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Muscle metabolic alterations induced by genetic ablation of 4E‐BP1 and 4E‐BP2 in response to diet‐induced obesity
Author(s) -
Le Bacquer Olivier,
Combe Kristell,
Montaurier Christophe,
Salles Jérôme,
Giraudet Christophe,
Patrac Véronique,
DominguesFaria Carla,
Guillet Christelle,
Louche Katie,
Boirie Yves,
Sonenberg Nahum,
Moro Cédric,
Walrand Stéphane
Publication year - 2017
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201700128
Subject(s) - medicine , endocrinology , skeletal muscle , insulin resistance , biology , diacylglycerol kinase , lipid metabolism , insulin , microbiology and biotechnology , signal transduction , protein kinase c
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.