ALTERED GENE-EXPRESSION FOR TUMOR-NECROSIS-FACTOR-ALPHA AND ITS RECEPTORS DURING DRUG AND DIETARY MODULATION OF INSULIN-RESISTANCE
ALTERED GENE-EXPRESSION FOR TUMOR-NECROSIS-FACTOR-ALPHA AND ITS RECEPTORS DURING DRUG AND DIETARY MODULATION OF INSULIN-RESISTANCE
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DOI：
10.1210/en.134.1.264
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发表时间：
1994-01-01
期刊：
影响因子：
4.8
通讯作者：
SPIEGELMAN, BM
中科院分区：
文献类型：
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作者：
HOFMANN, C;LORENZ, K;SPIEGELMAN, BM
由于肥胖是非胰岛素依赖型糖尿病的主要危险因素，脂肪组织可能会产生一种影响多种靶组织胰岛素活性的介质。最近的证据表明，一种细胞因子，肿瘤坏死因子- α (TNF α)可能起着这种作用。本研究探讨肿瘤坏死因子α及其受体的表达是否在药物治疗过程中被调节以降低胰岛素抵抗。通过饮食限制适度减肥的效果也进行了研究。我们在这里表明，与非糖尿病小鼠相比，肥胖相关糖尿病小鼠模型（KKA(y)）的脂肪组织中出现了TNF α mRNA的显著诱导（C57）。同样，编码TNF R2受体的RNA转录本（p75）在肥胖糖尿病动物的脂肪组织中显著增加。在这些糖尿病动物的肌肉中，编码TNF R1 （p55）和R2的RNA转录本显著升高，尽管R2转录本丰度的升高程度低于脂肪。我们还观察到，通过使用胰岛素增敏剂吡格列酮治疗糖尿病动物，TNF α及其两种受体mRNA的过表达至少可以部分正常化。通过食物限制治疗肥胖糖尿病动物可降低肌肉中TNF R2 mRNA的表达，但不影响脂肪。这些结果清楚地表明，TNF系统的基因表达可以通过胰岛素增敏药物和减轻体重来调节。这些发现支持这种细胞因子在胰岛素抵抗型糖尿病状态中的作用，并显示其通过逆转疾病的治疗进行调节。
As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKA(y)) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.