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Published on: November 16, 2011
Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2
Olivier Le Bacquer1, Emmanuel Petroulakis, Sabina Paglialunga
1Department of Biochemistry, McGill University, Montréal, Québec, Canada.
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.
Insights
Mice lacking 4E-BP1 and 4E-BP2 proteins showed increased sensitivity to diet-induced obesity. These findings highlight the role of 4E-binding proteins as a metabolic brake, impacting obesity and insulin resistance.
Area of Science:
- Metabolic signaling pathways
- Obesity and diabetes research
- Mammalian Target of Rapamycin (mTOR) pathway
Background:
- Insulin resistance, a common obesity pathology, often leads to type 2 diabetes mellitus.
- The mammalian target of rapamycin (mTOR) signaling pathway is implicated in obesity.
- Eukaryotic translation initiation factor 4E-binding (4E-BP) proteins are downstream effectors of mTOR, repressing translation.
Purpose of the Study:
- To investigate the role of 4E-binding proteins (4E-BPs) in diet-induced obesity.
- To examine the impact of combined 4E-BP1 and 4E-BP2 disruption on metabolic parameters.
- To elucidate the mechanisms linking 4E-BP function to obesity and insulin resistance.
Main Methods:
- Generation and analysis of 4E-BP1 and 4E-BP2 double knockout (KO) mice.
- Assessment of sensitivity to diet-induced obesity.
- Evaluation of adipogenesis, energy expenditure, lipolysis, and fatty acid reesterification.
- Analysis of insulin signaling pathways (Akt) and ribosomal protein S6 kinase (S6K) activity.
Main Results:
- Combined disruption of 4E-BP1 and 4E-BP2 in mice increased sensitivity to diet-induced obesity.
- Accelerated adipogenesis, reduced energy expenditure, and altered lipid metabolism were observed in double KO mice.
- Increased insulin resistance in double KO mice correlated with elevated S6K activity and impaired Akt signaling.
Conclusions:
- 4E-binding proteins (4E-BPs) function as a critical metabolic brake in preventing obesity.
- Disruption of 4E-BP1 and 4E-BP2 promotes obesity and insulin resistance.
- These findings reinforce the link between deregulated mTOR signaling and the metabolic syndrome.
