Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

棕色脂肪细胞命运和能量代谢的分子控制

• 批准号: 10094152
• 负责人: Shingo Kajimura
• 金额: $ 49.56万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094152
• 关键词: ATP Synthesis Pathway; Address; Adipocytes; Adipose tissue; Adrenergic Receptor; Antidiabetic Drugs; Binding; Bioenergetics; Biological; Cell Respiration; Cues; Data; Devices; Diabetes Mellitus; Diet; Disease; Elderly; Endoplasmic Reticulum; Energy Metabolism; Evolution; Family suidae; Fatty acid glycerol esters; Funding; Glucose; Glucose Intolerance; Health; Homeostasis; Human; Knockout Mice; Lead; Mediating; Medicine; Metabolic Diseases; Mitochondria; Mitochondrial Proteins; Molecular; Monitor; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Physiological; Physiology; Population; Proteins; Publishing; Regulation; Reporter; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Stimulus; System; Temperature; Testing; Therapeutic Intervention; Thermogenesis; Transmembrane Domain; Treatment Efficacy; Wireless Technology; blood glucose regulation; diabetic; glucose tolerance; improved; in vivo; innovation; loss of function; metabolic phenotype; obesity treatment; optogenetics; oxidation; response; spatiotemporal; subcutaneous; uncoupling protein 1

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.

解偶联蛋白 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，可解偶联细胞呼吸和线粒体 ATP 合成，以热量形式耗散能量。由于 UCP1 被认为是负责脂肪组织中非颤抖产热的唯一产热蛋白，因此普遍认为 UCP1 的作用主要介导棕色和米色脂肪的功能，激活后可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 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不耐受，而 UCP1 敲除小鼠也会出现肥胖和葡萄糖不耐症。 小鼠没有糖尿病，只有在热中性的情况下才会出现肥胖。这种差异促使我们寻找独立于 UCP1 的能量稳态调节机制。我们最近发现了一种非规范的（独立于 UCP1 的）生热机制，可以解释上述困境。 UCP1 独立的生热作用涉及 ATP 依赖性 Ca2+ 通过肌节/内质网 Ca2+-ATPase2b (SERCA2b) 和米色脂肪中 Ryanodine 受体 2 (RyR2) 的循环。 Ca2+ 循环生热作用部分是通过响应冷刺激的 α1-AR 信号传导而被激活的，并且需要主动的葡萄糖氧化。因此，米色脂肪起到“葡萄糖汇”的作用，并改善全身葡萄糖耐量。值得注意的是，Ca2+ 循环生热作用是人类、小鼠以及猪（一种缺乏功能性 UCP1 蛋白的稀有哺乳动物）中进化上保守的机制。因此，当前的提案旨在确定与米色脂肪中这种非典型生热作用相关的生物学意义和机制。