慢性炎症是肥胖相关慢性疾病的关键机制，而脂肪组织是肥胖诱导的慢性炎症发生发展的关键位点。如何特异性的抑制脂肪炎症而不影响全身性免疫功能是一个巨大的挑战。本项前期研究发现肥胖引起脂肪细胞过量表达MHCII分子。全身MHCII功能缺失小鼠在高脂饮食喂养后，与野生型小鼠相比脂肪组织炎症和胰岛素抵抗都得到了改善，揭示了MHCII分子在脂肪组织炎症中的重要作用。为了进一步探讨脂肪细胞MHCII在肥胖诱导炎症和胰岛素抵抗中的关键作用，本项目将使用脂肪细胞特异性MHCII敲除小鼠和过表达小鼠展开研究。同时我们将使用MHCII抗体探索能否通过阻断MHCII抑制脂肪组织炎症。本项目还将研究PPARγ激动剂抑制脂肪细胞MHCII的作用对PPARγ激动剂药理活性的贡献，并阐明PPARγ激动剂抑制脂肪细胞MHCII的分子机制。本项目研究成果可能为安全有效的抑制脂肪组织炎症提供新思路。

Obesity and obesity-related chronic inflammation are major risk factors for insulin resistance and cardiovascular disease. Adipose resident T-cells (ARTs) and adipose tissue macrophages (ATMs) play major roles in obesity-induced inflammation and insulin resistance. ATM polarization to a pro-inflammatory M1 phenotype is a hallmark of adipose inflammation and is associated with insulin resistance. Studies also suggest that high-fat diet (HFD) induces pro-inflammatory ARTs subtypes that promote ATM M1 polarization and insulin resistance. However, the mechanisms responsible for HFD-induced ART activation are largely unknown. We have recently identified adipocytes as functional antigen presenting cells (APCs), which can activate CD4+ T-cells in a MHC class II (MHCII) restricted fashion. We found adipocyte MHCII expression is induced in the early stage of HFD-induced obesity and genetic ablation of MHCII leads to attenuated adipose inflammation and insulin resistance in obesity. However, while these results suggest adipocyte MHCII expression may play an important role in obesity-induced inflammation, the regulation of adipocyte MHCII expression and its contribution to HFD CD4+ ART responses are still unclear..Preliminary studies in adipocyte specific MHCII deficient mice (AKO mice) indicate that lack of MHCII in adipocytes improves systemic insulin resistance during early HFD challenge. We also found that HFD induced adipocyte MHCII expression is inhibited by activation of PPARgamma, a recognized anti-diabetic and anti-inflammatory target. Thus, we hypothesize that adipocyte MHCII triggers adipose tissue inflammation and systemic insulin resistance, and that this pathway is down-regulated by PPARgamma. We will test this hypothesis by investigating fat tissue inflammation and metabolic changes in AKO and aCiita-Tg mice in HFD-induced obesity . We will focus on the changes in adipocytes, ARTs, and ATMs to identify the mechanism(s) underlying the effects of adipocyte MHCII deficiency . To further determine if MHCII could be a target to treat adipose inflammation and insulin resistance, we will neutralize MHCII by injecting blocking antibody into mice fed HFD for 2 weeks (early phase of obesity, indicated by induction of adipocyte MHCII) and in mice fed HFD for 12 weeks (late phase of obesity, indicated by accumulation of ATMs), and subsequently test the adipose inflammation and insulin sensitivity in these mice . Our preliminary data indicates that PPARgamma agonist inhibits adipocyte MHCII in vitro and in long-term HFD fed mice via involvement of PU.1. We will explore the possibility that the inhibition of adipocyte MHCII by PPARgamma contributes the anti-inflammatory function of PPARgamma agonist, which can be tested by using AKO mice. Moreover, we will determine the role of PU.1 in PPARgamma regulation of adipocyte MHCII expression..Our proposed study aims to identify the key role of adipocyte MHCII in initiation of obesity-induced inflammation, and decipher inhibitory effect of PPARgamma on adipocyte MHCII, which may provide new strategies to prevent obesity-induced inflammation.