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PMID:17273556

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Citation

Le Bacquer, O, Petroulakis, E, Paglialunga, S, Poulin, F, Richard, D, Cianflone, K and Sonenberg, N (2007) Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J. Clin. Invest. 117:387-96

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.

Links

PubMed PMC1783830 Online version:10.1172/JCI29528

Keywords

Adipogenesis; Animals; Base Sequence; Carrier Proteins/genetics; 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 X/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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DEFA1

acts_upstream_of_or_within

GO:0050829: defense response to Gram-negative bacterium

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:94882
MGI:MGI:94883
MGI:MGI:99582

P

Seeded From UniProt

complete


See also

References

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