GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein

Endocrinology. 2002 Feb;143(2):558-68. doi: 10.1210/endo.143.2.8633.


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.

MeSH terms

  • Absorptiometry, Photon
  • Adipose Tissue / drug effects
  • Adipose Tissue / physiology*
  • Agouti-Related Protein
  • Animals
  • Body Weight / drug effects
  • Bone Development / drug effects
  • Calorimetry, Indirect
  • Chromatography, High Pressure Liquid
  • Eating / drug effects
  • Genotype
  • Hormones / blood
  • Hypothalamus / physiology*
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Neuropeptide Y / genetics
  • Neuropeptide Y / physiology*
  • Oligopeptides / pharmacology*
  • Proteins / physiology*
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / physiology*
  • Receptors, Corticotropin / agonists
  • Receptors, G-Protein-Coupled*
  • Receptors, Ghrelin
  • Receptors, Melanocortin
  • Reverse Transcriptase Polymerase Chain Reaction


  • Agouti-Related Protein
  • Agrp protein, mouse
  • Hormones
  • Intercellular Signaling Peptides and Proteins
  • Neuropeptide Y
  • Oligopeptides
  • Proteins
  • Receptors, Cell Surface
  • Receptors, Corticotropin
  • Receptors, G-Protein-Coupled
  • Receptors, Ghrelin
  • Receptors, Melanocortin
  • growth hormone-releasing peptide-2