Fig. 6. Summary of the proposed mechanism for adipocyte-mediated insulin resistance in human obesity, illustrating the central role of interferon gamma.

Obese adipocytes acquire increased antigen presenting capability leading to an increase in CD4 + Th1 cells in AT that produce IFNγ. Increased IFNγ suppresses Treg differentiation and enhances Treg exhaustion, augments adipocyte MHCII pathway which is not common to other cytokines, and attenuates adipocyte mitochondrial function and fatty acid flux to create an escalating cycle of inflammation and insulin resistance. Exhaustion features in human Tregs include increased expression of inhibitory co-receptors and markers of apoptosis and suppressed LKB1.