TIMP3 overexpression in macrophages protects from insulin resistance, adipose inflammation, and nonalcoholic fatty liver disease in mice.
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.
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Rossella
R
Menghini
Viviana
V
Casagrande
Stefano
S
Menini
Arianna
A
Marino
Valeria
V
Marzano
Marta L
ML
Hribal
Paolo
P
Gentileschi
Davide
D
Lauro
Orazio
O
Schillaci
Giuseppe
G
Pugliese
Paolo
P
Sbraccia
Andrea
A
Urbani
Renato
R
Lauro
Massimo
M
Federici
D000273:Adipose Tissue / Q000473:pathology*; D050154:Adiposity; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000517:prevention & control*; D019788:Fluorodeoxyglucose F18; D007249:Inflammation / Q000517:prevention & control; D007333:Insulin Resistance; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000502:physiology*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D019788:Fluorodeoxyglucose F18; D012333:RNA, Messenger; D019717:Tissue Inhibitor of Metalloproteinase-3; C081026:CD68 protein, mouse; D000097382:CD68 Molecule