Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b–RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.
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We thank W. Chen at the University of Calgary for providing the RyR2 overexpression construct. We are also grateful to C. Paillart for his support in the CLAMS studies, Y. Seo for his support in [18F]FDG uptake assays, R. Zalpuri for technical assistance in electron microscope analysis, K. Nakamura for his advice in tissue temperature recording, and B.M. Spiegelman, E.T. Chouchani and L. Kazak for their feedback. This work was supported by the National Institutes of Health (DK97441 and DK108822), the Pew Charitable Trust and Japan Science and Technology Agency to S.K., and by Agency for Medical Research and Development–Core research for Revolutionary Science and Technology (AMED–CREST) from the Japan Agency for Medical Research and Development, CREST from the Japan Science and Technology Agency, and research funds from the Yamagata prefectural government and the city of Tsuruoka to T.S. We also acknowledge support from the University of California San Francisco (UCSF) Diabetes Endocrinology Research Center (DERC) (DK63720), the Yale University Mouse Metabolic Phenotyping Center (MMPC) (U2CDK059635) and DK40936. K.I. and K.T. are supported by the Manpei Suzuki Diabetes Foundation. Q.K. is supported by the China Scholarship Council (201506350063). T.Y. is supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (2610103). K.S. is supported by National Institutes of Health K99 grant (DK110426). X.L. is supported by China Postdoctoral Council (2014M551176).
The authors declare no competing financial interests.
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Ikeda, K., Kang, Q., Yoneshiro, T. et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 23, 1454–1465 (2017). https://doi.org/10.1038/nm.4429
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