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PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells.

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 inflammation. 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 sensitivity. 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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  • Authors

    Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D

    Institution

    Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

    Source

    Nature 486:7404 2012 Jun 28 pg 549-53

    MeSH

    Adipose Tissue
    Animals
    Cell Differentiation
    Diabetes Mellitus, Type 2
    Epididymis
    Forkhead Transcription Factors
    Gene Expression
    Hypoglycemic Agents
    Inflammation
    Insulin Resistance
    Lymphocyte Count
    Male
    Mice
    Mice, Inbred C57BL
    Mice, Obese
    Obesity
    PPAR gamma
    Phenotype
    RNA, Messenger
    T-Lymphocytes, Regulatory
    Thiazolidinediones
    Transcription, Genetic

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22722857