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

被引：479

作者：

Ikeda, Kenji ^{[1
,2
,3
]}

Kang, Qianqian ^{[1
,2
,3
]}

Yoneshiro, Takeshi ^{[1
,2
,3
]}

Camporez, Joao Paulo ^{[4
,5
]}

Maki, Hiroko ^{[6
]}

Homma, Mayu ^{[6
]}

Shinoda, Kosaku ^{[1
,2
,3
]}

Chen, Yong ^{[1
,2
,3
]}

Lu, Xiaodan ^{[1
,2
,3
]}

Maretich, Pema ^{[1
,2
,3
]}

Tajima, Kazuki ^{[1
,2
,3
]}

Ajuwon, Kolapo M. ^{[7
]}

Soga, Tomoyoshi ^{[6
]}

Kajimura, Shingo ^{[1
,2
,3
]}

机构：

[1] Univ Calif San Francisco, Diabet Ctr, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA

[4] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA

[5] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[6] Keio Univ, Inst Adv Biosci, Yamagata, Japan

[7] Purdue Univ, Dept Anim Sci, W Lafayette, IN 47907 USA

来源：

NATURE MEDICINE | 2017年 / 23卷 / 12期

基金：

日本科学技术振兴机构; 美国国家卫生研究院;

关键词：

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;

D O I：

10.1038/nm.4429

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1454 / +

页数：15

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