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

Nat Med. 2017 Dec;23(12):1454-1465. doi: 10.1038/nm.4429. Epub 2017 Nov 13.


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.

MeSH terms

  • Adipose Tissue, Beige / metabolism*
  • Animals
  • Animals, Newborn
  • Calcium / metabolism*
  • Calcium Signaling / genetics
  • Cells, Cultured
  • Glucose / metabolism*
  • HEK293 Cells
  • Homeostasis / genetics
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / physiology*
  • Signal Transduction / genetics
  • Swine
  • Thermogenesis / genetics*
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / physiology*


  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A2 protein, human
  • Atp2a2 protein, mouse
  • Glucose
  • Calcium