期刊
NATURE MEDICINE
卷 23, 期 12, 页码 1454-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4429
关键词
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资金
- National Institutes of Health [DK97441, DK108822, DK110426]
- Pew Charitable Trust
- Japan Science and Technology Agency
- Agency for Medical Research and Development-Core research for Revolutionary Science and Technology (AMED-CREST) from Japan Agency for Medical Research and Development
- CREST from Japan Science and Technology Agency
- Yamagata prefectural government
- city of Tsuruoka
- University of California San Francisco (UCSF) Diabetes Endocrinology Research Center (DERC) [DK63720]
- Yale University Mouse Metabolic Phenotyping Center (MMPC) [U2CDK059635]
- Manpei Suzuki Diabetes Foundation
- China Scholarship Council [201506350063]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [2610103]
- China Postdoctoral Council [2014M551176]
- [DK40936]
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.
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