GH-Releasing Peptide-2 Increases Fat Mass in Mice Lacking NPY: Indication for a Crucial Mediating Role of Hypothalamic Agouti-Related Protein

Ghrelin, an endogenous GH secretagogue, is capable of stimulating adiposity in rodents.Because such adiposity was thought to be mediated by hypothalamic NPY neurons, we investigated by which mechanism a synthetic ghrelin receptor agonist, GHRP-2, would generate a positive energy balance in NPY-deficient [Npy(/) mice] and wild-type controls.A dose-dependent increase in body weight and food intake was observed during daily sc injections with GHRP-2.Preand posttreatment analysis of body composition indicated increased fat mass and bone mass but not lean mass.Respiratory quotient was increased in GHRP-2-treated mice, indicating preservation of fat.Hypothalamic mRNA levels of agouti-related protein (AGRP), an orexigenic melanocortin receptor antagonist, increased after GHRP-2 treatment.Competitive blockade of AGRP action by melanocortin-receptor agonist MT-II prevented GHRP-induced weight gain in Npy(/) mice.In conclusion, chronic peripheral treatment with a ghrelin receptor agonist induced a positive energy balance leading to fat gain in the absence of NPY.These effects could be mediated in part by AGRP.To date, there are few therapeutics that can produce a positive energy balance.Ghrelin receptor agonists offer a treatment option for syndromes like anorexia nervosa, cancer cachexia, or AIDS wasting.(Endo-