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.

中文翻译：

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涉及 SERCA2b 介导的钙循环的 UCP1 独立信号传导可调节米色脂肪产热和全身葡萄糖稳态。


解偶联蛋白 1 (UCP1) 在棕色脂肪的非颤抖产热过程中发挥着核心作用；然而，它在米色脂肪中的作用仍不清楚。在这里，我们报告了米色脂肪中强大的 UCP1 独立生热机制，涉及通过肌浆/内质网 Ca ²⁺ -ATPase 2b (SERCA2b) 和兰尼碱受体 2 (RyR2) 增强 ATP 依赖性 Ca ²⁺循环。 SERCA2b 的抑制会损害人类、小鼠以及猪（缺乏功能性 UCP1 蛋白的物种）中不依赖于 UCP1 的米色脂肪产热作用。相反，通过激活α1-和/或β3-肾上腺素能受体或SERCA2b-RyR2途径增强Ca ²⁺循环会刺激米色脂肪细胞中不依赖于UCP1的产热作用。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 途径实现 ATP 依赖性产热；因此，米色脂肪起到“葡萄糖汇”的作用，并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典型的生热机制，米色脂肪通过 Ca ²⁺循环控制全身能量稳态。