The Role of Adipocyte Lipolysis in Thermoregulation

项目摘要 脂肪组织对全身能量平衡起着至关重要的调节作用。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)。水储存多余的能量，而蝙蝠则消散 作为热的能量，用于非颤动的生热作用。Wat中的一些脂肪细胞，如棕色脂肪细胞，表达 解偶联蛋白-1(UCP1)，一种通过解偶联线粒体呼吸来调节产热的蛋白质 来自三磷酸腺苷的合成。这群脂肪细胞最近被命名为“米色”或“褐褐色”脂肪细胞。数量 在冷适应或交感神经激活期间，米色脂肪细胞的数量增加，这一过程称为Wat 布朗宁。动员存储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)需要对储存在胞内脂滴(即细胞内)中的甘油三酯进行水解 脂肪分解)。与细胞内脂肪分解密切相关的一个基因是CGI-58(比较基因鉴定-58)。在……里面 在哺乳动物中，CGI-58普遍表达，在脂肪中的表达最高。它与LD涂层相互作用 蛋白质并激活ATGL(脂肪甘油三酯脂肪酶)以促进细胞内脂肪分解。人们相信， 蝙蝠细胞内的脂解作用对产热是必不可少的，但这一点尚未在体内得到验证。我们 令人惊讶的是，在BAT中缺乏CGI-58的小鼠，即BAT特异性CGI-58基因敲除(BAT-KO)小鼠，并不是 即使在禁食状态下也对寒冷敏感。这项提议是为了定义基本的适应机制。我们的 初步研究表明一个中心假说：细胞内脂肪分解中的BAT缺乏症可能重新编程BAT 摄取更多来自水脂肪分解和饮食的循环生热底物和通过诱导水 通过激活交感神经系统来产热。我们将通过检验这一假设来检验这一假设 不同条件下的BAT产热、BAT对循环底物的吸收和WAT的产热 体温、交感神经和营养状态。我们还将探索BAT-KO中米色脂肪细胞的来源 老鼠。此外，我们将研究Wat脂肪分解是否是生热和Wat褐变所必需的。 BAT-KO小鼠通过使用一种细胞内脂解的药物抑制剂并同时缺失 在BAT和WAT(FAT-KO小鼠)中均有CGI-58表达。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的其他降脂作用。此外，我们将定义BAT如何 脂肪分解作用调节能量平衡、葡萄糖代谢、胰岛素敏感性和组织脂代谢。最后，我们 将寻求关于脂肪分解缺陷如何增强脂肪交感驱动的新见解。我们会 通常测量血液中的脂类/脂肪因子/激素水平和组织中的脂类/基因表达水平 确定不同脂肪细胞中CGI-58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。生热作用消散能量。能量平衡的扰动是常见的 代谢紊乱，这在很大程度上导致了疾病的发病率和死亡率。来自我们的调查结果 研究有望揭示控制营养过剩引起的代谢性疾病的新方法。

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.