Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance.
- 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.
- 2014-10-09
Published in:
- 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
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.cmet.2014.08.002
- PMID 25295788
- Persistent URL
- https://sonar.ch/global/documents/97175
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