p38α Deficiency in T Cells Ameliorates Diet-Induced Obesity, Insulin Resistance, and Adipose Tissue Senescence.

Abstract

Adipose tissue-resident T cells play vital roles in regulating inflammation and metabolism in obesity, but the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding enhances p38 activity in adipose-resident T cells. T cell-specific deletion of p38α, an essential subunit of p38 expressed in most immune cells, protected mice from HFD-induced obesity, hepatic steatosis, adipose tissue inflammation, and insulin resistance. Mice with p38α deletion in T cells exhibited higher energy expenditure. Mechanistically, p38α promoted T-cell glycolysis through mechanistic target of rapamycin signaling, leading to enhanced Th1 differentiation. Accordingly, genetic deletion of p38α alleviated ongoing diet-induced obesity. Unexpectedly, p38α signaling in T cells promoted adipose tissue senescence during obesity and aging. Taken together, our results identify p38α in T cells as an essential regulator of obesity, insulin resistance, and adipose tissue senescence, and p38α may be a therapeutic target for obese- or aging-associated diseases.