PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization.

Proceedings of the National Academy of Sciences of the United States of America 2009 Dec 29

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Although peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARgamma 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, PPARgamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARgamma-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 PPARgamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARgamma modulators in diabetic therapy.

Citation

Shigeki Sugii, Peter Olson, Dorothy D Sears, Maziyar Saberi, Annette R Atkins, Grant D Barish, Suk-Hyun Hong, Glenda L Castro, Yun-Qiang Yin, Michael C Nelson, Gene Hsiao, David R Greaves, Michael Downes, Ruth T Yu, Jerrold M Olefsky, Ronald M Evans. PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proceedings of the National Academy of Sciences of the United States of America. 2009 Dec 29;106(52):22504-9