PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels
Description
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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We generated inducible adipocyte-specific Paqr4 gain- and loss-of-function mouse models and characterized their metabolic phenotypes under chow- and high-fat diet (HFD)-fed conditions. Adipocyte remodeling was assessed using lineage tracing and single-cell sequencing. We identified the effects of PAQR4 on ceramide homeostasis through LC-MS/MS and demonstrated its regulation of CERS via direct interaction and modulation of enzymatic activity.
Institutions
- UT Southwestern Medical Center Touchstone Diabetes Center
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Funders
- American Heart AssociationUnited States