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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.

Original publication

DOI

10.1073/pnas.0912487106

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

29/12/2009

Volume

106

Pages

22504 - 22509

Keywords

3T3-L1 Cells, Adipocytes, White, Animals, Cell Line, Chemokines, Gene Expression, Humans, Hypoglycemic Agents, Inflammation Mediators, Insulin, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, PPAR gamma, Rats, Rats, Zucker, Recombinant Fusion Proteins, Signal Transduction, Thiazolidinediones