UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro, Joao Paulo Camporez, Hiroko Maki, Mayu Homma, Kosaku Shinoda, Yong Chen, Xiaodan Lu, Pema Maretich, Kazuki Tajima, Kolapo M. Ajuwon, Tomoyoshi Soga, Shingo Kajimura

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

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 Ca22+ cycling by sarco/endoplasmic reticulum Ca22+-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 Ca22+ 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 Ca22+ cycling.

Original languageEnglish (US)
Pages (from-to)1454-1465
Number of pages12
JournalNature Medicine
Volume23
Issue number12
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ikeda, K., Kang, Q., Yoneshiro, T., Camporez, J. P., Maki, H., Homma, M., Shinoda, K., Chen, Y., Lu, X., Maretich, P., Tajima, K., Ajuwon, K. M., Soga, T., & Kajimura, S. (2017). UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nature Medicine, 23(12), 1454-1465. https://doi.org/10.1038/nm.4429