hormone research.

[15]  P S Kalra,et al.  Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. , 1999, Endocrine reviews.

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

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

[18]  S. Dickson,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Induction of c-fos Messenger Ribonucleic Acid in Neuropeptide Y and Growth Hormone (GH)-Releasing Factor Neurons in the Rat Arcuate Nucleus Following Systemic Injection of the GH Secretagogue, GH , 2022 .

[19]  Y. Taché,et al.  Peripheral ghrelin selectively increases Fos expression in neuropeptide Y – synthesizing neurons in mouse hypothalamic arcuate nucleus , 2002, Neuroscience Letters.

[20]  C. D. D. L. Cour,et al.  A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control , 2001, Regulatory Peptides.

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

[22]  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.

[23]  M. Smith,et al.  Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels , 1997, Nature.

[24]  E. Connolly,et al.  ER-X: A Novel, Plasma Membrane-Associated, Putative Estrogen Receptor That Is Regulated during Development and after Ischemic Brain Injury , 2002, The Journal of Neuroscience.

[25]  K. Hosoda,et al.  Kidney produces a novel acylated peptide, ghrelin , 2000, FEBS letters.

[26]  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.

[27]  M. Papotti,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Endocrine Activities of Ghrelin, a Natural Growth Hormone Secretagogue (GHS), in Humans: Comparison and Interactions with Hexarelin, a Nonnatura , 2022 .

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

[29]  M. Matsubara,et al.  Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract , 2002, Peptides.

[30]  L W Swanson,et al.  Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat , 1987, The Journal of comparative neurology.

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

[32]  M. Brownstein,et al.  The regional distribution of somatostatin in the rat brain. , 1975, Endocrinology.

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

[34]  S. Dickson,et al.  Systemic Administration of Ghrelin Induces Fos and Egr‐1 Proteins in the Hypothalamic Arcuate Nucleus of Fasted and Fed Rats , 2000, Journal of neuroendocrinology.

[35]  G. Frost,et al.  Ghrelin enhances appetite and increases food intake in humans. , 2001, The Journal of clinical endocrinology and metabolism.

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

[37]  J. Kamegai,et al.  Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. , 2000, Endocrinology.

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

[39]  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.

[40]  M. Low,et al.  Activation of Central Melanocortin Pathways by Fenfluramine , 2002, Science.

[41]  M. Papotti,et al.  0013-7227/02/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 87(3):1300–1308 Printed in U.S.A. Copyright © 2002 by The Endocrine Society Expression of Ghrelin and of the GH Secretagogue Receptor by Pancreatic Islet Cells and Related , 2022 .

[42]  Clifford B. Saper,et al.  Leptin Regulation of Neuroendocrine Systems , 2000, Frontiers in Neuroendocrinology.

[43]  Y. Tung,et al.  Actions of leptin on growth hormone secretagogue-responsive neurones in the rat hypothalamic arcuate nucleus recorded in vitro. , 2001 .

[44]  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.

[45]  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.

[46]  R. Cone,et al.  Integration of NPY, AGRP, and Melanocortin Signals in the Hypothalamic Paraventricular Nucleus Evidence of a Cellular Basis for the Adipostat , 1999, Neuron.

[47]  R. Cone,et al.  Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat. , 1999, Endocrinology.

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

[49]  C. Inagaki,et al.  GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. , 2001, The Journal of clinical endocrinology and metabolism.

[50]  M. Tota,et al.  ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. , 1997, Biochemical and biophysical research communications.

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

[52]  J. Bains,et al.  Leptin depolarizes rat hypothalamic paraventricular nucleus neurons. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[53]  K. Fuxe,et al.  NPY Y1 receptor like immunoreactivity exists in a subpopulation of β-endorphin immunoreactive nerve cells in the arcuate nucleus: a double immunolabelling analysis in the rat , 1997, Neuroscience Letters.

[54]  T. Horvath.  An Alternate Pathway for Visual Signal Integration into the Hypothalamo-Pituitary Axis: Retinorecipient Intergeniculate Neurons Project to Various Regions of the Hypothalamus and Innervate Neuroendocrine Cells Including Those Producing Dopamine , 1998, The Journal of Neuroscience.

[55]  C. Léránth,et al.  Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations , 1997, Brain Research.

[56]  T. Suter,et al.  GH-Releasing Peptide-2 Increases Fat Mass in Mice Lacking NPY: Indication for a Crucial Mediating Role of Hypothalamic Agouti-Related Protein. , 2002, Endocrinology.

[57]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

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

[59]  K. Toshinai,et al.  Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. , 2001, Biochemical and biophysical research communications.

[60]  N. Nakai,et al.  Testis-specific and developmentally induced expression of a ghrelin gene-derived transcript that encodes a novel polypeptide in the mouse. , 2001, Biochimica et biophysica acta.

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

[62]  J. Rømer,et al.  Co-Localization of Growth Hormone Secretagogue Receptor and NPY mRNA in the Arcuate Nucleus of the Rat , 1999, Neuroendocrinology.

[63]  F. Casanueva,et al.  Ghrelin, a novel placental-derived hormone. , 2001 .