Introduction and Objective: Adipose tissue (AT) immunoregulatory T cells (Tregs) are major determinants of systemic metabolism. In the lean phenotype, Tregs protect against inflammation and maintain homeostasis in AT. However, their abundance profoundly decreases in obesity, leading to inflammation, insulin resistance, and other inflammation-driven comorbidities. The transcription factor forkhead box protein P3 (Foxp3) is essential for the abundance and function of Tregs. Distinct global DNA methylation patterns at the Foxp3 locus have been associated with obesity and diabetes in humans; however, whether such changes could be triggered in AT Tregs to cause their dramatic decrease in obesity remains unclear.Methods: We performed targeted bisulfite sequencing of Foxp3 locus and gene expression analysis of visceral adipose tissue (VAT) and peripheral blood Tregs isolated from individuals with obesity. Then to elucidate whether increased DNA methylation is causal in AT inflammation, a novel mouse model was created by deleting DNMT3A, a major de novo DNA methylation enzyme, specifically in Tregs.Results: VAT Tregs isolated from individuals with obesity had 50% higher Foxp3 methylation compared to those isolated from peripheral blood and had increased expression of Dnmt3a compared to lean subjects. Consistently, Dnmt3afl/flFoxp3cre mice were protected from high-fat diet-mediated loss of AT Tregs, AT inflammation, and metabolic complications such as systemic insulin resistance and fatty liver disease.Conclusion: Exploring these mechanisms of AT Treg loss and its potential reversibility will allow the development of new strategies to prevent AT inflammation and other comorbidities of obesity.
D. Shantaram: None. J.Z. Liu: None. V.P. Wright: None. A. Amari: None. X.Y. Rima: None. D. Roy: None. D. Bradley: Advisory Panel; Madrigal Pharmaceuticals, Inc. H.E. Ghoneim: None. W. Hsueh: None.
American Diabetes Association (1-16-ICTS-049); National Institutes of Health (1R56AI157202-01A1)
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