Adipocyte CREB Promotes Insulin Resistance in Obesity

Cell Metab. 2009 Mar;9(3):277-86. doi: 10.1016/j.cmet.2009.01.006.

Abstract

Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.

Publication types

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

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / metabolism
  • Adenylate Kinase / metabolism
  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adiponectin / metabolism
  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Disease Progression
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gluconeogenesis / physiology
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Insulin Resistance / physiology*
  • Liver / cytology
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Obese
  • Mice, Transgenic
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Obesity / metabolism
  • Obesity / physiopathology*
  • Transcription Factors / metabolism

Substances

  • Activating Transcription Factor 3
  • Adiponectin
  • Atf3 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Glucose Transporter Type 4
  • Slc2a4 protein, mouse
  • Transcription Factors
  • Adenylate Kinase