DHA通过SIRT1调节脂肪组织血管新生改善胰岛素抵抗及其机制研究

Prediabetes Melitius (PDM) is a state between diabetes and normal blood sugar. Overweight and obesity are the strongest risk factors for PDM. Our previous study found that docosahexenoic acid (DHA) can reduce adipose tissue angiogenesis and alleviate insulin resistance in middle-aged obese diabetic mice. However, the molecular basis of such beneficial effect of DHA remains to be determined. Activation and/or increasing expression of SIRT1, an NAD+-dependent deacetylase, shows a marked anti-angiogenic effect. Thus, our hypothesis is that DHA reduces adipose tissue angiogenesis through SIRT1 and improves insulin resistance in PDM. The three Specific Aims are: (1) to investigate the role of DHA in adipose tissue angiogenesis and insulin sensitivity in early stage of both genetic (ob/ob mice) and diet-induced obesity (DIO) animal models, as well as in adipocytes-specific SIRT1 knockout (SIRT1AD-/-) model to understand the role of SIRT1 in the process; (2) to elucidate the molecular pathways mediating the effects of DHA on angiogenesis in vitro; and (3) to study the effects of DHA on insulin sensitivity and subcutaneous adipose tissue angiogenesis in overweight / obese volunteers with PDM. Overall, results from this study will provide new information of DHA on regulating angiogenesis in adipose tissue, and provide scientific basis for nutritional intervention in the prevention and treatment of PDM and even type 2 diabetes.

糖尿病前期（Prediabetes Melitius，PDM）是2型糖尿病的必经阶段，本质是胰岛素抵抗。我们前期研究发现二十二碳六烯酸（docosahexenoic acid, DHA）可减少中年肥胖糖尿病小鼠脂肪组织血管新生并缓解胰岛素抵抗，其作用机制尚不明确。研究表明，SIRT1有明显的抗血管新生作用。本研究拟在此基础上利用ob/ob小鼠、膳食诱导肥胖小鼠（DIO）及脂肪细胞特异性敲除SIRT1模型（SIRT1AD-/-），观察DHA对肥胖导致的PDM小鼠脂肪组织血管新生及胰岛素敏感性的影响以及SIRT1在其中的作用；其次，采用体外血管新生模型揭示其分子机制；最后，招募超重/肥胖PDM自愿者，从临床角度观察DHA在糖尿病前期调节脂肪组织血管新生改善胰岛素抵抗的作用。本研究将阐明DHA调节脂肪组织血管新生改善胰岛素抵抗的作用及其分子机制，为DHA预防PDM向2型糖尿病发展提供科学依据。