脂肪组织是调节机体糖脂代谢及胰岛素敏感性的重要器官。免疫系统与脂肪组织，特别是巨噬细胞与脂肪细胞之间的相互作用在糖稳态调节及失衡过程中的机制是亟待阐明的重要问题。基于前期研究和预实验证据，我们提出：巨噬细胞炎性激活导致组织微环境的亚硝基化应激对脂肪细胞代谢性核受体PPARγ的巯基亚硝基化修饰可能是抑制其转录激活功能，进而损伤脂肪组织的内分泌功能、导致糖稳态失衡的关键机制。课题将围绕这一中心假说开展工作： 1）阐明巨噬细胞不同表型激活对脂肪组织功能的影响；2）探讨巨噬细胞促脂肪细胞PPARγ蛋白巯基亚硝基化的分子机制；3）解析PPARγ亚硝基化/去亚硝基化过程对代谢性炎症及机体代谢稳态的作用；4）明确脂肪细胞对局部巨噬细胞表型转化的调节作用及机制。以上研究将阐明免疫炎症细胞-脂肪组织间交互作用调节机体糖稳态的新机制，为阐明以胰岛素抵抗为中心环节的代谢性疾病如糖尿病及代谢综合征的发病机制提出新

Adipose tissue is an essential organ maintaining the homeostasis of insulin signaling and glucose metabolism. The mechanisms underlying the interaction between immune system and adipose tissue, in particular, the interplay of macrophages and adipocytes, remain largely unknown. Based on our previous studies and preliminary results, we hypothesize that excessive nitrosative stress derived from pro-inflammatory macrophages may cause S-nitrosylation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and negatively regulate its transcriptional activity, which leads to the impairment of the adipocytes’ endocrine function and the glucose intolerance. Driven by this central hypothesis, we propose the following studies: 1) define the differential effects of classical and alternative activations of macrophages on the functions of adipocytes; 2) elucidate the molecular mechanisms by which PPARγ undergoes S-nitrosylation; 3) characterize the roles of the S-nitrosylation/denitrosylation of PPARγ in the metabolic inflammation and glucose metabolism; and 4) examine the regulatory mechanism of the polarization of resident macrophages by adipocytes. Overall, these studies should provide new insights into our understanding of the cross-talk between immune and adipose tissues and, hence, elucidation of the pathophysiology of metabolic diseases featured by insulin resistance such as type 2 diabetes and metabolic syndrome.