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Cell Metab. 2014 Oct 7;20(4):678-86. doi: 10.1016/j.cmet.2014.08.002.

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

Author information

1
Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
2
CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Max Planck Institute for the Biology of Aging, Cologne, North Rhine-Westphalia 50931, Germany.
3
CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
4
Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, Lausanne 1015, Switzerland.
5
Department of Medicine, University of Leipzig, Leipzig, Saxony 04103, Germany.
6
CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Institute for Medical Microbiology, University Hospital Cologne, Cologne, North Rhine-Westphalia 50931, Germany.
7
Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, North Rhine-Westphalia 50931, Germany. Electronic address: bruening@nf.mpg.de.

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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PMID:
25295788
DOI:
10.1016/j.cmet.2014.08.002
[Indexed for MEDLINE]
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