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
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.
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 Ca cycling by sarco/endoplasmic reticulum Ca-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 Ca 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 Ca cycling.
解偶联蛋白1（UCP1）在棕色脂肪的非颤抖性产热中起核心作用；然而，其在米色脂肪中的作用仍不清楚。在此，我们报告了米色脂肪中一种强大的不依赖UCP1的产热机制，该机制涉及通过肌浆/内质网钙-ATP酶2b（SERCA2b）和兰尼碱受体2（RyR2）增强ATP依赖的钙循环。抑制SERCA2b会损害人类、小鼠以及缺乏功能性UCP1蛋白的猪的米色脂肪不依赖UCP1的产热。相反，通过激活α1-和/或β3-肾上腺素能受体或SERCA2b-RyR2途径增强钙循环，可刺激米色脂肪细胞中不依赖UCP1的产热。在缺乏UCP1的情况下，米色脂肪通过增强糖酵解、三羧酸代谢和丙酮酸脱氢酶活性，动态消耗葡萄糖，通过SERCA2b途径进行ATP依赖的产热；米色脂肪因此起到“葡萄糖汇”的作用，独立于体重减轻而改善葡萄糖耐量。我们的研究揭示了一种非经典的产热机制，米色脂肪通过该机制通过钙循环控制全身能量稳态。
