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

Autor:	Turpin SM; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Nicholls HT; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Willmes DM; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Mourier A; CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Max Planck Institute for the Biology of Aging, Cologne, North Rhine-Westphalia 50931, Germany., Brodesser S; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Wunderlich CM; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Mauer J; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Xu E; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Hammerschmidt P; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Brönneke HS; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Trifunovic A; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., LoSasso G; Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, Lausanne 1015, Switzerland., Wunderlich FT; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Kornfeld JW; Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany., Blüher M; Department of Medicine, University of Leipzig, Leipzig, Saxony 04103, Germany., Krönke M; CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Institute for Medical Microbiology, University Hospital Cologne, Cologne, North Rhine-Westphalia 50931, Germany., Brüning JC; 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.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2014 Oct 07; Vol. 20 (4), pp. 678-86.
DOI:	10.1016/j.cmet.2014.08.002
Abstrakt:	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. (Copyright © 2014 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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