Effect of troglitazone on tumor necrosis factor alpha and transforming growth factor beta expression and action in human adipocyte precursor cells in primary culture.
Troglitazone is a member of the class of thiazolidinediones that are known to act as insulin-sensitizing agents. Administration of these compounds ameliorates insulin resistance in type 2 diabetic patients, but may also promote weight gain. The main site of action is adipose tissue, where troglitazone binds to and activates the nuclear receptor peroxisome proliferator-activated receptor gamma2. The aim of this study was to investigate whether troglitazone is able to affect the adipose expression and function of tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta). Both TNF-alpha and TGF-beta blocked adipose differentiation in vitro and led to a marked reduction in glycerol-3-phosphate dehydrogenase activity, a marker enzyme of adipose differentiation, by 69% +/- 11% and 75% +/- 15%, respectively. Addition of 2 mumol/L troglitazone significantly reduced this inhibitory effect of both cytokines on glycerol-3-phosphate dehydrogenase activity. Peroxisome proliferator-activated receptor gamma messenger RNA (mRNA) was reduced by TNF-alpha in freshly isolated adipocytes. This effect was completely counteracted by troglitazone, whereas TGF-beta had no immediate effect on peroxisome proliferator-activated receptor gamma mRNA. Moreover, troglitazone alone promoted adipose differentiation in a time- and dose-dependent manner. Troglitazone treatment was found to result in a marked reduction of TNF-alpha mRNA expression in human preadipocytes to 54% +/- 13% compared with untreated cultures. Furthermore, troglitazone was observed to partially antagonize the inhibitory effect of TNF-alpha on insulin-stimulated 2-deoxy-glucose uptake in newly differentiated human fat cells. In conclusion, troglitazone exerts a potent adipogenic activity in human preadipocytes, which may be mediated by suppression of the endogenous production of TNF-alpha and by counteracting the antiadipogenic effect of TGF-beta. In addition, troglitazone improved insulin-stimulated glucose uptake in differentiated fat cells.
Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University Munich, D-85350 Freising/Weihenstephan, Germany. nutritional.medicine@wzw.tum.de
Thomas
T
Skurk
Michael
M
Birgel
Yu-Mi
YM
Lee
Hans
H
Hauner
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000328:Adult; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002839:Chromans / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000077288:Troglitazone; D005947:Glucose