IL-33–associated type 2 innate immunity has been shown to support beige fat formation and thermogenesis in subcutaneous inguinal white adipose tissue (iWAT), but little is known about how it is regulated in iWAT. Chemerin, as a newly identified adipokine, is clinically associated with obesity and metabolic disorders. We here show that cold exposure specifically reduces chemerin and its receptor chemerin chemokine-like receptor 1 (CMKLR1) expression in iWAT. Lack of chemerin or adipocytic CMKLR1 enhances cold-induced thermogenic beige fat via potentiating type 2 innate immune responses. Mechanistically, we identify adipocytes, particularly beige adipocytes, as the main source for cold-induced IL-33, which is restricted by the chemerin-CMKLR1 axis via dampening cAMP-PKA signaling, thereby interrupting a feed-forward circuit between beige adipocytes and type 2 innate immunity that is required for cold-induced beige fat and thermogenesis. Moreover, specific deletion of adipocytic IL-33 inhibits cold-induced beige fat and type 2 innate immune responses. Last, genetic blockade of adipocytic CMKLR1 protects against diet-induced obesity and enhances the metabolic benefits of cold stimulation in preestablished obese mice. Thus, our study identifies the chemerin-CMKLR1 axis as a physiological negative regulator of thermogenic beige fat via interrupting adipose-immune communication and suggests targeting adipose CMKLR1 as a potential therapeutic strategy for obesity-related metabolic disorders.

IL-33 相关的 2 型先天免疫已被证明支持皮下腹股沟白色脂肪组织 (iWAT) 中的米色脂肪形成和产热，但人们对它在 iWAT 中的调节方式知之甚少。Chemerin 作为一种新发现的脂肪因子，在临床上与肥胖和代谢紊乱有关。我们在这里表明，冷暴露会特异性降低 iWAT 中凯莫瑞及其受体凯莫瑞趋化因子样受体 1 (CMKLR1) 的表达。缺乏凯莫瑞或脂肪细胞 CMKLR1 通过增强 2 型先天免疫反应增强冷诱导的产热米色脂肪。从机制上讲，我们将脂肪细胞，特别是米色脂肪细胞鉴定为冷诱导的 IL-33 的主要来源，IL-33 通过抑制 cAMP-PKA 信号传导受到凯莫瑞-CMKLR1 轴的限制，从而中断米色脂肪细胞和 2 型先天免疫之间的前馈回路，这是寒冷诱导的米色脂肪和产热所需的。此外，脂肪细胞 IL-33 的特异性缺失可抑制冷诱导的米色脂肪和 2 型先天免疫反应。最后，脂肪细胞 CMKLR1 的基因阻断可防止饮食诱导的肥胖，并增强预先建立的肥胖小鼠冷刺激的代谢益处。因此，我们的研究将 chemerin-CMKLR1 轴鉴定为通过中断脂肪-免疫通讯而产生的产热米色脂肪的生理负调节因子，并建议靶向脂肪 CMKLR1 作为肥胖相关代谢疾病的潜在治疗策略。脂肪细胞 IL-33 的特异性缺失抑制冷诱导的米色脂肪和 2 型先天免疫反应。最后，脂肪细胞 CMKLR1 的基因阻断可防止饮食诱导的肥胖，并增强预先建立的肥胖小鼠冷刺激的代谢益处。因此，我们的研究将 chemerin-CMKLR1 轴鉴定为通过中断脂肪-免疫通讯而产生的产热米色脂肪的生理负调节因子，并建议靶向脂肪 CMKLR1 作为肥胖相关代谢疾病的潜在治疗策略。脂肪细胞 IL-33 的特异性缺失抑制冷诱导的米色脂肪和 2 型先天免疫反应。最后，脂肪细胞 CMKLR1 的基因阻断可防止饮食诱导的肥胖，并增强预先建立的肥胖小鼠冷刺激的代谢益处。因此，我们的研究将 chemerin-CMKLR1 轴鉴定为通过中断脂肪-免疫通讯而产生的产热米色脂肪的生理负调节因子，并建议靶向脂肪 CMKLR1 作为肥胖相关代谢疾病的潜在治疗策略。