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

Sarah M Turpin; Hayley T Nicholls; Diana M Willmes; Arnaud Mourier; Susanne Brodesser; Claudia M Wunderlich; Jan Mauer; Elaine Xu; Philipp Hammerschmidt; Hella S Brönneke; Aleksandra Trifunovic; Giuseppe LoSasso; F Thomas Wunderlich; Jan-Wilhelm Kornfeld; Matthias Blüher; Martin Krönke; Jens C Brüning

doi:10.1016/j.cmet.2014.08.002

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

Sarah M Turpin
, Hayley T Nicholls
, Diana M Willmes
, Arnaud Mourier
, Susanne Brodesser
, Claudia M Wunderlich
, Jan Mauer
, Elaine Xu
, Philipp Hammerschmidt
, Hella S Brönneke
, Aleksandra Trifunovic
, Giuseppe LoSasso
, F Thomas Wunderlich
, Jan-Wilhelm Kornfeld
, Matthias Blüher
, Martin Krönke
, Jens C Brüning

Max Planck Institute for Metabolism Research
University of Cologne
Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, Lausanne 1015, Switzerland.
Leipzig University
University Hospital Cologne

Research output: Contribution to journal › Journal article › Research › peer-review

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.

Original language	English
Journal	Cell Metabolism
Volume	20
Issue number	4
Pages (from-to)	678-686
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2014.08.002
Publication status	Published - 7. Oct 2014
Externally published	Yes

Keywords

Adipose Tissue, Brown/metabolism
Animals
Body Mass Index
Ceramides/metabolism
Diet, High-Fat
Female
Glucose Intolerance
Humans
Lipid Peroxidation
Liver/metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Obesity/metabolism
PPAR gamma/genetics
Sphingosine N-Acyltransferase/deficiency
Weight Gain

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Turpin, S. M., Nicholls, H. T., Willmes, D. M., Mourier, A., Brodesser, S., Wunderlich, C. M., Mauer, J., Xu, E., Hammerschmidt, P., Brönneke, H. S., Trifunovic, A., LoSasso, G., Wunderlich, F. T., Kornfeld, J.-W., Blüher, M., Krönke, M., & Brüning, J. C. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metabolism, 20(4), 678-686. https://doi.org/10.1016/j.cmet.2014.08.002

@article{090a70a49ff443e08cca91a3587e7ee5,

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. ",

keywords = "Adipose Tissue, Brown/metabolism, Animals, Body Mass Index, Ceramides/metabolism, Diet, High-Fat, Female, Glucose Intolerance, Humans, Lipid Peroxidation, Liver/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Obesity/metabolism, PPAR gamma/genetics, Sphingosine N-Acyltransferase/deficiency, Weight Gain",

author = "Turpin, \{Sarah M\} and Nicholls, \{Hayley T\} and Willmes, \{Diana M\} and Arnaud Mourier and Susanne Brodesser and Wunderlich, \{Claudia M\} and Jan Mauer and Elaine Xu and Philipp Hammerschmidt and Br{\"o}nneke, \{Hella S\} and Aleksandra Trifunovic and Giuseppe LoSasso and Wunderlich, \{F Thomas\} and Jan-Wilhelm Kornfeld and Matthias Bl{\"u}her and Martin Kr{\"o}nke and Br{\"u}ning, \{Jens C\}",

year = "2014",

month = oct,

day = "7",

doi = "10.1016/j.cmet.2014.08.002",

language = "English",

volume = "20",

pages = "678--686",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "4",

}

Turpin, SM, Nicholls, HT, Willmes, DM, Mourier, A, Brodesser, S, Wunderlich, CM, Mauer, J, Xu, E, Hammerschmidt, P, Brönneke, HS, Trifunovic, A, LoSasso, G, Wunderlich, FT, Kornfeld, J-W, Blüher, M, Krönke, M & Brüning, JC 2014, 'Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance', Cell Metabolism, vol. 20, no. 4, pp. 678-686. https://doi.org/10.1016/j.cmet.2014.08.002

TY - JOUR

T1 - Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance

AU - Turpin, Sarah M

AU - Nicholls, Hayley T

AU - Willmes, Diana M

AU - Mourier, Arnaud

AU - Brodesser, Susanne

AU - Wunderlich, Claudia M

AU - Mauer, Jan

AU - Xu, Elaine

AU - Hammerschmidt, Philipp

AU - Brönneke, Hella S

AU - Trifunovic, Aleksandra

AU - LoSasso, Giuseppe

AU - Wunderlich, F Thomas

AU - Kornfeld, Jan-Wilhelm

AU - Blüher, Matthias

AU - Krönke, Martin

AU - Brüning, Jens C

PY - 2014/10/7

Y1 - 2014/10/7

N2 - 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.

AB - 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.

KW - Adipose Tissue, Brown/metabolism

KW - Animals

KW - Body Mass Index

KW - Ceramides/metabolism

KW - Diet, High-Fat

KW - Female

KW - Glucose Intolerance

KW - Humans

KW - Lipid Peroxidation

KW - Liver/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Obesity/metabolism

KW - PPAR gamma/genetics

KW - Sphingosine N-Acyltransferase/deficiency

KW - Weight Gain

U2 - 10.1016/j.cmet.2014.08.002

DO - 10.1016/j.cmet.2014.08.002

M3 - Journal article

C2 - 25295788

SN - 1550-4131

VL - 20

SP - 678

EP - 686

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

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

Abstract

Keywords

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