| Literature DB >> 25295788 |
Sarah M Turpin1, Hayley T Nicholls1, Diana M Willmes1, Arnaud Mourier2, Susanne Brodesser3, Claudia M Wunderlich1, Jan Mauer1, Elaine Xu1, Philipp Hammerschmidt1, Hella S Brönneke1, Aleksandra Trifunovic3, Giuseppe LoSasso4, F Thomas Wunderlich1, Jan-Wilhelm Kornfeld1, Matthias Blüher5, Martin Krönke6, Jens C Brüning7.
Abstract
Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 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 C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6(Δ/Δ)) mice exhibit reduced C16:0 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(Δ/Δ) mice, but also in brown adipose tissue- (CerS6(ΔBAT)) and liver-specific (CerS6(ΔLIVER)) 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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 25295788 DOI： 10.1016/j.cmet.2014.08.002
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287