title: GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein.
abstract: 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.
authors.affiliation: Endocrine Research, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA. tschoep@gmx.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Tschöp
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
authors.forename: Todd M
authors.initials: TM
authors.lastname: Suter
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heiman
mesh_terms: D015502:Absorptiometry, Photon; D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology*; D054369:Agouti-Related Protein; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects; D002153:Calorimetry, Indirect; D002851:Chromatography, High Pressure Liquid; D004435:Eating / Q000187:drug effects; D005838:Genotype; D006728:Hormones / Q000097:blood; D007031:Hypothalamus / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000235:genetics / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology*; D011506:Proteins / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000502:physiology*; D018043:Receptors, Corticotropin / Q000819:agonists; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D044101:Receptors, Melanocortin; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D006728:Hormones; D036341:Intercellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009842:Oligopeptides; D011506:Proteins; D011956:Receptors, Cell Surface; D018043:Receptors, Corticotropin; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D044101:Receptors, Melanocortin; C091874:growth hormone-releasing peptide-2