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 1

Increased obesity and insulin resistance in 4E-BP1 and 4E-BP2 DKO mice.

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Increased obesity and insulin resistance in 4E-BP1 and 4E-BP2 DKO mice. ...
(A) Weight of the heart, gonadal (GWAT), retroperitoneal (RWAT), and inguinal (IWAT) white adipose tissue (n = 7–10) of WT and DKO mice fed HFD or normal chow diet (control). (B) Histological analysis of WT and DKO gonadal white adipose tissue from mice fed normal chow or HFD. Sections obtained from 4 different animals were stained with hematoxylin and eosin. Original magnification, ×400. (C) Adipocyte cell size in WT and DKO gonadal adipose tissue. (D) Mean VO2 in WT and DKO mice fed normal chow or HFD (n = 5). (E) Respiratory quotient, calculated as the ratio of VO2 to carbon dioxide production, in WT and DKO mice fed normal chow or HFD during light and dark phases. (F) Insulin resistance test. Fed mice given normal chow or HFD received an intraperitoneal injection of 0.75 U/kg insulin, and blood samples were taken at the indicated times (n = 7–14). (G) Glucose tolerance test. Mice fed normal chow or HFD were fasted overnight before receiving an intraperitoneal injection of 2 g/kg glucose, and blood samples were taken at the indicated times (n = 7–14). Data are mean ± SEM. *P < 0.05 versus WT (2-tailed, unpaired Student’s t test).