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

PDF icon Ikeda et al. Nat Med 2017.pdf3.52 MB
Ikeda K., Kang Q., Yoneshiro T., Camporez J.P., Maki H., Homma M., Shinoda K., Lu, X., Maretich P., Ajuwon K.M., Soga T., & Kajimura S.
Nature Medicine
Publication Date: 
Mon, 2017-11-13
Diabetes Center, University of California, San Francisco, San Francisco, California, USA. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA. Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA. Departments of Medicine and of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA. Institute for Advanced Biosciences, Keio University, Yamagata, Japan. Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
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 1- and/or 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.