The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit.

1. Sci Immunol. 2021 Jul 30;6(61):eabg9698. doi: 10.1126/sciimmunol.abg9698.

The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit.

Lin Y(1), Xiao L(2)(3), Cai Q(1), Zhu C(2), Li S(2), Li B(1), Liu T(1), Zhang Q(4), Wang Y(4), Li Y(4), He X(5), Pan D(2), Tang Q(2), Wu X(6), Pan W(5), Wang J(7), Li X(8), He R(9)(10).

Author information: (1)Department of Immunology and Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (2)Key Laboratory of Metabolic Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (3)Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA. (4)Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, China. (5)Department of Tropical Diseases, Naval Medical University, Shanghai 200433, PR China. (6)State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China. (7)Shanghai National Clinical Research Center for Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China. (8)Biology Science Institutes, Chongqing Medical University, Chongqing 400032, China. ruihe@fudan.edu.cn lixi@shmu.edu.cn. (9)Department of Immunology and Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. ruihe@fudan.edu.cn lixi@shmu.edu.cn. (10)National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.

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.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

DOI: 10.1126/sciimmunol.abg9698 PMID: 34330814 [Indexed for MEDLINE]