| First Author | Zhu Q | Year | 2024 |
| Journal | Nat Metab | Volume | 6 |
| Issue | 7 | Pages | 1347-1366 |
| PubMed ID | 38961186 | Mgi Jnum | J:352590 |
| Mgi Id | MGI:7707645 | Doi | 10.1038/s42255-024-01078-9 |
| Citation | Zhu Q, et al. (2024) PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels. Nat Metab 6(7):1347-1366 |
| abstractText | 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. |
