TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity
TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity
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DOI：
10.1152/ajpheart.00271.2012
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发表时间：
2012-09-01
影响因子：
4.8
通讯作者：
Lesniewski, Lisa A.
中科院分区：
文献类型：
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作者：
Donato, Anthony J.;Henson, Grant D.;Lesniewski, Lisa A.
Donato AJ，Henson GD，Morgan RG，Enz RA，步行者AE，Lesniewski LA. TNF-α损害饮食诱导肥胖小鼠脂肪组织阻力动脉的内皮功能Am J Physiol Heart Circ Physiol 303：H672-H679，2012年。首次发表于2012年7月20日; doi：10.1152/ajpheart.00271.2012. -我们检验了高脂肪（HF）喂养导致附睾白色脂肪组织（eWAT）阻力动脉内皮功能障碍并由脂肪组织炎症介导的假设。当与正常食物（NC）喂养的小鼠（n = 17）相比时，HF喂养的雄性B6D2F1小鼠通过葡萄糖耐量试验评估为葡萄糖不耐受和胰岛素抵抗（曲线下面积; HF，18，174 +/-1，889 vs. NC，15，814 +/-666 mg. dl（-1）. min（-1）; P <0.05）和稳态模型评估（HF，64.1 +/-4.3 vs. NC，85.7 +/-6.4; P = 0.05）。HF饮食诱导的代谢功能障碍伴随着以更大的巨噬细胞浸润为特征的促炎性eWAT表型（HF，3.9 +/-0.8 vs. NC，0.8 +/-0.4%; P = 0.01）和TNF-α（HF，22.6 +/-4.3 vs. NC，11.4 +/-2.5 pg/dl; P <0.05），并与阻力动脉功能障碍相关，表现为内皮依赖性舒张功能受损（EDD）（最大扩张; HF，49.2 +/-10.7 vs. NC，92.4 +/-1.4%; P <0.01）。通过N-ω-硝基-L-精氨酸甲酯（L-NAME）抑制一氧化氮（NO）合酶减少NC的扩张（28.9 +/-6.3%; P <0.01）-并倾向于减少HF的扩张（29.8 +/-9.9%; P = 0.07）喂养的小鼠，消除NC和HF喂养的小鼠之间eWAT动脉EDD的差异，表明HF喂养后eWAT阻力动脉中NO生物利用度降低。用重组TNF-α（rTNF）体外处理切除的eWAT动脉，在NC（59.7 +/-10.9%）-但不是HF（59.0 +/-9.3%）-喂养的小鼠中损害EDD（P <0.01）。在rTNF处理的NC（21.9 +/-6.4%）和HF（29.1 +/-9.2%）喂养小鼠动脉中，L-NAME降低EDD（均P <0.01）。用TNF-α中和抗体（abTNF）体外处理动脉可改善HF（88.2 +/-4.6%; P = 0.05）喂养小鼠的EDD，但对NC（89.0 +/-5.1%）喂养小鼠的最大扩张没有影响。L-NAME降低了来自NC（25.4 +/-7.5%）和HF（27.1 +/-16.8%）喂养小鼠的abTNF处理的动脉中的EDD（均P <0.01）。这些结果表明，由饮食诱导的肥胖引起的内脏脂肪组织中的炎症损害了相关阻力动脉中的内皮功能和NO生物利用度。这种功能障碍可能对脂肪组织血流和适当的组织功能具有重要意义。
Donato AJ, Henson GD, Morgan RG, Enz RA, Walker AE, Lesniewski LA. TNF-alpha impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity. Am J Physiol Heart Circ Physiol 303: H672-H679, 2012. First published July 20, 2012; doi:10.1152/ajpheart.00271.2012.-We tested the hypothesis that high fat (HF) feeding results in endothelial dysfunction in resistance arteries of epididymal white adipose tissue (eWAT) and is mediated by adipose tissue inflammation. When compared with normal chow (NC)-fed mice (n = 17), HF-fed male B6D2F1 mice were glucose intolerant and insulin resistant as assessed by glucose tolerance test (area under the curve; HF, 18,174 +/- 1,889 vs. NC, 15,814 +/- 666 mg.dl(-1).min(-1); P < 0.05) and the homeostatic model assessment (HF, 64.1 +/- 4.3 vs. NC, 85.7 +/- 6.4; P = 0.05). HF diet-induced metabolic dysfunction was concomitant with a proinflammatory eWAT phenotype characterized by greater macrophage infiltration (HF, 3.9 +/- 0.8 vs. NC, 0.8 +/- 0.4%; P = 0.01) and TNF-alpha (HF, 22.6 +/- 4.3 vs. NC, 11.4 +/- 2.5 pg/dl; P < 0.05) and was associated with resistance artery dysfunction, evidenced by impaired endothelium-dependent dilation (EDD) (maximal dilation; HF, 49.2 +/- 10.7 vs. NC, 92.4 +/- 1.4%; P < 0.01). Inhibition of nitric oxide (NO) synthase by N-omega-nitro-L-arginine methyl ester (L-NAME) reduced dilation in NC (28.9 +/- 6.3%; P < 0.01)- and tended to reduce dilation in HF (29.8 +/- 9.9%; P = 0.07)-fed mice, eliminating the differences in eWAT artery EDD between NC- and HF-fed mice, indicative of reduced NO bioavailability in eWAT resistance arteries after HF feeding. In vitro treatment of excised eWAT arteries with recombinant TNF-alpha (rTNF) impaired EDD (P < 0.01) in NC (59.7 +/- 10.9%)- but not HF (59.0 +/- 9.3%)-fed mice. L-NAME reduced EDD in rTNF-treated arteries from both NC (21.9 +/- 6.4%)- and HF (29.1 +/- 9.2%)-fed mice (both P < 0.01). In vitro treatment of arteries with a neutralizing antibody against TNF-alpha (abTNF) improved EDD in HF (88.2 +/- 4.6%; P = 0.05)- fed mice but was without effect on maximal dilation in NC (89.0 +/- 5.1%)-fed mice. L-NAME reduced EDD in abTNF-treated arteries from both NC (25.4 +/- 7.5%)- and HF (27.1 +/- 16.8%)-fed mice (both P < 0.01). These results demonstrate that inflammation in the visceral adipose tissue resulting from diet-induced obesity impairs endothelial function and NO bioavailability in the associated resistance arteries. This dysfunction may have important implications for adipose tissue blood flow and appropriate tissue function.