PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels

Qingzhang Zhu; Shiuhwei Chen; Jan-Bernd Funcke; Leon G Straub; Qian Lin; Shangang Zhao; Chanmin Joung; Zhuzhen Zhang; Dae-Seok Kim; Na Li; Christy M Gliniak; Charlotte Lee; Alberto Cebrian-Serrano; Line Pedersen; Nils Halberg; Ruth Gordillo; Christine M Kusminski; Philipp E Scherer

doi:10.1038/s42255-024-01078-9

PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels

Qingzhang Zhu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Qian Lin, Shangang Zhao, Chanmin Joung, Zhuzhen Zhang, Dae-Seok Kim, Na Li, Christy M Gliniak, Charlotte Lee, Alberto Cebrian-Serrano, Line Pedersen, Nils Halberg, Ruth Gordillo, Christine M Kusminski, Philipp E Scherer

Internal Medicine

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

6 Scopus citations

Abstract

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

Original language	English
Pages (from-to)	1347-1366
Number of pages	20
Journal	Nature Metabolism
Volume	6
Issue number	7
DOIs	https://doi.org/10.1038/s42255-024-01078-9
State	Published - Jul 2024

Bibliographical note

Keywords

Ceramides/metabolism
Adipocytes/metabolism
Animals
Mice
Adipogenesis
Membrane Proteins/metabolism
Adipose Tissue/metabolism
Obesity/metabolism
Humans

UN SDGs

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

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10.1038/s42255-024-01078-9

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Zhu, Q., Chen, S., Funcke, J.-B., Straub, L. G., Lin, Q., Zhao, S., Joung, C., Zhang, Z., Kim, D.-S., Li, N., Gliniak, C. M., Lee, C., Cebrian-Serrano, A., Pedersen, L., Halberg, N., Gordillo, R., Kusminski, C. M., & Scherer, P. E. (2024). PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels. Nature Metabolism, 6(7), 1347-1366. https://doi.org/10.1038/s42255-024-01078-9

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title = "PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels",

abstract = "PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.",

keywords = "Ceramides/metabolism, Adipocytes/metabolism, Animals, Mice, Adipogenesis, Membrane Proteins/metabolism, Adipose Tissue/metabolism, Obesity/metabolism, Humans",

author = "Qingzhang Zhu and Shiuhwei Chen and Jan-Bernd Funcke and Straub, {Leon G} and Qian Lin and Shangang Zhao and Chanmin Joung and Zhuzhen Zhang and Dae-Seok Kim and Na Li and Gliniak, {Christy M} and Charlotte Lee and Alberto Cebrian-Serrano and Line Pedersen and Nils Halberg and Ruth Gordillo and Kusminski, {Christine M} and Scherer, {Philipp E}",

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Zhu, Q, Chen, S, Funcke, J-B, Straub, LG, Lin, Q, Zhao, S, Joung, C, Zhang, Z, Kim, D-S, Li, N, Gliniak, CM, Lee, C, Cebrian-Serrano, A, Pedersen, L, Halberg, N, Gordillo, R, Kusminski, CM & Scherer, PE 2024, 'PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels', Nature Metabolism, vol. 6, no. 7, pp. 1347-1366. https://doi.org/10.1038/s42255-024-01078-9

TY - JOUR

T1 - PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels

AU - Zhu, Qingzhang

AU - Chen, Shiuhwei

AU - Funcke, Jan-Bernd

AU - Straub, Leon G

AU - Lin, Qian

AU - Zhao, Shangang

AU - Joung, Chanmin

AU - Zhang, Zhuzhen

AU - Kim, Dae-Seok

AU - Li, Na

AU - Gliniak, Christy M

AU - Lee, Charlotte

AU - Cebrian-Serrano, Alberto

AU - Pedersen, Line

AU - Halberg, Nils

AU - Gordillo, Ruth

AU - Kusminski, Christine M

AU - Scherer, Philipp E

PY - 2024/7

Y1 - 2024/7

N2 - PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

AB - PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

KW - Ceramides/metabolism

KW - Adipocytes/metabolism

KW - Animals

KW - Mice

KW - Adipogenesis

KW - Membrane Proteins/metabolism

KW - Adipose Tissue/metabolism

KW - Obesity/metabolism

KW - Humans

U2 - 10.1038/s42255-024-01078-9

DO - 10.1038/s42255-024-01078-9

M3 - Article

C2 - 38961186

VL - 6

SP - 1347

EP - 1366

JO - Nature Metabolism

JF - Nature Metabolism

IS - 7

ER -

PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels

Abstract

Bibliographical note

Keywords

UN SDGs

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