Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α -: Implications for insulin resistance
Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α -: Implications for insulin resistance
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DOI：
10.2337/diabetes.51.11.3176
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发表时间：
2002-11-01
期刊：
影响因子：
7.7
通讯作者：
Lodish, HF
中科院分区：
文献类型：
--
作者：
Ruan, H;Miles, PDG;Lodish, HF
尽管大量研究表明肿瘤坏死因子-α是导致胰岛素抵抗的原因之一，但肿瘤坏死因子-α改变体内能量代谢的机制(S)以及肿瘤坏死因子-α作用的组织特异性尚不清楚。在这里，我们研究了输注肿瘤坏死因子-α对成年大鼠基因表达和能量代谢的影响。1天的肿瘤坏死因子-α治疗降低了总体的胰岛素敏感性，并导致血浆游离脂肪酸水平增加了70%(P=0.005)，ACRP30下降了46%(P=0.01)。注射4d的肿瘤坏死因子-α导致胰岛素抵抗，血浆游离脂肪酸和甘油三酯水平显著升高，ACRP30水平降低。输注肿瘤坏死因子-α4d后，血糖浓度无明显变化。寡核苷酸芯片显示，肿瘤坏死因子-α引起脂肪细胞基因表达的重大而快速的变化，有利于FFA的释放和细胞因子的产生，而对肝脏基因表达的影响较小，但有利于FFA和胆固醇的合成以及VLDL的产生。对骨骼肌基因表达只有适度的抑制作用。我们证明，肿瘤坏死因子-α至少部分地通过调节脂肪细胞基因的表达来拮抗胰岛素的作用，包括减少ACRP30基因的表达和诱导脂解导致血浆游离脂肪酸的增加。后来，肿瘤坏死因子-α改变了与胰岛素抵抗表型非常相似的全身能量稳态。我们的数据表明，阻断脂肪组织中肿瘤坏死因子-α的作用可能会在体内阻止肿瘤坏死因子-α诱导的胰岛素抵抗。
Despite extensive studies implicating tumor necrosis factor (TNF)-alpha as a contributing cause of insulin resistance, the mechanism(s) by which TNF-alpha alters energy metabolism in vivo and the tissue specificity of TNF-alpha action are unclear. Here, we investigated the effects of TNF-alpha infusion on gene expression and energy metabolism in adult rats. A 1-day TNF-alpha treatment decreased overall insulin sensitivity and caused a 70% increase (P = 0.005) in plasma levels of free fatty acids (FFAs) and a 46% decrease (P = 0.01) in ACRP30. A 4-day TNF-a infusion caused insulin resistance and significant elevation of plasma levels of FFAs and triglycerides and reduction of ACRP30. Plasma glucose concentration was not altered following TNF-alpha infusion for up to 4 days. As revealed by oligonucleotide microarrays, TNF-alpha evoked major and rapid changes in adipocyte gene expression, favoring FFA release and cytokine production, and fewer changes in liver gene expression, but favoring FFA and cholesterol synthesis and VLDL production. There was only a moderate repressive effect on skeletal muscle gene expression. We demonstrate that TNF-alpha antagonizes the actions of insulin, at least in part, through regulation of adipocyte gene expression including reduction in ACRP30 mRNA and induction of lipolysis resulting in increased plasma FFAs. TNF-alpha later alters systemic energy homeostasis that closely resembles the insulin resistance phenotype. Our data suggest that blockade of TNF-alpha action in adipose tissue may prevent TNF-alpha-induced insulin resistance in vivo.