3 years ago

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

Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity
Stéphane Walrand, Kristell Combe, Véronique Patrac, Olivier Le Bacquer, Carla Domingues-Faria, Jérôme Salles, Yves Boirie, Katie Louche, Christelle Guillet, Nahum Sonenberg, Christophe Giraudet, Christophe Montaurier, Cédric Moro
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. The purpose of this study is to examine muscle lipid metabolism and lipotoxicity in 4E-BP1/2 DKO under normal chow and high-fat diet.Deletion of 4E-BP proteins is associated with increased ectopic accumulation of lipotoxic compounds and altered lipid metabolism in skeletal muscle. It is also revealed that despite the development of systemic insulin resistance by high-fat diet feeding, loss of 4E-BPs is able to induce an anabolic response in skeletal muscle.4E-BPs might represent an interesting pharmacological target to prevent muscle loss in situation of insulin resistance.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/mnfr.201700128

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