PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.
Nat Metab
; 6(7): 1347-1366, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38961186
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ceramidas
/
Adipócitos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Metab
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos