Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 microg/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRP-containing neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach.

[1]  A. Beaudet,et al.  Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the mediobasal hypothalamus. , 1998, Endocrinology.

[2]  J. Kamegai,et al.  Barrel rotation evoked by intracerebroventricular injection of somatostatin and arginine-vasopressin is accompanied by the induction of c-fos gene expression in the granular cells of rat cerebellum. , 1993, Brain research. Molecular brain research.

[3]  M. Schwartz,et al.  Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. , 2000, Diabetes.

[4]  L. Swanson.  The Rat Brain in Stereotaxic Coordinates, George Paxinos, Charles Watson (Eds.). Academic Press, San Diego, CA (1982), vii + 153, $35.00, ISBN: 0 125 47620 5 , 1984 .

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

[6]  D. Krupa,et al.  Repeat administration of the GH secretagogue MK-0677 increases and maintains elevated IGF-I levels in beagles. , 1997, The Journal of endocrinology.

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

[8]  F. Bloom,et al.  Stimulation of food intake in rats by centrally administered hypothalamic growth hormone-releasing factor , 1985, Nature.

[9]  R. Steiner,et al.  Short-term starvation decreases POMC mRNA but does not alter GnRH mRNA in the brain of adult male rats. , 1992, Neuroendocrinology.

[10]  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 .

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

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

[13]  C. Mobbs,et al.  Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

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

[15]  G. Sanacora,et al.  Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation. , 1990, Endocrinology.

[16]  Patrick R. Griffin,et al.  A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release , 1996, Science.

[17]  E. Ravussin,et al.  Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects , 1995, Nature Medicine.

[18]  M. Herkenham,et al.  Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats. , 1990, Neuroendocrinology.

[19]  Y. Yoshimasa,et al.  Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action. , 1999, Diabetes.

[20]  J. Kamegai,et al.  The growth hormone-releasing peptide KP-102 induces c-fos expression in the arcuate nucleus. , 1996, Brain research. Molecular brain research.

[21]  S. Bloom,et al.  A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. , 1998, Endocrinology.

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

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

[24]  C. Mobbs,et al.  Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. , 1999, Endocrinology.

[25]  R. Dyball,et al.  Central actions of peptide and non-peptide growth hormone secretagogues in the rat. , 1995, Neuroendocrinology.

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

[27]  C. Priest,et al.  Hypothalamic Pro-Opiomelanocortin mRNA Is Reduced By Fasting in ob/ob and db/db Mice, but Is Stimulated by Leptin , 1998, Diabetes.

[28]  J. Waelkens.  [The regulation of growth hormone secretion]. , 2018, Tijdschrift voor kindergeneeskunde.

[29]  S. Ishii,et al.  Intracerebroventricular administration of the growth hormone-releasing peptide KP-102 increases food intake in free-feeding rats. , 1996, Endocrinology.

[30]  C. Priest,et al.  Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. , 1998, Diabetes.

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

[32]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

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

[34]  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.

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

[36]  E. van Cauter,et al.  Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. , 1996, The Journal of clinical endocrinology and metabolism.

[37]  M. Berelowitz,et al.  Influence of food deprivation in the rat on hypothalamic expression of growth hormone-releasing factor and somatostatin. , 1990, Endocrinology.

[38]  J. Roberts,et al.  Fasting regulates hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin. , 1999, Endocrinology.