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

Endocrine Research, Lilly Research Laboratories Eli Lilly \|[amp ]\| Co., Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Matthias Tschöp, M.D., Endocrine Research, Lilly Research Laboratories Eli Lilly \|[amp ]\| Co., Lilly Corporate Center, Drop Code 0545, Indianapolis, Indiana 46285. E-mail: tschoep{at}gmx.de

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. Pre- and 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.

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