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

Obesity is characterized with low grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis has not been well established. We discovered that p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specific deletion of the p38 activators, MKK3/6, were protected against diet-induced obesity and AT inflammation improving their metabolic profile, higher browning and thermogenesis. We identified IL-35 as a driver of adipocyte thermogenic program through ATF2/UCP1/FGF21 pathway. IL-35 limits CD8⁺T cell infiltration and inflammation in AT. Interestingly, we found that IL35 was reduced in visceral fat from obese patients. Mechanistically we showed 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 and identify p38 and IL-35 as promising targets for metabolic diseases.