Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake

Nat Commun. 2016 Jan 8;7:10268. doi: 10.1038/ncomms10268.

Abstract

Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / genetics*
  • Agouti-Related Protein / metabolism
  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Eating / genetics*
  • HEK293 Cells
  • Humans
  • Hypothalamus / cytology
  • Hypothalamus / metabolism*
  • Immunohistochemistry
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Neurons / metabolism*
  • Neuropeptide Y / genetics*
  • Neuropeptide Y / metabolism
  • Patch-Clamp Techniques
  • Phosphoproteins
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Agouti-Related Protein
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Neuropeptide Y
  • Phosphoproteins
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • gamma-Aminobutyric Acid