Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis
Lisa Y. Beppu, … , Michael J. Jurczak, Louise M. D’Cruz
Lisa Y. Beppu, … , Michael J. Jurczak, Louise M. D’Cruz
Published December 22, 2020
Citation Information: JCI Insight. ;6(3):e140644. https://doi.org/10.1172/jci.insight.140644.
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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 4

Loss of Blimp-1 expression by Tregs decreases fat mass and increases insulin sensitivity.

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Loss of Blimp-1 expression by Tregs decreases fat mass and increases ins...
Male Foxp3-YFP-Cre+ (WT) and Blimp-1fl/fl mice crossed to Foxp3-YFP-Cre+ (CKO) were placed on SFD and analyzed at 26–28 weeks of age. (A) Bar graphs indicating BW of 26- to 28-week-old SFD-fed WT and CKO mice. (B) Bar graph showing fasting plasma insulin levels in SFD-fed WT and CKO mice. (C) Bar graph showing fasting blood glucose levels in SFD-fed WT and CKO mice. (D and E) 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. (F) An i.p. ITT was performed on WT and CKO mice. The graph indicates blood glucose levels in mice over time after i.p. insulin injection. Bar graph indicates the AUC for both groups. (G) Gross appearance, iWAT, epididymal VAT, and livers of SFD-fed WT and CKO mice. (H) Photographs and quantification of the colon length in WT and CKO mice. (I) Graph showing BW and lean and fat mass in grams of WT and CKO mice as measured by EchoMRI. (J–L) Food intake in grams per kilogram LM, total activity in meters, and RER in light, dark, and total as measured by Promethion Multiplexed Metabolic Cage System during 48-hour total duration. Data are presented as means ± SEM and are from 2–3 independent experiments with 3–29 mice, where each dot represents 1 mouse, and an unpaired 2-tailed Student’s t test or 1-way ANOVA was performed to determine significance. *P value of less than 0.05.