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Mol Nutr Food Res. 2017 Sep;61(9). doi: 10.1002/mnfr.201700128. Epub 2017 Jul 3.

Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity.

Author information

1
Université Clermont Auvergne, INRA, Clermont-Ferrand, France.
2
INSERM UMR1048, Institut des Maladies Cardiovasculaires et Métaboliques, Université Paul Sabatier, Toulouse, France.
3
CHU Clermont-Ferrand, Service Nutrition Clinique, Clermont Ferrand, France.
4
Department of Biochemistry, McGill University, Montreal, QC, Canada.

Abstract

SCOPE:

In recent years, several studies reported the role of eIF4E-binding proteins (4E-BPs) on the development of diet-induced obesity and insulin resistance. Our aim was to investigate the effect of 4E-BP protein deletion on lipid accumulation and metabolism in skeletal muscle in response to a high-fat diet induced obesity in 4E-BP1/2 DKO mice.

METHODS AND RESULTS:

Diet-induced obesity engendered increased ectopic accumulation of lipotoxic species in skeletal muscle of 4E-BP1 and 4E-BP2 double knockout mice (4E-BP1/2 DKO), namely diacylglycerols and ceramides. Increased lipid accumulation was associated with alterations in the expression of genes involved in fatty acid transport (FATP, CD36), diacylglycerol/triacylglycerol biosynthesis (GPAT1, AGPAT1, DGAT1), and β-oxidation (CPT1b, MCAD). Diet-induced obesity resulted in increased lean mass and muscle in 4E-BP1/2 DKO mice despite the development of a more severe systemic insulin resistance. Since increased expression of genes of several proteolytic systems (MuRF1, atrogin/MAFbx, and cathepsin-l) in 4EBP1/2 DKO skeletal muscle was reported, the increase of skeletal muscle mass in 4E-BP1/2 DKO mice suggests that ablation of 4E-BPs compensate with activation of muscle anabolism.

CONCLUSIONS:

These findings indicate that 4E-BP proteins may prevent excess lipid accumulation in skeletal muscle and suggest that 4E-BPs are key regulators of muscle homeostasis regardless of insulin sensitivity.

KEYWORDS:

ATGL; Lipid accumulation; Lipotoxicity; Protein homeostasis; mTOR

PMID:
28544394
DOI:
10.1002/mnfr.201700128
[Indexed for MEDLINE]

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