IL-21 Is a Major Negative Regulator of IRF4-Dependent Lipolysis Affecting Tregs in Adipose Tissue and Systemic Insulin Sensitivity
- Marta Fabrizi1,
- Valentina Marchetti1,
- Maria Mavilio1,
- Arianna Marino1,
- Viviana Casagrande1,
- Michele Cavalera1,
- Josè Maria Moreno-Navarrete2,
- Teresa Mezza3,
- Gian Pio Sorice3,4,
- Loredana Fiorentino1,
- Rossella Menghini1,
- Renato Lauro1,
- Giovanni Monteleone1,
- Andrea Giaccari3,5,
- José Manuel Fernandez Real2 and
- Massimo Federici1,6⇑
- 1Department of Systems Medicine, University of Rome “Tor Vergata,” Rome, Italy
- 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
- 3Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy
- 4Diabetic Care Clinics, Associazione dei Cavalieri Italiani del Sovrano Militare Ordine di Malta (ACI SMOM), Rome, Italy
- 5Fondazione Don Gnocchi, Milan, Italy
- 6Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, Rome, Italy
- Corresponding author: Massimo Federici, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0939/-/DC1.
See accompanying article, p. 1838.
- Received June 15, 2013.
- Accepted January 8, 2014.
- © 2014 by the American Diabetes Association.
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