title: Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats.
abstract: 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 x kg(-1) x 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.
authors.affiliation: Department of Psychiatry, Obesity Research Centre-Genome Research Institute, Univ. of Cincinnati-College of Medicine, Cincinnati, OH, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Strassburg
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Castaneda
authors.forename: Lukas
authors.initials: L
authors.lastname: Burget
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Ruben
authors.initials: R
authors.lastname: Nogueiras
authors.forename: Heather
authors.initials: H
authors.lastname: Halem
authors.forename: Jesse Z
authors.initials: JZ
authors.lastname: Dong
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.forename: Rakesh
authors.initials: R
authors.lastname: Datta
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000378:metabolism; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D054439:Ghrelin / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists*
chemical_list: C527636:BIM-28125; D054439:Ghrelin; D054440:Receptors, Ghrelin