PPARγ activation in adipocytes is sufficient for systemic insulin sensitization

Although peroxisome proliferator-activated receptorgamma (PPAR gamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPAR gamma in adipocytes, but not in macrophages, is sufficient for whole-body insulin sensitization equivalent to systemic TZD treatment. In addition to improved adipokine, inflammatory, and lipid profiles, PPAR gamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPAR gamma-activated adipocytes broadly suppress induction of inflammatory cytokines and C-X-C family chemokines in macrophages. Collectively, these data describe an adipocentric'' model in which adipose activation of PPAR gamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPAR gamma modulators in diabetic therapy.