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, Zackary 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
Lisa Y. Beppu, Raja Gopal Reddy Mooli, Xiaoyao Qu, Giovanni J. Marrero, Christopher A. Finley, Allen N. Fooks, Zackary 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
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Research Article Endocrinology Immunology

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

Abstract

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.

Authors

Lisa Y. Beppu, Raja Gopal Reddy Mooli, Xiaoyao Qu, Giovanni J. Marrero, Christopher A. Finley, Allen N. Fooks, Zackary 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

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Figure 6

Blimp-1 deficiency on short-term HFD is protective and increases beige gene expression in adipocytes.

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Blimp-1 deficiency on short-term HFD is protective and increases beige g...
Eight-week-old male Foxp3-YFP-Cre+ (WT) and Blimp-1fl/fl mice crossed to Foxp3-YFP-Cre+ (CKO) were placed on 60% HFD for 3 weeks prior to metabolic analysis. (A) Bar graphs indicating body weight of 11-week-old HFD-fed WT and CKO mice. (B) Bar graph showing fasting plasma insulin levels in WT and CKO mice. (C) Bar graph showing fasting blood glucose levels in WT and CKO mice. (D) Bar showing the HOMA-IR in WT and CKO mice. (E and F) An i.p. GTT was performed on WT and CKO mice. The graphs indicate plasma insulin and blood glucose levels in mice over time after glucose injection. Bar graphs indicate the AUC for both groups. (G) Bar graphs indicating the percentage of CD4+Foxp3+ cells in the VAT, iWAT, BAT, inguinal lymph nodes (iLNs), and spleen from short-term HFD-fed WT and CKO mice. Bar graphs also showing expression of ST2, CCR2, and KLRG1 on gated CD4+Foxp3+ cells in the indicated tissue from WT and CKO mice. (H) Bar graph showing relative mRNA expression of the indicated gene from total iWAT and VAT from short-term HFD-fed WT and CKO mice. Values were normalized to β-actin. Each dot represents 1 animal. Data are presented as means ± SEM and are representative of 2 experiments with 2–3 mice per group. An unpaired 2-tailed Student’s t test or 1-way ANOVA was performed to determine significance, and the P values are indicated on the graphs.