Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells.
Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells.
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发表时间：
1996-11
影响因子：
3.6
通讯作者：
J. Gimble;J. Gimble;C. E. Robinson;C. E. Robinson;Xiying Wu;K. Kelly;K. Kelly;Brenda R. Rodriguez;S. Kliewer;J. Lehmann;D. Morris
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作者：
J. Gimble;J. Gimble;C. E. Robinson;C. E. Robinson;Xiying Wu;K. Kelly;K. Kelly;Brenda R. Rodriguez;S. Kliewer;J. Lehmann;D. Morris
噻唑烷二酮类化合物在动物模型中改善胰岛素敏感性，有望成为有效的口服抗糖尿病药物。它们的临床使用受到限制，因为由此产生的贫血和心脏肥大。据报道，这类化合物中的一些化合物可诱导动物骨髓脂肪蓄积，这种作用可解释观察到的贫血。我们研究了导致这种现象的生物学机制。噻唑烷二酮类化合物BRL 49653和吡格列酮以剂量和时间依赖性方式诱导BMS 2骨髓基质细胞系中的脂肪细胞分化。糖皮质激素和其他成脂激动剂的存在进一步增强了这些作用。噻唑烷二酮类增加脂肪细胞特异性基因的mRNA水平，包括其受体过氧化物酶体增殖物激活受体-γ（PPAR γ）的mRNA水平。相比之下，编码其他PPAR家族成员（PPARalpha、PPARdelta或NUC-1）的基因的mRNA水平不变或降低。噻唑烷二酮处理的原代骨髓基质细胞引起了相当的剂量依赖性反应。使用多克隆抗体，在来自富含脂肪的骨髓的蛋白质裂解物中检测到PPAR γ。因此，噻唑烷二酮直接调节骨髓基质细胞分化，诱导的过氧化物酶体增殖物激活受体γ表达可能在这一过程中发挥关键的调节作用。
The thiazolidinediones improve insulin sensitivity in animal models and have promise as potent oral antidiabetic agents. Their clinical use has been limited because of the resulting anemia and cardiac hypertrophy. Some compounds of this class have been reported to induce bone marrow fat accumulation in animals, and this effect could account for the observed anemia. We examined the biological mechanism contributing to this phenomenon. The thiazolidinediones BRL49653 and pioglitazone induced adipocyte differentiation in the BMS2 bone marrow stromal cell line in a dose- and time-dependent manner. These actions were further enhanced by the presence of glucocorticoids and other adipogenic agonists. The thiazolidinediones increased the mRNA levels of adipocyte-specific genes, including that of their receptor, the peroxisome proliferator-activated receptor-gamma (PPAR gamma). In contrast, mRNA levels of genes encoding other PPAR family members (PPAR alpha, PPAR delta, or NUC-1) were unchanged or decreased. Thiazolidinedione treatment of primary bone marrow stromal cells elicited a comparable dose-dependent response. Using a polyclonal antibody, PPAR gamma was detected in protein lysates from adipose-rich bone marrow. Thus, thiazolidinedione directly regulates bone marrow stromal cell differentiation; induced PPAR gamma expression may play a key regulatory role in this process.