脂肪细胞单甲基支链脂肪酸的合成与代谢功能

Obesity is an important risk factor for developing type 2 diabetes, which is caused by insulin resistance in conjunction with inadequate pancreatic function. It is also associated with a constellation of health complications, including inflammation, heart disease and cancer. Adipose tissue is a highly active metabolic and endocrine organ, which plays critical roles in obesity-associated metabolic diseases by secreting a wide range of mediators regulating functions of peripheral metabolic tissues. Metabolomic studies have revealed that branched chain amino acids (BCAA) have strong correlations with incidence and progression of metabolic dysfunction. BCAA supplementation promotes insulin resistance only under condition of a high-fat diet, suggesting that their effects are tied to FA metabolism. Monomethyl branched chain fatty acids (mmBCFA) are de novo synthesized from branched chain acyl CoA precursors derived from BCAA. Recent studies suggested that they play critical roles in regulating specific lipid metabolism and cellular signaling pathways. However, their physiological role and metabolic regulation are unknown. Our preliminary data demonstrated that mmBCFA are present in human adipose tissues and their levels are significantly lower in tissues from obese subjects with insulin resistance as compared to lean subjects and increase after weight loss. Moreover, adipose tissue mmBCFA content correlates positively with skeletal muscle insulin sensitivity. We hypothesize that mmBCFA levels increase after weight loss due to enhanced de novo synthesis and this regulation contributes to the observed therapeutic benefits. We also hypothesize mmBCFA from adipose tissue have beneficial metabolic effects on peripheral tissues. In aim 1, we will examine regulation of mmBCFA synthesis, incorporation into complex lipids and its secretion from adipocytes. Aim 2 will explore mmBCFA effect on hepatocyte metabolism and whole body insulin action in mouse models of obesity. Collectively, our study aims to explore the metabolic functions of the little studied mmBCFA and to investigate whether they could serve as good predictors of the progression of metabolic diseases, since they would inform on activities of both BCAA catabolism and FA metabolism.

肥胖症中脂肪组织的过度扩张是导致胰岛素抵抗，进而造成2型糖尿病的一个重要危险因素。近年来越来越多的研究表明脂肪组织具有储能和内分泌双重功能。然而，对于脂肪组织如何调节周身代谢的分子机制还不清楚。申请人课题组近期发现脂肪细胞是由支链氨基酸（BCAA）代谢产物合成单甲基支链脂肪酸（mmBCFA）的重要场所，进一步研究表明脂肪组织mmBCFA的含量与人体胰岛素敏感度相关联。本项目拟结合稳定同位素标记质谱脂组学技术，脂肪细胞生物学技术，以及多种与脂肪储存相关的转基因小鼠模型，多层次探讨脂肪细胞中具有重要生物活性但还没有被足够关注的mmBCFA的代谢功能。我们将系统地检查脂肪细胞中mmBCFA的合成与代谢途径，并探讨脂肪细胞源性与外源性mmBCFA的体内代谢功能并研究相关机制。这些研究将为代谢综合征的病理生理学提供崭新的知识并可能提供能够用于预测这些疾病风险的新的生物标志物。

肥胖症中脂肪组织的过度扩张是导致胰岛素抵抗，进而造成2型糖尿病的一个重要危险因素。近年来越来越多的研究表明脂肪组织具有储能和内分泌双重功能。然而，对于脂肪组织如何调节周身代谢的分子机制还不清楚。我们的研究目标就是进一步检查脂肪细胞中非主要脂肪酸单甲基支链脂肪酸（mmBCFA）的合成与代谢途径，探讨其体内代谢功能并研究相关机制。为治疗肥胖及其相关代谢综合征提供新的靶标。..本研究的成果主要有：1）脂肪细胞源性的生物活性脂肪酸代谢物可能参与调节禁食减肥期间脂肪降解导致的与促炎症激活有关脂肪组织巨噬细胞的聚集，从而有助于限制局部脂质浓度和脂毒性的增加，而不像肥胖症白色脂肪组织中慢性激活的巨噬细胞的聚集。2）脂肪酸通过其转运蛋白CD36通过Fyn激酶来调节在细胞胰岛素信号传导中发挥重要作用的连接蛋白IRS1的泛素化和降解，CD36/Fyn/IRS1复合体的形成是CD36影响IRS1降解的关键。3）mmBCFA在维持细胞稳态中发挥的重要作用，并且可能与2-OHFA协同作用调节动物发育。4）FA2H通过降低GLUT1从而激活AMPK磷酸化而抑制mTOR信号转导，降低GLI1的表达从而降低细胞的增殖和迁移的能力并增强细胞对顺柏的敏感度。5）mmBCFA通过上调SCD-1的表达缓解了由PA诱导的内质网应激，表明其可能在预防肥胖引起的代谢性疾病中发挥重要作用。..有关在脂肪细胞中脂肪酸代谢以及在周身能量平衡中的作用一直没有得到深入研究，对于脂肪细胞源性生物活性脂分子的合成以及内分泌功能更是所知有限。我们的研究探讨了mmBCFA等非主要脂肪酸在胰岛素信号转导，胰岛素抵抗中的重要调节作用；通过线虫和小鼠等的表型研究，流行病学研究，利用包括脂组学在内的多种现代生物化学和分子生物学技术从多个角度探索羟基化脂肪酸的代谢调控作用；针对脂肪细胞的内分泌功能提出了新的科学假设。.