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，其代谢功能未知。在这里，我们确定了 PAQR4 在维持脂肪组织功能和全身代谢健康方面的关键作用。我们证明Paqr4在脂肪细胞中以可诱导和可逆的方式特异性表达，导致部分脂肪营养不良、高血糖和高胰岛素血症，而野生型脂肪组织移植或瘦素治疗可改善这种情况。相比之下，脂肪细胞中Paqr4的缺失可改善饮食诱导的肥胖症中的健康脂肪重塑和葡萄糖稳态。从机制上讲，PAQR4 通过介导神经酰胺合酶（CERS2 和 CERS5）的稳定性及其活性来调节神经酰胺水平。 PQAR4-CERS 轴的过度激活会导致神经酰胺积累，并通过抑制脂肪生成和触发脂肪细胞去分化来损害脂肪组织功能。阻断从头神经酰胺生物合成可挽救 PAQR4 诱导的代谢缺陷。总的来说，我们的研究结果表明 PAQR4 在调节细胞神经酰胺稳态中发挥着关键作用，并且靶向 PAQR4 为治疗代谢紊乱提供了一种方法。