Growth Hormone Releasing Peptide -2 (GHRP-2), like ghrelin, increases food intake in healthy men
2005

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 (1?g/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 ?g/L/240 min vs. 412±161 ?g/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.
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These are the first data to demonstrate that peripheral administration of GHRP-2 increases food intake in humans. The effect of GHRP-2 is robust and elicited an increase of food intake in all subjects tested. Subjects reported being hungrier while receiving GHRP-2. The magnitude of the effect of GHRP-2 on food intake (+35%) is comparable to that of ghrelin previously shown to increase food intake by 28% in healthy subjects (11) and by 31% in cancer patients (12). The effect of 1 ?g/kg/h of GHRP-2 is comparable to the effect of ghrelin (5 pmol/kg/min) not only on food intake, but also on GH release. In Wren's (5) study (also in healthy lean subjects), ghrelin raised GH to similar levels (about 35 ?g/L). Therefore, ghrelin or the ghrelin mimetic GHRP-2, when administered peripherally, is able to induce significant acute changes of similar magnitude in both GH levels and food intake behavior.

The hormonal regulation of food intake can be divided into long-term fat storage signals (leptin and insulin) and short-term meal initiation and satiety signals (ghrelin, CCK, and PYY). Ghrelin, although mainly secreted in the stomach, is believed to act centrally on the NPY-AGRP neurons of the arcuate nucleus (9,10). The mechanism for and amount of circulating peripheral ghrelin reaching these hypothalamic neurons is unclear. In rodents, both centrally and peripherally administered ghrelin (4) or GHS(s) (21,22) stimulate food intake. Evidence suggests that the spontaneous variation of endogenous serum ghrelin concentrations may play a role in intermeal duration, the recurrence of hunger and subsequent meal size (24). The postprandial suppression of ghrelin is proportional to meal size, but does not predict intermeal interval (25). Studies based on morning fasting serum levels of ghrelin have found no positive (25) or negative (26) relationship between fasting plasma ghrelin levels and ad libitum food intake. Whether fasting total (n-octanoyl plus desoctanoyl) ghrelin levels are the best marker for subsequent food intake is unclear. Furthermore, the integrated 24 h ghrelin release may be a better predictor of short-term energy balance/ food intake (27), just as integrated 24 h leptin levels are a better index of daytime food intake and insulin secretion (28) than morning fasting leptin levels. Both our data with the GHRP-2 and others with ghrelin (11,12) show that a peripheral infusion of these orexigenic peptides can elicit a robust acute change in food intake behavior in humans. This suggests, although does not prove, a possible role for peripheral circulating ghrelin in the meal to meal regulation (13, 25). It is unlikely, however, that simple alterations in the serum level of ghrelin alone dictate the magnitude or type of downstream effects via activation of central and peripheral receptors (29).
As previously reported (30), a subcutaneous infusion of GHRP-2 for 270 minutes is safe. Accordingly, no adverse side effects were reported during a 30-day sc continuous infusion of GHRP-2 (30) or 12 month oral administration of the drug in children (23).

Two studies revealed that chronic administration of GHRP-2 to short stature children with various degrees of GH deficiency induces a sustained enhancement in the rate of linear growth (23,31). This suggests the possibility that the acute effect of GHRP-2 on food intake observed in our study might result in a state of positive energy balance, were GHRP-2 administered chronically. Carefully designed and optimized chronic studies, including detailed body composition and food intake monitoring, will help to demonstrate the long-term effects of GHS(s) on food intake and body weight. Although GHRP-2 increased GH significantly, it is unlikely, judging from the results of rhGH alone, that this increase in GH levels is responsible for the acute changes in food intake in this study. In addition, the hypothalamic pathway and mechanism by which GHS(s) enhance food intake are distinctly different from those by which GHS(s) enhance GH secretion (4,7,33,34). Additionally, the stimulation of food intake by ghrelin or GHS persists in GH-deficient rats (10).

In most reports published thus far, the bioactive ghrelin molecule was not measured in human plasma and large pharmacological, rather than physiological, doses of ghrelin were administered. Other relevant future objectives to better understand the physiology and pathophysiology of the ghrelin system in humans will require more specific and frequent measurement of plasma ghrelin levels as well as determination of how closely the pharmacological and physiological actions of ghrelin parallel each other. GHRP-2, like ghrelin, is a useful tool for clinical study to help understand the complexity of food intake behavior regulation in humans.