Regulation of fatty acid metabolism in adipocytes

脂肪细胞能量储存和利用的调节是一个动态的过程，它影响 总体能量动态平衡。脂肪细胞以甘油三酯(TG)的形式将营养储存在脂滴中，并且 根据需要动员他们。而这些细胞通过增加甘油三酯脂解来对交感信号做出反应 为了释放游离脂肪酸(FFA)和甘油，它们还会重新吸收FFA，以甘油三酯的形式重新酯化或氧化。B--肾上腺素能受体的激活及其下游 环化AMP信号不仅增加脂解，而且以牺牲为代价促进脂肪酸氧化 对再酯化的影响，尽管其潜在的机制仍不清楚。我们假设 儿茶酚胺通过调节信号转导和调节来引导脂肪酸氧化 转录激活因子3(STAT3)与甘油-3-磷酸酰基转移酶3的抑制 (GPAT3)。我们的初步数据表明，STAT3在b-3肾上腺素能受体的刺激和脂肪细胞的脂解激活的反应中，特异性地在脂滴上经历Ser727的磷酸化。脂滴相关的STAT3池结合并抑制GPAT3，有效地抑制GPAT3催化的再酯化，促进脂肪酸氧化。脂肪细胞特异性的STAT3KO小鼠表现出正常的脂解率，但在脂解驱动的氧化代谢方面表现出特定的缺陷，导致高脂饮食下能量消耗的减少和肥胖率的增加。这项提案中概述的实验旨在扩大对STAT3这一新功能的洞察，确定其代谢结果，并描绘其作用机制。目的1研究儿茶酚胺对体内信号转导通路和信号转导通路中信号转导通路及信号转导通路中信号转导通路的影响。在AIM 2中，将使用免疫共沉淀和体外结合试验来研究STAT3与GPAT3的相互作用。此外，将使用体外GPAT活性分析和蛋白质组学方法来研究STAT3相互作用导致GPAT3活性抑制的机制。最后，在目标3中，将检验这一新的调控途径在男性和女性肥胖发展中的生理学相关性。此外，非磷酸化的STAT3 S727A突变脂肪细胞和小鼠将被用来确定该磷酸化位点在体内的作用。这些研究将使我们更全面地了解脂肪分解驱动的氧化代谢的调节，并将提高我们对白色脂肪组织中这一能量消耗途径的理解。这可能导致开发新的治疗方法来遏制肥胖和与肥胖相关的破坏性代谢性疾病。

The regulation of energy storage and utilization in adipocytes is a dynamic process that influences overall energy homeostasis. Adipocytes store nutrients in lipid droplets as triglycerides (TG), and mobilize them as needed. While these cells respond to sympathetic signals by increasing TG lipolysis to release free fatty acids (FFA) and glycerol, they also reabsorb FFA for re-esterification as triglycerides or alternatively for oxidation. Activation of b-adrenergic receptors and downstream cyclic AMP signaling not only increases lipolysis, but also promotes fatty acid oxidation at the expense of re-esterification, although the underlying mechanisms remain poorly understood. We hypothesize that catecholamines direct fatty acids for oxidation through regulation of signal transducer and activator of transcription 3 (STAT3) and suppression of glycerol-3-phosphate acyltransferase 3 (GPAT3). Our preliminary data demonstrate that STAT3 specifically undergoes Ser727 phosphorylation at the lipid droplet in response to stimulation of b-3 adrenergic receptors and activation of lipolysis in adipocytes. The pool of lipid droplet-associated STAT3 binds to and inhibits GPAT3, effectively suppressing GPAT3-catalyzed re-esterification, to promote fatty acid oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but manifest a specific defect in lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity on high fat diet. The experiments outlined in this proposal are designed to expand insights into this novel function of STAT3, determining its metabolic consequences and delineating the mechanism of action. Aim 1 will focus on the stimulation of STAT3 phosphorylation by catecholamines in vivo, delineating the signaling pathway and specific kinase(s) responsible for the critical STAT3 Ser727 phosphorylation event. The interaction of STAT3 with GPAT3 will be investigated in aim 2 using co-immunoprecipitation and in vitro binding assays. Additionally, the mechanism by which STAT3 interaction results in suppression of GPAT3 activity will be investigated using in vitro GPAT activity assays and proteomic approaches. Finally, in aim 3, the physiological relevance of this novel regulatory pathway in the development of obesity in males and females will be examined. Additionally, non-phosphorylatable STAT3 S727A mutant adipocytes and mice will be employed to determine the in vivo role of this phosphorylation site. These studies will provide a more complete understanding of the regulation of lipolysis-driven oxidative metabolism, and will improve our understanding of this energy expending pathway in white adipose tissue. This may lead to the development of new therapeutic approaches to curtail obesity and the devastating metabolic diseases with which obesity is associated.