Skurk Thomas, Birgel Michael, Lee Yu-Mi, Hauner Hans
Else Kröner-Fresenius-Center for Nutritional Medicine, Technical University Munich, D-85350 Freising/Weihenstephan, Germany.
Metabolism. 2006 Mar;55(3):309-16. doi: 10.1016/j.metabol.2005.09.004.
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.
曲格列酮是噻唑烷二酮类药物的一种，这类药物被认为是胰岛素增敏剂。给予这些化合物可改善2型糖尿病患者的胰岛素抵抗，但也可能促进体重增加。其主要作用部位是脂肪组织，在那里曲格列酮与核受体过氧化物酶体增殖物激活受体γ2结合并激活它。本研究的目的是调查曲格列酮是否能够影响肿瘤坏死因子α（TNF-α）和转化生长因子β（TGF-β）在脂肪组织中的表达及功能。TNF-α和TGF-β均在体外阻断脂肪分化，并导致脂肪分化的标志物酶——甘油-3-磷酸脱氢酶活性分别显著降低69%±11%和75%±15%。添加2μmol/L曲格列酮可显著降低这两种细胞因子对甘油-3-磷酸脱氢酶活性的抑制作用。在新鲜分离的脂肪细胞中，TNF-α使过氧化物酶体增殖物激活受体γ信使核糖核酸（mRNA）减少。曲格列酮完全抵消了这种作用，而TGF-β对过氧化物酶体增殖物激活受体γ mRNA没有直接影响。此外，单独使用曲格列酮可呈时间和剂量依赖性地促进脂肪分化。与未处理的培养物相比，发现曲格列酮处理可使人类前脂肪细胞中TNF-α mRNA表达显著降低至54%±13%。此外，观察到曲格列酮可部分拮抗TNF-α对新分化的人类脂肪细胞中胰岛素刺激的2-脱氧葡萄糖摄取的抑制作用。总之，曲格列酮在人类前脂肪细胞中发挥强大的成脂活性，这可能是通过抑制TNF-α的内源性产生以及抵消TGF-β的抗成脂作用来介导的。此外，曲格列酮改善了分化脂肪细胞中胰岛素刺激的葡萄糖摄取。
