期刊
CELL METABOLISM
卷 20, 期 4, 页码 678-686出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.08.002
关键词
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资金
- Leibniz Preis [BR1492/7-1]
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) - DFG within the Excellence Initiative by the German federal government
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) - DFG within the Excellence Initiative by the German state government
- Helmholtz Alliance-Imaging and Curing Environmental Metabolic Diseases (ICEMED, Helmholtz Association)
- Center for Molecular Medicine Cologne (CMMC)
- Alexander von Humboldt Foundation
- Outgoing AIRC/Marie Curie Fellowship
- Emmy-Noether program [KO4728.1-1]
- Koln Fortune Program
- Sanofi-Aventis
- Deutschland GmbH
Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C-14:0 to C-30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C-16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6 D/D) mice exhibit reduced C-16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6 D/D mice, but also in brown adipose tissue-(CerS6 DBAT) and liver-specific (CerS6 DLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition.
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