Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established. Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8 + T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients. Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function. Synopsis The p38 pathway regulates T cell-mediated adipose tissue inflammation and browning via IL-35. Lack of p38 activation in T cells increases IL-35, thereby inducing thermogenesis and reducing inflammation. T cell-specific deletion of p38 activators protects against diet-induced obesity, improves metabolic profiles, and enhances browning and thermogenesis. The p38 pathway plays a pivotal role in regulating T cell-mediated adipose tissue inflammation and browning. IL-35 is a significant driver of adipocyte thermogenesis and suppression of adipose tissue inflammation. The p38 pathway controls IL-35 expression in human and mouse regulatory T cells through mTOR pathway activation. The p38 pathway regulates T cell-mediated adipose tissue inflammation and browning via IL-35. Lack of p38 activation in T cells increases IL-35, thereby inducing thermogenesis and reducing inflammation.