The immune system plays an important role in the development of insulin resistance (IR) associated with obesity and type 2 diabetes mellitus (T2DM). Secretion of pro-inflammatory cytokines by adipose tissue macrophages (ATMs) causes chronical low-grade inflammation, which in turn contributes to the development of IR and, in some subjects, to the onset of T2DM. In addition, the high level of circulating non-esterified fatty acids (NEFAs) in obese subjects participates in the development of IR and T2DM.
Among cytokines secreted by ATMs, IL-1β is produced following activation of the NLRP3 inflammasome and contributes to the development of IR in insulin-sensitive tissues. It has been shown in our laboratory that opposite to unsaturated fatty acids (UFAs), saturated fatty acids (SFAs) activate the NLRP3 inflammasome, leading to IL-1β secretion. In addition, UFAs completely prevent activation of the NLRP3 inflammasome when combined with SFAs. However, knowledge of the underlying molecular mechanisms remains limited.
In this thesis, we used two models of human macrophages to understand these processes : macrophage-like PMA-differentiated THP-1 cells and monocyte-derived macrophages (MDMs). In both models, we tested the effect of NEFAs on the activation of the NLRP3 inflammasome by focusing on their metabolism. Using lipidomic, we analyzed the phospholipid composition of cells treated with NEFAs. We also analyzed membrane fluidity and the generation of lipid droplets (LDs). Following these analyses, we observed in the presence of SFAs an increase in the saturation of cellular phospholipids and a loss of membrane fluidity associated with a decrease of the Na, K-ATPase pump activity and a K+ efflux-mediated NLRP3 inflammasome activation. Interestingly, UFAs completely prevented the activation of the NLRP3 inflammasome by redirecting the flow of SFAs into the LDs.
Overall, our results led to a better characterization of the molecular mechanisms associated with NRLP3 inflammasome activation by NEFAs, contributing to a better understanding of how innate immunity works in the context of obesity and T2DM.