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 C_16:0 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

Research output: Contribution to journal › Article › Research › peer-review

622 Citations (Scopus)

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^Δ/Δ) 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^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
Pages (from-to)	678-686
Number of pages	9
Journal	Cell Metabolism
Volume	20
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2014.08.002
Publication status	Published - 7 Oct 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.cmet.2014.08.002

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Cite this

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 C_16:0 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{2dea263c79ff4f3f978ba626da7f9622,

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 (CerS6Δ/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 CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) 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.",

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",

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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 C_16:0 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 (CerS6Δ/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 CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) 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 (CerS6Δ/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 CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) 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.

UR - https://www.scopus.com/pages/publications/84907978697

U2 - 10.1016/j.cmet.2014.08.002

DO - 10.1016/j.cmet.2014.08.002

M3 - Article

C2 - 25295788

AN - SCOPUS:84907978697

SN - 1550-4131

VL - 20

SP - 678

EP - 686

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -