title: Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance.
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.
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Turpin
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Hayley T
authors.initials: HT
authors.lastname: Nicholls
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Willmes
authors.affiliation: CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Max Planck Institute for the Biology of Aging, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mourier
authors.affiliation: CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Wunderlich
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Elaine
authors.initials: E
authors.lastname: Xu
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hammerschmidt
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Hella S
authors.initials: HS
authors.lastname: Brönneke
authors.affiliation: CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, Lausanne 1015, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: LoSasso
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.affiliation: Max Planck Institute for Metabolism Research, Cologne, North Rhine-Westphalia 50931, Germany; CECAD, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Jan-Wilhelm
authors.initials: JW
authors.lastname: Kornfeld
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Saxony 04103, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: CECAD, Cologne, North Rhine-Westphalia 50931, Germany; Institute for Medical Microbiology, University Hospital Cologne, Cologne, North Rhine-Westphalia 50931, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.affiliation: 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.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D015992:Body Mass Index; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat; D005260:Female; D018149:Glucose Intolerance; D006801:Humans; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D002518:Ceramides; D047495:PPAR gamma; D051049:Sphingosine N-Acyltransferase