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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.*

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

Nat. Metab., DOI: 10.1038/s42255-024-01078-9 (2024)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adiponectin Receptors; Insulin-resistance; Reverse Activity; Assay; Sphingolipids; Adipogenesis; Inhibition; Activation; Deletion; Agonist
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Grants AHA Career Development Award
NIDDK-NORC
NIH
Voelcker Fund Young Investigator Award
DFG Walter Benjamin Fellowship
US National Institutes of Health (NIH)