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