Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13079-84. doi: 10.1073/pnas.1311557110. Epub 2013 Jul 22.

Abstract

Dysregulated inflammation in adipose tissue, marked by increased proinflammatory T-cell accumulation and reduced regulatory T cells (Tregs), contributes to obesity-associated insulin resistance. The molecular mechanisms underlying T-cell-mediated inflammation in adipose tissue remain largely unknown, however. Here we show a crucial role for signal transducer and activator of transcription 3 (Stat3) in T cells in skewing adaptive immunity in visceral adipose tissue (VAT), thereby contributing to diet-induced obesity (DIO) and insulin resistance. Stat3 activity is elevated in obese VAT and in VAT-resident T cells. Functional ablation of Stat3 in T cells reduces DIO, improves insulin sensitivity and glucose tolerance, and suppresses VAT inflammation. Importantly, Stat3 ablation reverses the high Th1/Treg ratio in VAT of DIO mice that is likely secondary to elevated IL-6 production, leading in turn to suppression of Tregs. In addition, Stat3 in T cells in DIO mice affects adipose tissue macrophage accumulation and M2 phenotype. Our study identifies Stat3 in VAT-resident T cells as an important mediator and direct target for regulating adipose tissue inflammation, DIO, and its associated metabolic dysfunctions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Blotting, Western
  • Diet, High-Fat / adverse effects
  • Fasting / blood
  • Female
  • Flow Cytometry
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Insulin / blood
  • Insulin Resistance / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Intra-Abdominal Fat / immunology*
  • Intra-Abdominal Fat / metabolism
  • Intra-Abdominal Fat / pathology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / blood
  • Obesity / etiology
  • Obesity / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology*
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism

Substances

  • Blood Glucose
  • Insulin
  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interferon-gamma