Troglitazone inhibits the expression of inducible nitric oxide synthase in adipocytes in vitro and in vivo study in 3T3-L1 cells and Otsuka Long-Evans Tokushima Fatty rats.
The aim of this study was to determine the mechanism of troglitazone action on nitric oxide (NO) production via inducible NO synthase (iNOS) in adipocytes in vitro and in vivo. The treatment of 3T3-L1 adipocytes with the combination of lipopolysaccharide (LPS), tumor necrosis factor-alpha and interferon-gamma synergistically induced de novo iNOS expression leading to enhanced NO production. The NO production was inhibited by co-treatment with aminoguanidine or N-nitro-L-arginine methylester hydrochloride. Troglitazone inhibited the NO production in a dose dependent manner by the suppression of iNOS expression. In the 24 week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, the mean weight and the blood glucose were 21% and 30%, respectively, higher than in their lean counterparts. The serum nitrite concentration was increased after injection of LPS (4 mg/kg, i.p.), more markedly in OLETF rats than in the lean rats. The epididymal fats from LPS-injected groups, but not the ones from the non-injected groups, expressed mRNA and protein of iNOS. Troglitazone pre-treatment blocked the LPS-induced expression of iNOS in adipose tissue and the increase in serum nitrite concentration. These results suggest that troglitazone inhibits the cytokine-induced NO production in adipocytes by blocking iNOS expression both in vitro and in vivo.
Dobashi
K
K
Department of Pediatrics, Yamanashi Medical University, Japan. kdobashi@res.yamanashi-med.ac.jp
Asayama
K
K
Nakane
T
T
Kodera
K
K
Hayashibe
H
H
Nakazawa
S
S
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D000818:Animals; D002454:Cell Differentiation; D002839:Chromans / Q000494:pharmacology*; D004926:Escherichia coli; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000032:analysis; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002839:Chromans; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D009573:Nitrites; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D000077288:Troglitazone