Lack of cAMP-response element-binding protein 1 in the hypothalamus causes obesity

J Biol Chem. 2011 Mar 11;286(10):8094-105. doi: 10.1074/jbc.M110.178186. Epub 2011 Jan 5.

Abstract

The melanocortin system in the hypothalamus controls food intake and energy expenditure. Its disruption causes severe obesity in mice and humans. cAMP-response element-binding protein 1 (CREB1) has been postulated to play an important role downstream of the melanocortin-4 receptor (MC4R), but this hypothesis has never been confirmed in vivo. To test this, we generated mice that lack CREB1 in SIM1-expressing neurons, of the paraventricular nucleus (PVN), which are known to be MC4R-positive. Interestingly, CREB1(ΔSIM1) mice developed obesity as a result of decreased energy expenditure and impairment in maintaining their core body temperature and not because of hyperphagia, defining a new role for CREB1 in the PVN. In addition, the lack of CREB1 in the PVN caused a reduction in vasopressin expression but did not affect adrenal or thyroid function. Surprisingly, MC4R function tested pharmacologically was normal in CREB1(ΔSIM1) mice, suggesting that CREB1 is not required for intact MC4R signaling. Thus CREB1 may affect other pathways that are implicated in the regulation of body weight.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Body Temperature Regulation / genetics
  • Body Weight*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Energy Metabolism / genetics
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Neurons / pathology
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Paraventricular Hypothalamic Nucleus / pathology
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptor, Melanocortin, Type 4 / metabolism
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Nerve Tissue Proteins
  • Receptor, Melanocortin, Type 4
  • Repressor Proteins
  • Sim1 protein, mouse