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.

Phenotypic and Functional Diversity in Regulatory T Cells

“…A recent study linked expression of the activated Treg transcription factor BLIMP1 to the VAT Treg phenotype, including expression of ST2 and KLRG1. Loss of BLIMP1 in Tregs reduced Treg production of IL-10 in VAT ( Beppu et al, 2021 ). While coordination of PPARγ expression and IL-33 sensing stabilizes and scales the VAT Treg compartment, questions remain regarding the requirements for VAT Treg functionality.…”

“…However, deletion of PPARγ also reduced Tregs in subcutaneous adipose tissue ( Bapat et al, 2015 ). The function of Tregs in non-VAT adipose depots is uncertain with some studies observing that Tregs promote metabolic homeostasis ( Medrikova et al, 2015 ; Kalin et al, 2017 ; Fang et al, 2020 ) while others argue that Tregs promote metabolic disorder ( Beppu et al, 2021 ). Regardless of the directionality, it is clear that adipose Tregs are a key regulator of systemic metabolic homeostasis.…”

Benefits of Polyphenols and Methylxanthines from Cocoa Beans on Dietary Metabolic Disorders

“…As we explained, cocoa polyphenols (flavanols) induced an increase in Lactobacilli and Bifidobacteria [ 113 ]. These species influenced the differentiation of the regulatory T cells, a substantial source of Il-10, an anti-inflammatory cytokine which presents anti-obesity actions by suppressing adipocyte energy expenditure, thermogenesis and by reducing insulin resistance [ 114 ]. Consequently, as prebiotics, cocoa flavanols might have immunomodulatory effects by interfering with GM.…”

“… Benefits of polyphenols and methylxanthines on gut microbiota some influence on dietary disorders related to them. ↑ mean an increase in the microorganism content ↓ mean a decrease in the microorganism content [ 73 , 109 , 111 , 113 , 114 , 121 , 122 , 123 , 124 ]. …”

Crosstalk between Metabolic Disorders and Immune Cells

“…FOXP3+ Treg cells secrete IL-13 to stimulate IL-10 production in macrophages, which might be mediated by TGF-β [ 103 , 104 ]. Thus, MHO may be associated with an increased expression of FOXP3, IL-10, and TGF-β [ 105 ]. A recent study illustrated the possibility of activating the TGF-β/BMP signaling pathway in obese individuals without type 2 diabetes, as well as MHO, through the transcription analysis comparing metabolically unhealthy individuals by RNA-seq [ 106 ].…”