Inflammation and insulin resistance in aging - Aging (referring to middle age) is commonly associated with visceral adiposity and insulin resistance. Impaired white adipose tissue (AT) “browning” and reduced energy expenditure that also occur in aging may contribute to age-linked adiposity, yet how AT browning and metabolism are regulated with age remains incompletely understood. AT inflammation, including T cell–related inflammation, has been implicated in metabolic dysfunction in obesity. Conventional T cells (Tcn) are elevated and promote inflammation in obese AT, whereas regulatory T cells (Treg) are enriched in lean AT and markedly reduced in obese AT. AT (fat) Treg (fTreg) protect against inflammation and insulin resistance in obesity. With aging, Tcn are also elevated in AT; but unlike in obesity, in aging fTreg are elevated and may promote adiposity and insulin resistance. The mechanism for the difference in fTreg in aging and obesity and the role of Tcn in age-linked metabolic functions are largely unknown. In our pilot study, despite increased number, fTreg in aging mice were dysfunctional and impaired in repressing Tcn proliferation, and Tcn (elevated in AT with age) inhibited adipocyte browning (both by direct contact with adipocytes and through secreted molecules). Thus, we hypothesize that fTreg dysfunction with Tcn inflammation plays a pivotal role in age-linked adiposity and insulin resistance via adverse regulation of AT browning and metabolism. Mechanistically, STAT1, a key transcription factor for Treg regulation and Tcn inflammation, was elevated and activated in AT T cells (which include Treg and Tcn) of aging mice and increased in human AT with age; and, importantly, STAT1 ablation in T cells in mice improved age-linked fTreg functions, reduced AT Tcn inflammation, and prevented adiposity, with increased AT browning and energy expenditure, and improved insulin sensitivity, supporting a pivotal role of STAT1 in age-linked fTreg dysfunction, Tcn inflammation, and adiposity. In this application, we propose to examine further the role and mechanism of T cells including Tcn and fTreg in age-linked inflammation and metabolic functions in three aims: aim 1 will examine how Tcn (direct drivers of inflammation) contribute to AT inflammation and metabolic functions with age in mice and by tissue culture; aim 2 will examine how Treg (regulators of inflammation) contribute to AT inflammation and metabolic functions with age in mice; aim 3 will examine effects of dietary and pharmacologic inhibition of the STAT1 pathway on age-linked fTreg function, inflammation, and metabolic functions in mice. Several novel mouse models generated in PI's lab and human AT specimens, with flow cytometry, quantitative PCR, RNA-seq, whole-body and tissue- specific metabolic assays, and other techniques, will be used. Our proposal aims to reveal how T cells, including Tcn and fTreg, contribute to AT inflammation and metabolic functions in aging and may help develop novel therapies to mitigate age-related inflammation and prevent metabolic disease with aging.
