Role of Novel Branched Chain Fatty Acids in Amelioration of Metabolic Disease

项目摘要/摘要(对文本的修改以斜体表示) 肥胖是一种世界性流行病，影响着6亿人，并与一系列新陈代谢相关 糖尿病和胰岛素抵抗等疾病。因此，肥胖和相关疾病日益增多。 成为一种社会负担，需要对其生理和发育有更深入的了解 强大的新疗法。代谢性疾病发病的罪魁祸首之一是脂质调节失调。 脂肪组织和整个生物体水平的代谢和信号。在一项脂质组学分析中 脂肪组织GLUT4过度表达(AG4OX)小鼠，对发生代谢性疾病具有抵抗力 鉴定了一类新的生物活性脂质，称为脂肪酸羟基脂肪酸(FAHFAs)。环流水平 棕榈酸羟基脂肪酸(PAHSA)与胰岛素抵抗呈负相关 啮齿动物和人类提示代谢功能障碍中脂类失调的新方面。此外，口述 PAHSA通过增加胰高血糖素样蛋白改善饮食诱导肥胖小鼠的糖耐量 多肽1(GLP-1)和胰岛素分泌，抑制脂肪组织炎症，改善胰岛素敏感性。 FAHFAs的发现及其在代谢反应中的作用引起了人们对其治疗潜力的兴趣， 以及监管和活动。该项目将整合生化、细胞培养和小鼠模型系统，以 了解FAHFAs在缓解代谢性疾病中的调节和活性。最近，一个新的 FAHFA水解酶是雄激素诱导基因1(AIG-1)，它优先在体内降解FAHFA。 体外实验提示AIG1在体内可以调节FAHFA水平和代谢功能。在目标1中，AIG-1在 将对FAHFA的调节和代谢进行评估。为此目的，将以WT计量FAHFA水平 以及AIG1-/-小鼠，以测试它们的水平是否在AIG1缺乏症中升高。下一步，WT和AIG1-/-升 将表征它们的亚代谢表型，以检验内源性 上调FAHFAs可改善代谢功能障碍。初步数据表明，PAHSA对 它们的有益作用至少部分是通过脂质受体GPR120导致胰岛素依赖型血糖 脂肪细胞的摄取。FAHFA是否是内源性GPR120配体和 它们的活性是否依赖于GPR120信号。在目标2中，GPR120信号在FAHFA中的作用 将对操作进行评估。GPR120-/-将利用细胞和小鼠模型对GPR120的贡献进行分层 WT和GPR120给予FAHFAs对代谢益处的活性-- 实验组行代谢表型和炎症表型分析。 总体而言，这些研究将扩大关于调节这些显著血脂的知识，并剖析 它们调节胰岛素敏感性和葡萄糖代谢的机制。这项研究的结果具有 有可能确定与FAHFA调控有关的新靶点以预防和治疗代谢 与肥胖有关的疾病。

Project Summary/Abstract (Modifications to text are denoted in italics) Obesity is a worldwide epidemic affecting 600 million people and is associated with a cluster of metabolic diseases such as diabetes and insulin resistance. Hence, obesity and associated disorders are increasingly becoming a societal burden that requires a deeper understanding of the physiology and the development of robust new treatments. One of the culprits in metabolic disease pathogenesis is dysregulation of lipid metabolism and signaling at the adipose tissue and the whole organism level. In a lipidomics analysis on adipose tissue GLUT4 overexpressing (AG4OX) mice, that are resistant to developing metabolic disease, a novel class of bioactive lipids called fatty acid hydroxy fatty acids (FAHFAs) were identified. Circulating levels of a sub-class, palmitic acid hydroxy fatty acids (PAHSAs) are negatively correlated with insulin resistance in rodents and humans suggesting a new aspect in lipid dysregulation in metabolic dysfunction. Furthermore, oral administration of PAHSAs improve glucose tolerance in diet-induced obese mice by increasing glucagon-like peptide 1 (GLP-1) and insulin secretion, inhibiting adipose tissue inflammation, and improving insulin sensitivity. Discovery of FAHFAs and their function in metabolic responses led to interest in their therapeutic potential, and regulation and activity. This project will integrate biochemical, cell culture and mouse model systems to understand the regulation and activity of FAHFAs in the alleviation of metabolic disease. Recently, a new FAHFA hydrolase, androgen-induced gene 1 (AIG-1), was identified that preferentially hydrolyzes FAHFAs in vitro suggesting AIG1 can regulate FAHFA levels and metabolic function in vivo. In aim 1, the role of AIG-1 in FAHFA regulation and metabolism will be evaluated. For this purpose, FAHFA levels will be measured in WT and AIG1-/- mice to test whether their levels are increased in AIG1 deficiency. Next, WT and AIG1-/- littermates will be characterized for their imetabolic phenotype in order to test the hypothesis that endogenous upregulation of FAHFAs improves metabolic dysfunction. Preliminary data demonstrated that PAHSAs exert their beneficial effects at least partially via the lipid receptor, GPR120 leading to insulin-dependent glucose uptake in adipocytes. It is yet to be determined whether FAHFAs are endogenous GPR120 ligands and whether their activity is dependent on GPR120 signaling. In aim 2, the role of GPR120 signaling in FAHFA action will be evaluated. GPR120-/- cell and mouse models will be utilized to stratify the contribution of GPR120 activity to metabolic benefits exerted by FAHFAs by administration of FAHFAs to WT and GPR120-/- experimental groups and analysis of metabolic as well as inflammatory phenotype. Overall, these studies will expand the knowledge on the regulation of these remarkable lipids and dissect mechanisms by which they regulate insulin sensitivity and glucose metabolism. Results of this study have the potential to identify new targets related to FAHFA modulation for prevention and treatment of metabolic diseases associated with obesity.