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

  1. Massimo Federici1,6
  1. 1Department of Systems Medicine, University of Rome “Tor Vergata,” Rome, Italy
  2. 2University Department of Diabetes, Endocrinology and Nutrition, University Hospital of Girona “Dr. Josep Trueta,” Institut d’Investigació Biomédica de Girona IdibGi, and CIBER Fisiopatología de la Obesidad y Nutrición, Girona, Spain
  3. 3Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy
  4. 4Diabetic Care Clinics, Associazione dei Cavalieri Italiani del Sovrano Militare Ordine di Malta (ACI SMOM), Rome, Italy
  5. 5Fondazione Don Gnocchi, Milan, Italy
  6. 6Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, Rome, Italy
  1. Corresponding author: Massimo Federici, federicm{at}


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.


  • Received June 15, 2013.
  • Accepted January 8, 2014.

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