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

新型支链脂肪酸在改善代谢疾病中的作用

• 批准号: 9329022
• 负责人: Meric Erikci Ertunc
• 金额: $ 5.71万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329022
• 关键词: Acute; Adipocytes; Adipose tissue; Affect; Androgens; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antidiabetic Drugs; Biochemical; Biological Assay; Biological Models; Biology; Bone Marrow; Cell Culture Techniques; Cell model; Cells; Chronic; Data; Dendritic Cells; Development; Diabetes Mellitus; Diet; Disease; Enzymes; Epidemic; Esters; Family; Fatty Acids; Functional disorder; G-Protein-Coupled Receptors; GLUT4 gene; Genes; Health system; High Fat Diet; Human; Hydrolase; Hydrolysis; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Isomerism; Italy; Knockout Mice; Knowledge; Ligands; Lipids; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Modification; Mus; Obese Mice; Obesity; Oral Administration; Palmitic Acids; Pathogenesis; Phenotype; Physiology; Positioning Attribute; Prevention; Proteins; Regulation; Reporting; Resistance; Rodent; Role; Serum; Signal Transduction; Stearic Acids; Testing; Text; Therapeutic; Threonine; Tissues; Treatment Efficacy; Up-Regulation; Whole Organism; Work; base; branched chain fatty acid; combat; cytokine; design; diabetic; enzyme activity; experimental study; glucagon-like peptide 1; glucose metabolism; glucose tolerance; glucose uptake; human disease; hydroxy fatty acid; improved; in vitro testing; in vivo; insulin secretion; insulin sensitivity; interest; knowledge translation; lipid metabolism; macrophage; metabolic phenotype; mouse model; novel; novel therapeutic intervention; overexpression; prevent; receptor; response

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.

项目摘要/摘要（对文本的修改以斜体表示） 肥胖是一种全球性流行病，影响6亿人，并与一组代谢紊乱有关。 糖尿病和胰岛素抵抗等疾病。因此，肥胖症和相关的疾病越来越多地受到关注。 成为一个社会负担，需要更深入地了解生理学和发展， 强有力的新治疗方法。代谢性疾病发病机制中的罪魁祸首之一是脂质调节异常 在脂肪组织和整个生物体水平上的代谢和信号传导。在一项关于 脂肪组织GLUT 4过表达（AG 4 OX）小鼠，对代谢疾病的发展具有抵抗力， 鉴定了一类称为脂肪酸羟基脂肪酸（FAHFA）的新型生物活性脂质。循环水平 棕榈酸羟基脂肪酸（PAHSAs）与胰岛素抵抗呈负相关， 啮齿类动物和人类的代谢功能障碍的脂质失调提出了一个新的方面。此外，口头 PAHSAs的施用通过增加胰高血糖素样蛋白酶来改善饮食诱导的肥胖小鼠的葡萄糖耐量 肽1（GLP-1）和胰岛素分泌，抑制脂肪组织炎症，并改善胰岛素敏感性。 FAHFA的发现及其在代谢反应中的功能引起了对其治疗潜力的兴趣， 以及监管和活动。该项目将整合生物化学、细胞培养和小鼠模型系统， 了解FAHFA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，雄激素诱导基因1（AIG-1），被鉴定为优先水解FAHFA， 表明AIG 1在体内可调节FAHFA水平和代谢功能。在目标1中，AIG-1的作用 将评价FAHFA调节和代谢。为此，将在WT中测量FAHFA水平 和AIG 1-/-小鼠，以测试它们的水平是否在AIG 1缺乏时增加。接下来，WT和AIG 1-/-同窝仔 将表征其代谢表型，以检验内源性 FAHFA的上调改善代谢功能障碍。初步数据表明，PAHSAs 其有益作用至少部分通过脂质受体GPR 120导致胰岛素依赖性葡萄糖 脂肪细胞中的摄取。尚不确定FAHFA是否是内源性GPR 120配体， 它们的活性是否依赖于GPR 120信号传导。在目的2中，GPR 120信号传导在FAHFA中的作用是通过调节细胞内的GPR 120信号传导来实现的。 将对行动进行评估。将使用GPR 120-/-细胞和小鼠模型对GPR 120的贡献进行分层 通过向WT和GPR 120-/-施用FAHFA对FAHFA发挥的代谢益处的活性 实验组和代谢以及炎症表型的分析。 总的来说，这些研究将扩大对这些显着的脂质和解剖调控的知识， 它们调节胰岛素敏感性和葡萄糖代谢的机制。这项研究的结果有 有可能确定与FAHFA调节相关的新靶点，用于预防和治疗代谢性 与肥胖有关的疾病。