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

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

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.

MeSH terms

  • Animals
  • Carrier Proteins / physiology*
  • Cell Cycle Proteins
  • Diet, High-Fat
  • Eukaryotic Initiation Factors / physiology*
  • Insulin Resistance
  • Lipid Metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism*
  • Phosphoproteins / physiology*
  • Proteostasis

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eif4ebp2 protein, mouse
  • Eukaryotic Initiation Factors
  • Phosphoproteins
  • Mechanistic Target of Rapamycin Complex 1