CRTC3 links catecholamine signalling to energy balance

Nature. 2010 Dec 16;468(7326):933-9. doi: 10.1038/nature09564.


The adipose-derived hormone leptin maintains energy balance in part through central nervous system-mediated increases in sympathetic outflow that enhance fat burning. Triggering of β-adrenergic receptors in adipocytes stimulates energy expenditure by cyclic AMP (cAMP)-dependent increases in lipolysis and fatty-acid oxidation. Although the mechanism is unclear, catecholamine signalling is thought to be disrupted in obesity, leading to the development of insulin resistance. Here we show that the cAMP response element binding (CREB) coactivator Crtc3 promotes obesity by attenuating β-adrenergic receptor signalling in adipose tissue. Crtc3 was activated in response to catecholamine signals, when it reduced adenyl cyclase activity by upregulating the expression of Rgs2, a GTPase-activating protein that also inhibits adenyl cyclase activity. As a common human CRTC3 variant with increased transcriptional activity is associated with adiposity in two distinct Mexican-American cohorts, these results suggest that adipocyte CRTC3 may play a role in the development of obesity in humans.

Publication types

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

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Body Temperature
  • Catecholamines / metabolism*
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dietary Fats / pharmacology
  • Energy Metabolism* / genetics
  • Female
  • Genome-Wide Association Study
  • Humans
  • Insulin Resistance
  • Mexican Americans / genetics
  • Mice
  • Obesity / chemically induced
  • Obesity / genetics
  • Obesity / metabolism
  • Phosphorylation
  • RGS Proteins / biosynthesis
  • RGS Proteins / genetics
  • Receptors, Adrenergic, beta / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription Factors / chemistry
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • CRTC3 protein, human
  • CRTC3 protein, mouse
  • Catecholamines
  • Cyclic AMP Response Element-Binding Protein
  • Dietary Fats
  • RGS Proteins
  • Receptors, Adrenergic, beta
  • Rgs2 protein, mouse
  • Transcription Factors
  • Cyclic AMP