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

• Published in: Diabetes (New York, N.Y.) Vol. 63; no. 6; pp. 2086 - 2096
• Main Authors: FABRIZI, Marta, MARCHETTI, Valentina, MENGHINI, Rossella, LAURO, Renato, MONTELEONE, Giovanni, GIACCARI, Andrea, FERNANDEZ REAL, José Manuel, FEDERICI, Massimo, MAVILIO, Maria, MARINO, Arianna, CASAGRANDE, Viviana, CAVALERA, Michele, MORENO-NAVARRETE, Josè Maria, MEZZA, Teresa, SORICE, Gian Pio, FIORENTINO, Loredana
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2014
• Subjects: 3T3-L1 Cells - metabolism; Adipose Tissue - metabolism; Animals; Biological and medical sciences; Blotting, Western; Cells, Cultured; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Flow Cytometry; Genotype & phenotype; Inflammation - immunology; Inflammation - metabolism; Insulin resistance; Insulin Resistance - immunology; Interferon Regulatory Factors - metabolism; Interleukins - genetics; Interleukins - metabolism; Lipolysis - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Obesity; Obesity - immunology; Obesity - metabolism; Receptors, Interleukin-21 - metabolism; RNA, Messenger - metabolism; Rodents; T cell receptors; T-Lymphocytes, Regulatory; Tissues; Up-Regulation; Endocrinopathy; Pancreatic hormone; Sensitivity; Adipose tissue; Diabetes mellitus; Insulin; Lipolysis
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db13-0939

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.