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

1. Nat Metab. 2024 Jul;6(7):1347-1366. doi: 10.1038/s42255-024-01078-9. Epub 2024 Jul 3.

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

Zhu Q(1), Chen S(1), Funcke JB(1), Straub LG(1), Lin Q(1), Zhao S(1)(2), Joung C(1), Zhang Z(1), Kim DS(1), Li N(1), Gliniak CM(1), Lee C(3), Cebrian-Serrano A(4)(5), Pedersen L(1)(6), Halberg N(6), Gordillo R(1), Kusminski CM(1), Scherer PE(7).

Author information: (1)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. (2)Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. (3)Center for Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. (4)Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. (5)German Center for Diabetes Research (DZD), Neuherberg, Germany. (6)Department of Biomedicine, University of Bergen, Bergen, Norway. (7)Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. philipp.scherer@utsouthwestern.edu.

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.

© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

DOI: 10.1038/s42255-024-01078-9 PMCID: PMC11891014 PMID: 38961186 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Interests The authors declare no competing interests.