Turpin, Sarah M., Nicholls, Hayley T., Willmes, Diana M., Mourier, Arnaud, Brodesser, Susanne, Wunderlich, Claudia M., Mauer, Jan ORCID: 0000-0002-0189-5876, Xu, Elaine, Hammerschmidt, Philipp, Broenneke, Hella S., Trifunovic, Aleksandra, LoSasso, Giuseppe, Wunderlich, F. Thomas, Kornfeld, Jan-Wilhelm ORCID: 0000-0002-6802-4442, Blueher, Matthias, Kroenke, Martin and Bruening, Jens C. (2014). Obesity-Induced CerS6-Dependent C-16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance. Cell Metab., 20 (4). S. 678 - 687. CAMBRIDGE: CELL PRESS. ISSN 1932-7420

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Abstract

Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C-14:0 to C-30:0 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 C-16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6 D/D) mice exhibit reduced C-16:0 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 D/D mice, but also in brown adipose tissue-(CerS6 DBAT) and liver-specific (CerS6 DLIVER) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Turpin, Sarah M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicholls, Hayley T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willmes, Diana M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mourier, ArnaudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodesser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, Claudia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauer, JanUNSPECIFIEDorcid.org/0000-0002-0189-5876UNSPECIFIED
Xu, ElaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broenneke, Hella S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
LoSasso, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornfeld, Jan-WilhelmUNSPECIFIEDorcid.org/0000-0002-6802-4442UNSPECIFIED
Blueher, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroenke, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-425892
DOI: 10.1016/j.cmet.2014.08.002
Journal or Publication Title: Cell Metab.
Volume: 20
Number: 4
Page Range: S. 678 - 687
Date: 2014
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1932-7420
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INDUCED INSULIN-RESISTANCE; DIET-INDUCED OBESITY; SKELETAL-MUSCLE; SYNTHASE 2; DISRUPTION; EXPRESSION; INFLAMMATION; ADIPONECTIN; INHIBITION; METABOLISMMultiple languages
Cell Biology; Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42589

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