Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity

Abstract

Abstract Visceral adipose tissue regulatory T cells (VAT Tregs) protect against systemic inflammation and metabolic disease by limiting expansion of pro-inflammatory Th1 cells and M1 macrophages, and by preserving insulin sensitivity and glucose tolerance. Although their basic markers and roles have been studied, less is known about the transcriptional machinery regulating their differentiation and function. B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional regulator known to be involved in the development, polarization, and maintenance of various immune cells including CD4+ T cells. Using Blimp-1 reporter mice, we discovered that Blimp-1 is constitutively expressed in a subset of VAT Tregs compared to lymphoid Tregs, and that Blimp-1+ VAT Tregs are phenotypically distinct from their Blimp-1− counterparts. Blimp-1 is not required for VAT Treg development, however Treg-specific deletion of Blimp-1 led to unique changes in VAT Treg markers in lean versus obese adipose tissue. In addition, Blimp-1 knockout mice fed high fat diet had fewer adipose-resident NK cells and increased CD8 T cells. Surprisingly, loss of Blimp-1+ Tregs led to less adipose tissue IL-10, increased expression of thermogenic genes, reduced body fat, decreased weight, and improved insulin sensitivity. Based on these data, we hypothesize that Blimp-1+ Treg dependent IL-10 production suppresses adipocyte beiging, and that loss of these cells results in increased thermogenesis, greater weight loss and improved insulin sensitivity in obese mice.