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

Nature. 2012 Jun 28;486(7404):549-53. doi: 10.1038/nature11132.


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.

Publication types

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

MeSH terms

  • Adipose Tissue / cytology*
  • Adipose Tissue / immunology
  • Adipose Tissue / pathology
  • Animals
  • Cell Differentiation
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Epididymis / cytology
  • Epididymis / immunology
  • Forkhead Transcription Factors / metabolism
  • Gene Expression
  • Hypoglycemic Agents / pharmacology
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Insulin Resistance / physiology
  • Lymphocyte Count
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / metabolism
  • Obesity / pathology
  • PPAR gamma / metabolism*
  • Phenotype
  • Pioglitazone
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism*
  • Thiazolidinediones / pharmacology
  • Transcription, Genetic


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hypoglycemic Agents
  • PPAR gamma
  • RNA, Messenger
  • Thiazolidinediones
  • Pioglitazone

Associated data

  • GEO/GSE37532
  • GEO/GSE37533
  • GEO/GSE37534
  • GEO/GSE37535