Abstract
Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation1. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity2. Here we identify peroxisome proliferator-activated receptor (PPAR)-γ, the ‘master regulator’ of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-γ expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends.
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Acknowledgements
We thank A. Rudensky, F. Gonzalez, R. Kahn, B. Spiegelman and D. Vignali for providing materials; K. Hattori, M. Davenport, J. LaVecchio, G. Buruzala, J. Ericson, K. Leatherbee and S. Davis for technical assistance; A. Ergun, A. Morton and J. Shu for experimental help; and M. Wilson and J. Hill for discussions. Supported by grants from the National Institutes of Health (NIH; DK092541) and Ellison Foundation (Boston) to D.M. and C.B., Dana Foundation to D.M. and S.E.S.; the American Diabetes Association (RA 110BS97) to J.L., and the NIH (DK51729) to S.E.S.; as well as by core facilities of the Joslin Diabetes Center (P30DK36836). M.F. received a postdoctoral fellowship from the King Trust.
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All authors designed research; D.C. and A.L. performed research; D.C., S.E.S., C.B. and D.M. analysed data; D.C., C.B. and D.M. wrote the paper.
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D.M., C.B., M.F. and S.E.S. have a patent pending on fat Treg cells.
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Cipolletta, D., Feuerer, M., Li, A. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012). https://doi.org/10.1038/nature11132
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DOI: https://doi.org/10.1038/nature11132
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