PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells.
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.
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Daniela
D
Cipolletta
Markus
M
Feuerer
Amy
A
Li
Nozomu
N
Kamei
Jongsoon
J
Lee
Steven E
SE
Shoelson
Christophe
C
Benoist
Diane
D
Mathis
D000273:Adipose Tissue / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004822:Epididymis / Q000166:cytology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D010641:Phenotype; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077205:Pioglitazone