Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

解偶联蛋白1 （Uncoupling Protein 1, UCP1）是一种产热脂肪细胞（棕色和米色脂肪）特有的线粒体蛋白，它能解偶联细胞呼吸和线粒体ATP合成，以热量的形式消散能量。由于UCP1一直被认为是脂肪组织中唯一负责非寒颤产热的产热蛋白，普遍的观点是UCP1的作用主要介导棕色和米色脂肪的功能，这些功能在被激活时促进抗肥胖和抗糖尿病的作用。然而，我们来自上一个资助周期和其他实验室的数据表明，棕色/米色脂肪缺乏症和UCP1缺乏症之间的代谢表型不一致：我们发现，由PRDM16或其辅助因子EHMT1的脂肪特异性缺失引起的米色脂肪缺乏症小鼠即使在环境温度下也会出现肥胖和葡萄糖耐受不良，而UCP1敲除小鼠则不会出现糖尿病，仅在热中性下才会出现肥胖。这种差异促使我们寻找与ucp1无关的能量稳态调节机制。我们最近发现了一种非规范（独立于ucp1）的产热机制，可以解释上述困境。在米色脂肪中，不依赖ucp1的产热作用涉及atp依赖的Ca2+通过Sarco/内质网Ca2+-ATPase2b （SERCA2b）和Ryanodine受体2 （RyR2）循环。Ca2+循环产热在一定程度上是通过α1-AR信号响应冷刺激而激活的，并且需要活跃的葡萄糖氧化。因此，米色脂肪起着“葡萄糖汇”的作用，可以改善全身葡萄糖耐量。值得注意的是，Ca2+循环产热在人类、小鼠和猪（一种缺乏功能性UCP1蛋白的罕见哺乳动物物种）中是一种进化保守的机制。因此，目前的建议旨在确定与米色脂肪中这种非规范产热有关的生物学意义和机制。

Uncoupling Protein 1 (UCP1) is a mitochondrial protein specific to thermogenic adipocytes (brown and beige fat) that uncouples cellular respiration and mitochondrial ATP synthesis to dissipate energy in the form of heat. Because UCP1 has been considered the sole thermogenic protein responsible for non-shivering thermogenesis in the adipose tissue, the prevailing dogma is that the action of UCP1 primarily mediates the functions of brown and beige fat, which promote the anti-obesity and anti-diabetic effects when activated. However, our data from the previous funding cycle and other labs suggest an incongruity in the metabolic phenotypes between brown/beige fat-deficiency and UCP1-deficiency: we found that beige fat-deficient mice, caused by the fat-specific deletion of PRDM16 or its co-factor EHMT1, develop obesity and glucose intolerance even under ambient temperature, whereas UCP1 knockout mice are not diabetic and develop obesity only under thermoneutrality. This discrepancy motivated us to search for UCP1-independent mechanisms in the regulation of energy homeostasis. We recently identified a non-canonical (UCP1-independent) thermogenic mechanism that may explain the above quandary. UCP1-independent thermogenesis involves ATP-dependent Ca2+ cycling through Sarco/endoplasmic reticulum Ca2+-ATPase2b (SERCA2b) and Ryanodine Receptor 2 (RyR2) in beige fat. Ca2+ cycling thermogenesis is activated, in part, through α1-AR signaling in response to a cold stimulus, and requires active glucose oxidation. Thereby beige fat functions as a “glucose sink” and improves systemic glucose tolerance. Notably, Ca2+ cycling thermogenesis is an evolutionally conserved mechanism in humans, mice, and also in pigs, a rare mammalian species that lacks a functional UCP1 protein. Accordingly, the current proposal aims to determine the biological significance and the mechanisms pertinent to this non-canonical thermogenesis in beige fat.