Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance

Sarah M. Turpin, Hayley T. Nicholls, Diana M. Willmes, Arnaud Mourier, Susanne Brodesser, Claudia M. Wunderlich, Jan Mauer, Elaine Xu, Philipp Hammerschmidt, Hella S. Brönneke, Aleksandra Trifunovic, Giuseppe Losasso, F. Thomas Wunderlich, Jan-Wilhelm Kornfeld, Matthias Blüher, Martin Krönke, Jens C. Brüning

Research output: Contribution to journalArticleResearchpeer-review

302 Citations (Scopus)

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 (CerS6Δ/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 CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) 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.

Original languageEnglish
Pages (from-to)678-686
Number of pages9
JournalCell Metabolism
Volume20
Issue number4
DOIs
Publication statusPublished - 7 Oct 2014
Externally publishedYes

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