Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

解偶联蛋白1（UCP 1）是一种产热脂肪细胞（棕色和米色脂肪）特有的线粒体蛋白，其解偶联细胞呼吸和线粒体ATP合成，以热量的形式耗散能量。由于UCP 1被认为是唯一的产热蛋白，负责脂肪组织中的非颤抖性产热，流行的教条是UCP 1的作用主要介导棕色和米色脂肪的功能，当激活时，其促进抗肥胖和抗糖尿病作用。然而，我们从上一个资助周期和其他实验室获得的数据表明，棕色/米色脂肪缺乏症和UCP 1缺乏症之间的代谢表型不一致：我们发现由PRDM 16或其辅因子EHMT 1的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发展肥胖和葡萄糖耐受不良，而UCP 1敲除小鼠不患糖尿病，仅在热中性下发生肥胖。这种差异促使我们寻找UCP 1独立的机制，在调节能量稳态。我们最近确定了一个非典型的（UCP 1独立）产热机制，可以解释上述困境。UCP 1独立产热涉及ATP依赖性Ca 2+循环通过肌浆网/内质网Ca 2 +-ATP酶2b（SERCA 2b）和Ryanodine受体2（RyR 2）在米色脂肪。Ca 2+循环产热作用部分地通过α1-AR信号传导响应于冷刺激而被激活，并且需要活性葡萄糖氧化。因此，米色脂肪起到“葡萄糖库”的作用，并改善全身葡萄糖耐量。值得注意的是，Ca 2+循环产热在人类、小鼠和猪中是一种进化保守的机制，猪是一种缺乏功能性UCP 1蛋白的罕见哺乳动物物种。因此，目前的建议旨在确定生物学意义和相关机制，这种非典型的产热米色脂肪。

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.