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

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

doi:10.1172/jci.insight.140644

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 significant 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 (HFD)-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 (DIO), 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.

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

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

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