Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

• Published in: International Journal of Obesity Vol. 42; no. 8; pp. 1458 - 1470
• Main Authors: Becerril, S, Rodríguez, A, Catalán, V, Méndez-Giménez, L, Ramírez, B, Sáinz, N, Llorente, M, Unamuno, X, Gómez-Ambrosi, J, Frühbeck, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 38/39; 38/90; 42/89; 631/208; 631/443/319; 64/110; 82/80; 96/21; 96/63; Adipocytes; Adipose tissue; Animal models; Collagen; Disruption; Epidemiology; Extracellular matrix; Fibrosis; Gene expression; Genes; Health aspects; Health Promotion and Disease Prevention; Impact analysis; Infiltration; Inflammation; Insulin; Internal Medicine; Leptin; Macrophages; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic rate; Mice; Nitric oxide; Nitric-oxide synthase; Nitrogen oxides; Obesity; Phenotypes; Proteins; Public Health; Risk factors; Rodents; Secretion; Synthesis; Tenascin; Tenascin C; Tumor necrosis factor
• ISSN: 0307-0565; 1476-5497; 1476-5497
• DOI: 10.1038/s41366-018-0005-5

Background/Objectives: Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase ( iNOS ), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. Subjects/Methods: The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg −1 day −1 ) and pair-fed]. Results: Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf , Emr1 , Hif1a , Col6a1 , Col6a3, and Tnc , as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Conclusions: Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.