脂肪组织特异性Grb10敲除在肥胖诱导的内脏白脂CD4+ T细胞免疫应答中的作用及机制研究

脂肪细胞与免疫细胞的相互作用在介导炎症发生以及胰岛素抵抗中发挥了重要作用。生长因子受体结合蛋白10 (Grb10)是mTORC1信号的关键负调控因子。我们之前的报道发现，脂肪组织特异性Grb10敲除小鼠(Grb10fKO)高脂喂养后其胰岛素抵抗显著上升，然而其作用机制仍不清楚。在前期实验中，我们发现Grb10fKO 小鼠高脂喂养4周后，内脏白脂中促炎性Th1细胞标记基因T-bet和IFN-γ表达明显上升，且Grb10敲除显著促进了脂肪细胞中MHCII表达。结合报道MHCII能促进Th1细胞分化，我们提出假说：Grb10可通过调控MHCII分子表达抑制脂肪组织促炎性Th1细胞分化，从而改善脂肪组织炎症和胰岛素抵抗。本项目将利用Grb10fKO 小鼠模型并结合细胞模型探讨Grb10在介导促炎性Th1免疫应答中的作用和机制，为从炎症角度治疗肥胖及相关代谢疾病提供了科学依据。

The crosstalk between adipocytes and immune cells is the principal driver for the onset of adipose inflammation and insulin resistance. Growth factor receptor binding protein-10 (Grb10) is a key negtive regulator of mTORC1 signaling. Our previous work showed that fat-specific disruption of Grb10 (Grb10fKO) could promote HFD-induced insulin resistance while the mechanisms remained unknown. Here, we found T-bet and IFN-γ, which are Th1 marker genes, were highly enriched in epididymal WAT (eWAT) of Grb10fKO mice fed with HFD for 4 w. And MHCII, which was reported to promote Th1 cell polarization, was markedly induced in Grb10-deficient adipocytes. Therefore, we hypothesize that Grb10 can restrain pro-inflammatory Th1 cell immune responses in eWAT by down-regulating MHCII expression in adipocytes, which further helps to control adipose inflammation and improve insulin resistance. In this proposed study, we will for the first time investigate the role of Grb10 on eWAT inflammation mediated by Th1 cells with adopting Grb10fKO mice together with cell models. Our work will provide futher evidence that adipose inflammation could be targeted to modulate obesity and associated metabolic diseases.