TIMP3 Overexpression in Macrophages Protects From Insulin Resistance, Adipose Inflammation, and Nonalcoholic Fatty Liver Disease in Mice

• DOI: 10.2337/db11-0613
• Publication Date: 2012-01-07T06:04:54Z
• Authors: Rossella Menghini; Viviana Casagrande; Stefano Menini; Arianna Marino; Valeria Marzano; Marta L. Hribal; Paolo Gentileschi; Davide Lauro; Orazio Schillaci; Giuseppe Pugliese; Paolo Sbraccia; Andrea Urbani; Renato Lauro; Massimo Federici
• Keywords: Inflammation; Tissue Inhibitor of Metalloproteinase-3; 0301 basic medicine; 570; Macrophages; Settore MED/09 - MEDICINA INTERNA; 610; Antigens, Differentiation, Myelomonocytic; Settore MED/49 - SCIENZE TECNICHE DIETETICHE APPLICATE; Diet, High-Fat; Pathophysiology; Fatty Liver; Mice; 03 medical and health sciences; Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA; Adipose Tissue; Antigens, CD; Fluorodeoxyglucose F18; Non-alcoholic Fatty Liver Disease; Animals; Obesity; RNA, Messenger; Insulin Resistance; Adiposity

The tissue inhibitor of metalloproteinase (TIMP)3, a stromal protein that restrains the activity of proteases and receptors, is reduced in inflammatory metabolic disorders such as type 2 diabetes mellitus (T2DM) and atherosclerosis. We overexpressed Timp3 in mouse macrophages (MacT3) to analyze its potential antidiabetic and antiatherosclerotic effects. Transgenic mice with myeloid cells targeting overexpression of TIMP3 were generated and fed a high-fat diet for 20 weeks. Physical and metabolic phenotypes were determined. Inflammatory markers, lipid accumulation, and insulin sensitivity were measured in white adipose tissue (WAT), liver, and skeletal muscle. In a model of insulin resistance, MacT3 mice were more glucose tolerant and insulin sensitive than wild-type mice in both in vitro and in vivo tests. Molecular and biochemical analyses revealed that increased expression of TIMP3 restrained metabolic inflammation and stress-related pathways, including Jun NH2-terminal kinase and p38 kinase activation, in WAT and liver. TIMP3 overexpression in macrophages resulted in reduced activation of oxidative stress signals related to lipid peroxidation, protein carbonylation, and nitration in WAT and liver. Our data show that macrophage-specific overexpression of TIMP3 protects from metabolic inflammation and related metabolic disorders such as insulin resistance, glucose intolerance, and nonalcoholic steatohepatitis.