4.8 Article

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

Journal

CELL REPORTS
Volume 26, Issue 1, Pages 1-+

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2018.12.031

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Funding

  1. Leibniz Preis [BR1492/7-1]
  2. Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) (DFG within the Excellence Initiative by German Federal and State Governments)
  3. federal government (BMBF) through collaboration in Deutsche Zentrum fur Diabetesforschung e.V. (DZD) [FKZ 82DZD00502]
  4. Cologne Center for Molecular Medicine Cologne (CMMC)
  5. Alexander von Humboldt Foundation fellowship
  6. CECAD Senior Postdoctoral Research Grant
  7. Koln Fortune Program
  8. Swiss National Science Foundation
  9. University of Basel, Switzerland
  10. Sanofi-Aventis
  11. Deutschland GmbH

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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 C-18:0 ceramide content, concomitant with increased expression of ceramide synthase (CerS)1. Mice lacking CerS1, either globally or specifically in skeletal muscle (CerS1 Delta(SkM)), exhibit reduced muscle C-18:0 ceramide content and significant improvements in systemic glucose homeostasis. CerS1 Delta(SkM) 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 C-16:0 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.

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