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

  1. Hua Yua,g,1
  1. aDepartment of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute,
  2. bDepartment of Immunology, Beckman Research Institute,
  3. cDepartment of Surgery, City of Hope Medical Center,
  4. dDepartment of Medical Oncology, City of Hope Medical Center,
  5. eDepartment of Molecular Medicine, Beckman Research Institute, and
  6. fDepartment of Diabetes and Metabolic Diseases, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010; and
  7. gCenter for Translational Medicine, Zhangjiang Hi-Tech Park, Shanghai 201203, China

  1. Contributed by Arthur D. Riggs, June 25, 2013 (sent for review April 13, 2013)

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.

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: ariggs{at}coh.org or hyu{at}coh.org.

  • Author contributions: S.J.P. and H.Y. designed research; S.J.P., M.K., S.S., G.A.C., and C.Z. performed research; S.J.P., M.K., S.S., G.A.C., H.L., C.Z., and H.Y. analyzed data; and S.J.P., M.K., S.S., H.L., L.K., J.M., R.J., A.D.R., and H.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1311557110/-/DCSupplemental.

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