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”, 00133 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, ACI SMOM, Rome, Italy
- 5Fondazione Don Gnocchi, Milan, Italy
- 6Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, 00133 Rome, Italy.
- #Address correspondence to: Massimo Federici, E-mail:
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.
- Received June 15, 2013.
- Accepted January 8, 2014.
- © 2014 by the American Diabetes Association.
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