title: 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.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Fabrizi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchetti
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mavilio
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Marino
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Casagrande
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavalera
authors.affiliation: University 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.
authors.forename: Josè Maria
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mezza
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, ItalyDiabetic Care Clinics, Associazione dei Cavalieri Italiani del Sovrano Militare Ordine di Malta (ACI SMOM), Rome, Italy.
authors.forename: Gian Pio
authors.initials: GP
authors.lastname: Sorice
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Fiorentino
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Università Cattolica del Sacro Cuore, Rome, ItalyFondazione Don Gnocchi, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giaccari
authors.affiliation: University 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.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernandez Real
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome, ItalyCenter for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, Rome, Italy federicm@uniroma2.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007333:Insulin Resistance / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008066:Lipolysis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory; D015854:Up-Regulation; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007378:Interleukins; D012333:RNA, Messenger; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4