Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2
Olivier Le Bacquer, … , Katherine Cianflone, Nahum Sonenberg
Olivier Le Bacquer, … , Katherine Cianflone, Nahum Sonenberg
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):387-396. https://doi.org/10.1172/JCI29528.
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Research Article

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

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 δ (C/EBPδ), C/EBPα, and PPARγ 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.

Authors

Olivier Le Bacquer, Emmanuel Petroulakis, Sabina Paglialunga, Francis Poulin, Denis Richard, Katherine Cianflone, Nahum Sonenberg

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Figure 3

Deletion of 4E-BP1 and 4E-BP2 led to impairment of insulin signaling.

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Deletion of 4E-BP1 and 4E-BP2 led to impairment of insulin signaling. (A...
(A) Increased S6K activity and reduced Ser473 phosphorylation of Akt in muscle, liver, and adipose tissue from WT and DKO animals. Mice were fasted for 6 hours before receiving a 0.75 U/kg insulin injection in the tail vein. Animals were sacrificed 10 minutes later, and tissues were collected for Western blotting. An immunoblot of WT and DKO mouse tissue is shown. S473 pAkt, phosphorylated Ser473 of Akt; T389 pS6K1, phosphorylated Thr389 of S6K1; S240/244 pS6, phosphorylated Ser240/244 of S6. (B) Reduced IRS-1 expression in DKO adipose tissue. (C) Quantification of IRS-1 protein levels in WT and DKO adipose tissue. Levels were normalized to actin (n = 6–7). Data are mean ± SEM. *P < 0.05 versus WT (2-tailed, unpaired Student’s t test). (D) Immunoblot analysis showed increased inhibitory serine phosphorylation of IRS-1 (S636/639 pIRS-1 and S1101 pIRS-1) and sustained Thr389 phosphorylation of S6K1 in DKO MEFs following insulin treatment.