The Role of Adipocyte Lipolysis in Thermoregulation

项目摘要 脂肪组织严格调节全身能量平衡。哺乳动物有两种主要的脂肪组织： 白色脂肪组织（WAT）和棕色脂肪组织（BAT）。WAT存储多余的能量，而BAT消耗 能量作为热量，用于非颤抖产热。WAT中的一些脂肪细胞，如棕色脂肪细胞，表达 解偶联蛋白-1（UCP 1），一种通过解偶联线粒体呼吸介导产热的蛋白质 ATP合成。这群脂肪细胞最近被命名为“米色”或“brite”脂肪细胞。数量 在冷适应或交感神经激活过程中，米色脂肪细胞的数量增加，这一过程称为WAT 布朗宁。动员储存的细胞能量以在饥饿或增加的能量需求期间使用（例如， 冷适应）需要水解储存在胞质脂滴（LD）中的甘油三酯（即，细胞内 脂肪分解）。与细胞内脂解密切相关的基因是CGI-58（比较基因鉴定-58）。在 在哺乳动物中，CGI-58普遍表达，在脂肪中表达最高。它与LD涂层相互作用 蛋白质和激活ATGL（脂肪甘油三酯脂肪酶），以促进细胞内脂解。人们相信 BAT中的细胞内脂解作用对于产热是必不可少的，但这还没有在体内进行过研究。我们 令人惊讶地发现BAT中缺乏CGI-58的小鼠，即，BAT特异性CGI-58敲除（BAT-KO）小鼠， 即使在禁食状态下也对寒冷敏感。这一建议是为了界定基本的适应机制。我们 初步研究提出了一个中心假设：细胞内脂解中BAT的缺陷可能会重新编程BAT 吸收更多来自WAT脂解和饮食的循环产热底物，并通过诱导WAT 通过激活交感神经系统产生热。我们将通过检验 BAT产热、BAT对循环基质的吸收以及不同条件下的WAT产热 体温、交感神经和营养状态。我们还将探索BAT-KO中米色脂肪细胞的起源 小鼠此外，我们将研究WAT脂解是否是产热和WAT布朗宁所必需的， 通过使用细胞内脂解的药理学抑制剂并通过同时缺失 BAT和WAT（FAT-KO小鼠）中的CGI-58。在一些实验中，我们将比较脂肪CGI-58和 ATGL KO小鼠，以深入了解CGI-58的其他脂解作用。此外，我们将定义BAT如何 脂解调节能量平衡、葡萄糖处置、胰岛素敏感性和组织脂质代谢。最后我们 将寻找新的见解如何脂解缺乏增强脂肪交感神经驱动。我们将 通常测量脂质/脂肪因子/激素的血液水平，以及脂质/基因表达的组织水平， 确定CGI-58在不同脂肪细胞中的缺乏如何在生化和能量代谢方面调节脂质/能量代谢， 分子水平。生热作用消耗能量。能量平衡的扰动是一种常见的 代谢紊乱，这大大有助于疾病的发病率和死亡率。我们的调查结果 研究有望揭示控制营养过剩引起的代谢疾病的新方法。

Project Summary Adipose tissue critically regulates whole-body energy homeostasis. Mammals have two major adipose tissues: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT stores excess energy while BAT dissipates energy as heat for non-shivering thermogenesis. Some adipocytes in WAT, like brown adipocytes, express uncoupling protein-1 (UCP1), a protein that mediates heat generation by un-coupling mitochondrial respiration from ATP synthesis. This population of adipocytes is recently named “beige” or “brite” adipocytes. The quantity of beige adipocytes increases during cold adaptation or sympathetic activation, a process referred to as WAT browning. Mobilization of stored cellular energy for use during starvation or increased energy demand (e.g., cold adaptation) requires hydrolysis of triglycerides stored in cytosolic lipid droplets (LDs) (i.e., intracellular lipolysis). A gene critically implicated in intracellular lipolysis is CGI-58 (Comparative Gene Identification-58). In mammals, CGI-58 is ubiquitously expressed with the highest expression in fat. It interacts with LD coat proteins and activates ATGL (Adipose Triglyceride Lipase) to promote intracellular lipolysis. It was believed that intracellular lipolysis in BAT is essential for thermogenesis, but this has not been examined in vivo. We surprisingly found that mice lacking CGI-58 in BAT, i.e., BAT-specific CGI-58 knockout (BAT-KO) mice, are not cold sensitive even in the fasted state. This proposal is to define the underlying adaptive mechanisms. Our preliminary studies suggest a central hypothesis: BAT deficiency in intracellular lipolysis may reprogram BAT to take up more circulating thermogenic substrates derived from WAT lipolysis and diet and by inducing WAT thermogenesis through activation of the sympathetic nervous system. We will test this hypothesis by examining BAT thermogenesis, BAT uptake of circulating substrates, and WAT thermogenesis under different temperature, sympathetic, and nutritional states. We will also explore the origin of beige adipocytes in BAT-KO mice. Additionally, we will examine whether WAT lipolysis is required for thermogenesis and WAT browning in BAT-KO mice by using a pharmacological inhibitor of intracellular lipolysis and by simultaneous deletion of CGI-58 in both BAT and WAT (FAT-KO mice). In some experiments, we will compare adipose CGI-58 and ATGL KO mice to gain insights into other lipolytic roles of CGI-58. Furthermore, we will define how BAT lipolysis regulates energy balance, glucose disposal, insulin sensitivity, and tissue lipid metabolism. Finally, we will search for novel insights into how lipolysis deficiency augments adipose sympathetic drive. We will generally measure blood levels of lipids/adipokines/hormones, and tissue levels of lipids/gene expression to establish how CGI-58 deficiency in different adipocytes regulates lipid/energy metabolism at biochemical and molecular levels. Thermogenesis dissipates energy. Perturbation of energy balance is a hallmark of common metabolic disorders, which contribute substantially to disease morbidity and mortality. Findings from our studies hold promise of revealing novel approaches for control of overnutrition-induced metabolic disease.