PPARγ Activation in Adipocytes is Sufficient for Systemic Insulin Sensitization

Although peroxisome proliferator-activated receptor gamma (PPARγ) 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-indep...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2009-12, Vol.106 (52), p.22504-22509
Main Authors: Sugii, Shigeki, Olson, Peter, Sears, Dorothy D., Saberi, Maziyar, Atkins, Annette R., Barish, Grant D., Hong, Suk-Hyun, Castro, Glenda L., Yin, Yun-Qiang, Nelson, Michael C., Hsiao, Gene, Greaves, David R., Downes, Michael, Yu, Ruth T., Olefsky, Jerrold M., Evans, Ronald M.
Format: Article
Language:English
Subjects:
Adipocytes
Adipose tissues
Biological Sciences
Insulin
Insulin resistance
Ligands
Lipid metabolism
Macrophages
Muscles
Sensitization
Transgenes
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Summary:Although peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ 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, PPARγ activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARγ-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 PPARγ is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARγ modulators in diabetic therapy.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0912487106