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

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.

PAQR4是PAQR家族中的孤儿受体（orphan receptor），其在代谢调控中的功能尚不明确。本研究鉴定了PAQR4在维持脂肪组织功能与全身代谢健康中的关键作用。我们证实，在脂肪细胞中以诱导且可逆的方式特异性表达Paqr4，会引发部分脂肪营养不良、高血糖与高胰岛素血症，该病理表型可通过野生型脂肪组织移植或瘦素（leptin）治疗得到改善。与之相反，在脂肪细胞中敲除Paqr4，可改善饮食诱导肥胖模型的健康脂肪重塑与葡萄糖稳态（glucose homoeostasis）。从机制层面而言，PAQR4通过调控神经酰胺合酶（ceramide synthases，CERS2与CERS5）的稳定性来调控其酶活性，进而影响细胞内神经酰胺水平。PQAR4–CERS轴的过度激活会导致神经酰胺蓄积，并通过抑制成脂过程、触发脂肪细胞去分化，进而损伤脂肪组织功能。阻断神经酰胺的从头生物合成（de novo ceramide biosynthesis）可挽救PAQR4诱导的代谢缺陷。综上，本研究结果表明PAQR4在调控细胞神经酰胺稳态中发挥关键功能，靶向PAQR4可为代谢紊乱的治疗提供有效策略。