The Baf60c/Deptor Pathway Links Skeletal Muscle Inflammation to Glucose Homeostasis in Obesity

  1. Jiandie D. Lin1,*
  1. 1Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
  1. * Corresponding Author: Jiandie Lin, Email: jdlin{at}umich.edu

Abstract

Skeletal muscle insulin resistance in type 2 diabetes is associated with a shift from oxidative to glycolytic metabolism in myofibers. However, whether this metabolic switch is detrimental or adaptive for metabolic homeostasis has not been resolved. We recently demonstrated that the Baf60c/Deptor pathway promotes glycolytic metabolism in the muscle and protects mice from diet-induced insulin resistance. However, the nature of the signals that impinge on this pathway and the role of Baf60c in glucose homeostasis in severe insulin resistant state remain unknown. Here we show that expression of Baf60c and Deptor was downregulated in skeletal muscle in obesity, accompanied by ERK activation. In cultured myotubes, inhibition of ERK, but not JNK and IKK, blocked the downregulation of Baf60c and Deptor by proinflammatory cytokine TNFα. Treatment of obese mice with ERK inhibitor U0126 rescued Baf60c and Deptor expression in skeletal muscle and lowered blood glucose. Transgenic rescue of Baf60c in skeletal muscle restored Deptor expression and Akt phosphorylation and ameliorated insulin resistance in ob/ob mice. This study identifies the Baf60c/Deptor pathway as a target of pro-inflammatory signaling in skeletal muscle that may link meta-inflammation to skeletal myofiber metabolism and insulin resistance.

  • Received July 5, 2013.
  • Accepted January 18, 2014.

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