Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

解偶联蛋白1(UCP1)是一种线粒体蛋白，专为产热脂肪细胞(棕色和米色脂肪)所特有，它将细胞呼吸和线粒体ATP合成解偶联，以热量的形式散失能量。由于UCP1一直被认为是脂肪组织中唯一负责非颤抖产热的生热蛋白，所以普遍认为UCP1的作用主要是介导棕色和米色脂肪的功能，当被激活时，这些功能促进了抗肥胖和抗糖尿病的效果。然而，我们来自上一个资金周期和其他实验室的数据表明，棕色/米色脂肪缺乏和UCP1缺乏之间的代谢表型不一致：我们发现，由PRDM16或其辅助因子EHMT1脂肪特异性缺失引起的米色脂肪缺乏小鼠，即使在环境温度下也会出现肥胖和葡萄糖耐量异常，而UCP1基因敲除小鼠不会患糖尿病，只有在中温条件下才会出现肥胖。这种差异促使我们在能量稳态的调节中寻找UCP1不依赖的机制。我们最近发现了一种非正则(不依赖于UCP1)的生热机制，可以解释上述困境。非依赖于UCP1的产热作用涉及依赖于ATP的钙循环，通过褐色脂肪中的Sarco/内质网钙-ATPase2b(SERCA2b)和Ryanodine受体2(RyR2)。钙循环生热作用部分通过α1-AR信号被激活以响应冷刺激，并且需要活跃的葡萄糖氧化。因此，米色脂肪起到了“葡萄糖接收器”的作用，改善了全身的葡萄糖耐量。值得注意的是，在人类、小鼠和猪身上，钙循环产热是一种进化上保守的机制，猪是一种罕见的哺乳动物，缺乏功能性的UCP1蛋白。因此，目前的建议旨在确定与米色脂肪的这种非典型产热相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.