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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/E78    most recent 00040.2008v2 00040.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Strassburg, S. Articles by Tschöp, M. H. PubMed PubMed Citation Articles by Strassburg, S. Articles by Tschöp, M. H.

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

¹Department of Psychiatry, Obesity Research Center-Genome Research Institute, University of Cincinnati, Cincinnati, Ohio; ²Applied Cachexia Research, Department of Cardiology, Charité, Campus Virchow-Klinikum 13353, Berlin, Germany; and ³Biomeasure Incorporated/IPSEN, Milford, Massachusetts

Submitted 22 January 2008 ; accepted in final form 29 April 2008

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 mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore 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. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol·kg^–1·day^–1 using implanted subcutaneous minipumps 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, whereas 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/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.

body weight; food intake; cachexia