Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2

J Clin Invest. 2007 Feb;117(2):387-96. doi: 10.1172/JCI29528.

Abstract

The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), C/EBPalpha, and PPARgamma coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adipogenesis
  • Animals
  • Base Sequence
  • Carrier Proteins / genetics
  • Cell Cycle Proteins
  • DNA Primers / genetics
  • Diet / adverse effects
  • Eukaryotic Initiation Factors / deficiency*
  • Eukaryotic Initiation Factors / genetics
  • Humans
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Lipid Metabolism
  • Liver / metabolism
  • Liver / pathology
  • Metabolic Syndrome / etiology
  • Mice
  • Mice, Congenic
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Mutant Strains
  • Obesity / etiology*
  • Obesity / genetics
  • Obesity / physiopathology
  • Phosphoproteins / deficiency*
  • Phosphoproteins / genetics
  • Protein Kinases / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA Primers
  • Eif4ebp1 protein, mouse
  • Eif4ebp2 protein, mouse
  • Eukaryotic Initiation Factors
  • Phosphoproteins
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse