UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

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

来源：Nature Medicine, 2017, 23(12): 1454-+.

DOI：10.1038/nm.4429

• BROWN ADIPOSE-TISSUE
• ADAPTIVE NONSHIVERING THERMOGENESIS
• FK506-BINDING PROTEIN FKBP12.6
• ENDOPLASMIC-RETICULUM STRESS
• RYANODINE RECEPTOR GENE
• RELEASE CHANNEL
• UNCOUPLING PROTEIN-1
• WHITE FAT
• UCP1
• ADIPOCYTES

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 alpha 1-and/or beta 3-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.

• 出版日期2017-12