IL-21 Is a Major Negative Regulator of IRF4-Dependent Lipolysis Affecting Tregs in Adipose Tissue and Systemic Insulin Sensitivity

Abstract

Obesity elicits immune cell infiltration of adipose tissue provoking chronic low-grade inflammation. Regulatory T cells (Tregs) are specifically reduced in adipose tissue of obese animals. Since interleukin (IL)-21 plays an important role in inducing and maintaining immune-mediated chronic inflammatory processes and negatively regulates Treg differentiation/activity, we hypothesized that it could play a role in obesity-induced insulin resistance. We found IL-21 and IL-21R mRNA expression upregulated in adipose tissue of high-fat diet (HFD) wild-type (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 (KO) mice compared with WT animals fed both normal diet and HFD. In a context of diet-induced obesity, IL-21 KO mice, compared with WT animals, exhibited lower body weight, improved insulin sensitivity, and decreased adipose and hepatic inflammation. This metabolic phenotype is accompanied by a higher induction of interferon regulatory factor 4 (IRF4), a transcriptional regulator of fasting lipolysis in adipose tissue. Our data suggest that IL-21 exerts negative regulation on IRF4 and Treg activity, developing and maintaining adipose tissue inflammation in the obesity state.

Tissue Tregs

“…Other factors reported to influence VAT Treg accumulation include IL-21 (55) and Stat3 (56), both as negative regulators. Interestingly, Helicobacter pylori colonization of lean mice augments the VAT Treg population, diminishes the VAT inflammatory macrophage population, and improves systemic metabolic indices, via a PPARγ-dependent mechanism (57).…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…88 In addition, Kong et al 89 recently reported that IRF4 functions as a dominant transcriptional regulator of thermogenesis via its direct interaction with peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) to effectively enhance downstream antiobesity factors. As a negative mediator of diet-induced metabolic disorder, the increased expression of IRF4 also reasonably explains the antagonistic effect of IL-21 deficiency on metabolic deregulation, 120 potentially benefiting from a mechanism by which IL-21 inhibited the activation of the forkhead box O1 (FoxO1)-IRF4 axis via a fasting signal.…”

IL-21 and IRF4: A Complex Partnership in Immune and Metabolic Regulation

“…In this issue, Fabrizi et al (9) demonstrate that mice lacking Il-21 are protected against high-fat diet–induced metabolic dysfunction. Il-21 is produced by Th17 cells, which in turn promotes expansion of Th17 cells and inhibits induction of Tregs (10).…”

“…Fabrizi et al (9) demonstrate the ability of Il-21 to modulate metabolic homeostasis through inhibition of adipose tissue Tregs and Irf4-mediated lipolysis. However, these findings also raise several unanswered questions.…”