JCI Insight (Feb 2021)

Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

  • Lisa Y. Beppu,
  • Raja Gopal Reddy Mooli,
  • Xiaoyao Qu,
  • Giovanni J. Marrero,
  • Christopher A. Finley,
  • Allen N. Fooks,
  • Zachary P. Mullen,
  • Adolfo B. Frias Jr.,
  • Ian Sipula,
  • Bingxian Xie,
  • Katherine E. Helfrich,
  • Simon C. Watkins,
  • Amanda C. Poholek,
  • Sadeesh K. Ramakrishnan,
  • Michael J. Jurczak,
  • Louise M. D’Cruz

Journal volume & issue
Vol. 6, no. 3

Abstract

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Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell–derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+Foxp3+ regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet–fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10–deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1–deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1–regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.

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