Turpin SM Nicholls HT Willmes DM Mourier A Brodesser S Wunderlich CM Mauer J Xu E Hammerschmidt P Brönneke HS Trifunovic A LoSasso G Wunderlich FT Kornfeld JW Blüher M Krönke M Brüning JC 2014 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. application/pdf https://sonar.ch/global/documents/97175 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cmet.2014.08.002 info:eu-repo/semantics/altIdentifier/pmid/25295788 info:eu-repo/semantics/openAccess Cell metabolism. - 2014 Adipose Tissue, Brown Animals Body Mass Index Ceramides Diet, High-Fat Female Glucose Intolerance Humans Lipid Peroxidation Liver Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Obesity PPAR gamma Sphingosine N-Acyltransferase Weight Gain Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. http://purl.org/coar/resource_type/c_6501