The Orphan Receptor Gpr83 Regulates Systemic Energy Metabolism via Ghrelin-Dependent and Ghrelin-Independent Mechanisms

Nat Commun. 2013;4:1968. doi: 10.1038/ncomms2968.

Abstract

The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / metabolism
  • Animals
  • Arcuate Nucleus of Hypothalamus / drug effects
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Body Composition / drug effects
  • Body Weight / drug effects
  • Diet, High-Fat
  • Energy Metabolism* / drug effects
  • Feeding Behavior / drug effects
  • Gene Expression Profiling
  • Ghrelin / administration & dosage
  • Ghrelin / metabolism*
  • Ghrelin / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism
  • Phenotype
  • Protein Multimerization / drug effects
  • Protein Transport / drug effects
  • Rats
  • Receptor, Melanocortin, Type 3 / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Ghrelin / metabolism
  • Signal Transduction / drug effects

Substances

  • Agouti-Related Protein
  • Ghrelin
  • Gpr83 protein, mouse
  • MC3R protein, human
  • Receptor, Melanocortin, Type 3
  • Receptors, G-Protein-Coupled
  • Receptors, Ghrelin