Chronic Central Infusion of Ghrelin Increases Hypothalamic Neuropeptide Y and Agouti-Related Protein mRNA Levels and Body Weight in Rats

Abstract

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 g/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/AGRPcontaining neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach. Diabetes 50:2438 -2443, 2001 E nergy intake and expenditure are tightly regulated in mammals (1). Several neuronal populations, particularly in the hypothalamic arcuate nucleus (ARC), are involved in the regulation of energy homeostasis and have been implicated as possible targets of orexigenic peptides (1). These include neuropeptide Y (NPY)/agouti-related protein (AGRP) coexpressing neurons, pro-opiomelanocortin (POMC) neurons, and growth hormone-releasing hormone (GHRH) neurons, which are known to be stimulated (NPY and AGRP) or suppressed (POMC and GHRH) by starvation (2-10). However, central administration of NPY, AGRP, and GHRH increased food intake in rats, whereas ␣-melanocyte-stimulating hormone (␣-MSH), an end product of POMC processing, decreased food intake when injected centrally (11-13).The growth hormone secretagogues (GHSs) are synthetic peptide and nonpeptide compounds that stimulate the pulsatile release of growth hormone (GH) after intravenous administration (14). Central administration of GHSs also stimulates feeding behavior (15). GHS receptor (GHS-R) mRNA is expressed in the pituitary gland and in several areas of the brain, including the hypothalamus (16). In the hypothalamus, GHS-R mRNA is expressed in NPY/AGRP-, POMC-, and GHRH-containing neurons (17)(18)(19). Ghrelin, an end...

MTII attenuates ghrelin- and food deprivation-induced increases in food hoarding and food intake

“…This idea is partially, but not wholly, supported by the results of the present study using peripheral ghrelin injections and food deprivation to stimulate the ingestive behaviors, and the MC3/4-R agonist, MTII, to block these responses. Ghrelin-induced increases in food intake appear to act through the MC3/4-Rs in laboratory rats (Kamegai et al, 2000;Kamegai et al, 2001;Nakazato et al, 2001), and in the present study ghrelin-induced increased food intake was blocked 50% of the time across the various foraging conditions. The ghrelin-induced increased food hoarding was more consistently blocked by MTII than the ghrelin-induced increased food intake.…”

Ghrelin Stimulates Appetite, Imagination of Food, GH, ACTH, and Cortisol, but does not Affect Leptin in Normal Controls

“…Preclinical data suggest an inverse interaction of ghrelin and leptin (Shintani et al, 2001), whereas leptin levels remained unchanged in the rat after i.v. administration of a synthetic peptide corresponding to amino acid 1-28 of rodent ghrelin (Kamegai et al, 2001). Our present study shows acute CNS and pituitary effects of ghrelin, but no effects on leptin levels during the relatively short interval of the examination.…”

Clinical application of ghrelin administration for gastric cancer patients undergoing gastrectomy

“…H. pylori infection also markedly reduces ghrelin-producing cells and plasma ghrelin. [17,58,59] Ghrelin, which increases c-fos expression in the arcuate nucleus, also activates hypothalamic neuropeptide Y (NPY)/Y1 receptors and agouti-related peptide (AgRP) pathways Stimulation of GH secretion from the pituitary gland [17,[60][61][62] Ghrelin is involved in GH release in a non-acute setting. GH regulates IGF-I levels, promotes anabolism, and increases muscle strength.…”