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. 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.
Tschöp
Matthias
M
Endocrine Research, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA. tschoep@gmx.de
Statnick
Michael A
MA
Suter
Todd M
TM
Heiman
Mark L
ML
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
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