Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance - PubMed (original) (raw)

. 2014 Oct 7;20(4):678-86.

doi: 10.1016/j.cmet.2014.08.002.

Hayley T Nicholls 1, Diana M Willmes 1, Arnaud Mourier 2, Susanne Brodesser 3, Claudia M Wunderlich 1, Jan Mauer 1, Elaine Xu 1, Philipp Hammerschmidt 1, Hella S Brönneke 1, Aleksandra Trifunovic 3, Giuseppe LoSasso 4, F Thomas Wunderlich 1, Jan-Wilhelm Kornfeld 1, Matthias Blüher 5, Martin Krönke 6, Jens C Brüning 7

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• PMID: 25295788
• DOI: 10.1016/j.cmet.2014.08.002

Free article

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

Sarah M Turpin et al. Cell Metab. 2014.

Free article

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.

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Comment in

• C16:0-ceramide signals insulin resistance.
  Hla T, Kolesnick R. Hla T, et al. Cell Metab. 2014 Nov 4;20(5):703-705. doi: 10.1016/j.cmet.2014.10.017. Epub 2014 Nov 4. Cell Metab. 2014. PMID: 25440051 Free PMC article.

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