Ivana Nikolić, Irene Ruiz-Garrido, María Crespo, Rafael Romero-Becerra, Luis Leiva-Vega, Alfonso Mora, Marta León, Elena Rodríguez, Magdalena Leiva, Ana Belén Plata-Gómez, Maria Beatriz Alvarez Flores, Jorge L Torres, Lourdes Hernández-Cosido, Juan Antonio López, Jesús Vázquez, Alejo Efeyan, Pilar Martin, Miguel Marcos & Guadalupe Sabio.

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.

Reduction of fat mass of mice lacking MKK3/6 as seen by MRI (Image: Ivana Nikolić).

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.