CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance

Cell Rep. 2019 Jan 2;26(1):1-10.e7. doi: 10.1016/j.celrep.2018.12.031.


Skeletal muscle accumulates ceramides in obesity, which contribute to the development of obesity-associated insulin resistance. However, it remained unclear which distinct ceramide species in this organ contributes to instatement of systemic insulin resistance. Here, ceramide profiling of high-fat diet (HFD)-fed animals revealed increased skeletal muscle C18:0 ceramide content, concomitant with increased expression of ceramide synthase (CerS)1. Mice lacking CerS1, either globally or specifically in skeletal muscle (CerS1ΔSkM), exhibit reduced muscle C18:0 ceramide content and significant improvements in systemic glucose homeostasis. CerS1ΔSkM mice exhibit improved insulin-stimulated suppression of hepatic glucose production, and lack of CerS1 in skeletal muscle improves systemic glucose homeostasis via increased release of Fgf21 from skeletal muscle. In contrast, muscle-specific deficiency of C16:0 ceramide-producing CerS5 and CerS6 failed to protect mice from obesity-induced insulin resistance. Collectively, these results reveal the tissue-specific function of distinct ceramide species during the development of obesity-associated insulin resistance.

Keywords: CerS1; FGF-21; ceramide; ceramide synthase 1; diabetes mellitus; insulin resistance; obesity; skeletal muscle; sphingolipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ceramides / adverse effects*
  • Diet, High-Fat / adverse effects*
  • Humans
  • Insulin Resistance / genetics*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Muscle, Skeletal / metabolism*
  • Obesity / genetics*
  • Sphingosine N-Acyltransferase / metabolism*


  • Ceramides
  • Membrane Proteins
  • CerS1 protein, mouse
  • Sphingosine N-Acyltransferase