GHRP-2 is a synthetic agonist of ghrelin, the newly-discovered gut peptide which binds to the growth hormone (GH) secretagogue receptor. Ghrelin has been shown to have two major effects, stimulating both GH secretion and appetite/meal initiation. GHRP-2 has been extensively studied for its utility as a growth hormone secretagogue (GHS). Animal studies have shown its effect on food intake. However, whether GHRP-2 can also stimulate appetite in humans when administered acutely is not known. We subcutaneously infused 7 lean, healthy males with GHRP-2 (1μg/kg/h) or saline for 270 minutes and then measured their intake of an ad libitum, buffet-style meal. Similar to what has been reported for ghrelin administration, our subjects ate 35.9±10.9 % more when infused with GHRP-2 vs. saline, with every subject increasing their intake even when calculated per kg body weight (136.0±13.0 kJ/kg vs 101.3±10.5 kJ/kg, p=0.008). The macronutrient composition of consumed food was not different between conditions. As expected, serum GH levels rose significantly during GHRP-2 infusion (AUC 5550±1090 μg/L/240 min vs. 412±161 μg/L/240 min, p=0.003). These data are the first to demonstrate that GHRP-2, like ghrelin, increases food intake, suggesting that GHRP-2 is a valuable tool for investigating ghrelin effects on eating behavior in humans.
Introduction
Ghrelin, the recently identified peptide secreted by gastric endocrine cells, has attracted much interest for its dual effects. This endogenous ligand for the growth hormone secretagogue receptor (GHS-R) which was cloned in 1996 regulates growth hormone (GH) release . Ghrelin also appears to play a role in the regulation of food intake and energy balance. When administered either centrally or peripherally to rodents, ghrelin increases food intake and body weight. Interestingly, its effects on food intake are independent of GH secretion and appear to be mediated via the NPY/Agouti gene-related protein (AGRP) neurons in the hypothalamic arcuate nucleus. Peripheral ghrelin administration has recently been shown to stimulate food intake in lean, healthy men and women and in cancer patients.
Data suggest that circulating ghrelin is also implicated in meal to meal regulation. Ghrelin levels increase in anticipation of a meal and are suppressed by food ingestion but the underlying mechanisms are not known. The meal-related suppression of ghrelin is proportional to the carbohydrate (CHO) content of the meal but does not appear to be directly related to glucose or insulin although insulin administration decreases ghrelin.
Serum ghrelin levels vary as a function of energy balance. Ghrelin levels are increased in anorexia and decreased in obesity. Thus, it is possible that ghrelin may be an important player in food intake behavior and perhaps in chronic over- and undernutrition as well. Because of its dual effects, ghrelin may be a critical hormonal signal of nutritional status to the somatotropic axis, playing a role in integrating energy balance with the growth process.
Ghrelin is not available for long-term studies in human subjects in the United States, however, the synthetic GHS-R agonist GHRP-2 (DalaDßNalAlaTrpDPheLysNH2) is available for clinical studies. GHRP-2 belongs to a family of GHS(s) discovered in the 1980’s and extensively studied for their effect on GH release. Despite the very different chemistry of natural ghrelin and synthetic GHS, evidence strongly and increasingly supports that they have the same biological actions. Like ghrelin, GHS(s) increase food intake and body weight in rodents. GHRP-2 has been shown to increase appetite ratings in children with idiopathic GH treated chronically with oral GHRP-2.
The aim of this study was to investigate whether GHRP-2 stimulates food intake in healthy human subjects. Similar to the study by Wren et al.which used ghrelin, we tested the effect of a short-term subcutaneous (sc) infusion of GHRP-2 on food intake during a buffet meal.
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