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独立信号调节米色脂肪的生热作用和全身性葡萄糖稳态。

解偶联蛋白1（UCP1）在棕色脂肪的不发抖的生热中起着核心作用。然而，其在米色脂肪中的作用仍不清楚。在这里，我们报告了一种稳定的米色脂肪中不依赖UCP1的产热机制，该机制涉及通过肌/内质网Ca ²⁺ -ATPase 2b（SERCA2b）和ryanodine受体2（RyR2）增强的ATP依赖性Ca ²⁺循环。抑制SERCA2b会削弱人和小鼠以及缺乏功能性UCP1蛋白的猪中不依赖UCP1的米色脂肪的生热作用。相反，增强的Ca ²⁺通过激活α1-和/或β3-肾上腺素受体或SERCA2b-RyR2途径进行循环，可刺激米色脂肪细胞中UCP1依赖性生热。在没有UCP1的情况下，米色脂肪通过增强的糖酵解，三羧酸代谢和丙酮酸脱氢酶活性，通过SERCA2b途径动态消耗葡萄糖，从而实现ATP依赖的生热作用。因此，米色脂肪可充当“葡萄糖槽”，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经典的热生成机制，米色脂肪通过该机制通过Ca ²⁺循环控制全身能量稳态。