Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is predominantly mediated by central nervous system pathways controlling food intake, energy expenditure and nutrient partitioning. The ghrelin pathway therefore may offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half life and the fragility of its bioactivity ensuring acylation at serine 3. We therefore tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, in comparison with ghrelin. All agents were administered continuously for one month in doses of 50 and 500 nmol/kg/day using implanted subcutaneous mini-pumps in rats. High-dose treatment with single agonists or ghrelin increased body-weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, while no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times a day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states, such as cachexia.