IL-21 is a major negative regulator of IRF4-dependent lipolysis affecting Tregs in adipose tissue and systemic insulin sensitivity

Obesity elicits immune cells infiltration of adipose tissue provoking chronic low-grade inflammation. Regulatory T cells (Tregs) are specifically reduced in adipose tissue of obese animals. Since Interleukin 21 (IL-21) plays an important role in inducing and maintaining immune-mediated chronic inflammatory processes and negatively regulates Tregs differentiation/activity we hypothesized that it could play a role in obesity-induced insulin resistance.We found IL-21 and IL-21R mRNA expression up-regulated in adipose tissue of high fat diet WT mice and in stromal-vascular fraction from human obese subjects in parallel to macrophage and inflammatory markers. Interestingly a larger infiltration of Treg cells was seen in the adipose tissue of IL-21 knockout (IL-21 KO) mice compared to WT animals fed both ND and HFD.In a context of diet-induced obesity, IL-21 KO mice, when compared to WT animals, exhibited lower body weight improved insulin sensitivity and decreased adipose and hepatic inflammation. This metabolic phenotype is accompanied by an higher induction of IRF4, a transcriptional regulator of fasting lipolysis in adipose tissue. Our data suggest that IL-21 exerts negative regulation on IRF4 and Tregs activity, developing and maintaining adipose tissue inflammation in the obesity state.