Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.
Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.
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DOI：
10.1371/journal.pone.0116163
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Murohara T
中科院分区：
文献类型：
--
作者：
Hayashi M;Takeshita K;Uchida Y;Yamamoto K;Kikuchi R;Nakayama T;Nomura E;Cheng XW;Matsushita T;Nakamura S;Murohara T
心理压力和胰岛素抵抗以及高血压之间存在很强的因果关系。同时，应激相关反应在高血压患者的糖代谢中起关键作用。由于临床试验表明血管紧张素受体阻滞剂可以延缓高血压患者糖尿病的发病，我们研究了厄贝沙坦对应激性脂肪组织炎症和胰岛素抵抗的影响。C57BL/6J小鼠给予2周的间歇性约束应激，并口服厄贝沙坦3、10 mg/kg/d。采用酶联免疫吸附法测定血脂和促炎细胞因子[单核细胞趋化蛋白-1 （MCP-1）、肿瘤坏死因子-α和白细胞介素-6]的血浆浓度。采用免疫组织化学和RT-PCR方法分别检测cd11b阳性细胞计数和CD68、F4/80 mRNA表达，观察腹股沟白色脂肪组织（WAT）单核/巨噬细胞的积累。采用RT-PCR法检测WAT中血管紧张素原、促炎细胞因子和脂联素的mRNA水平。通过葡萄糖耐量试验（gts）和胰岛素耐量试验，以及胰岛素受体底物-1 （IRS-1）和葡萄糖转运蛋白4 （GLUT4）的mRNA表达来评估葡萄糖代谢。抑制应激增加了单核细胞积累、血浆游离脂肪酸、血管紧张素原和促炎细胞因子（包括MCP-1）的表达，并降低了脂联素。厄贝沙坦以剂量依赖的方式减少应激诱导的单核细胞在WAT中的积累。厄贝沙坦治疗还抑制了脂肪血管紧张素原和促炎细胞因子在WAT和血液中的诱导，逆转了脂联素表达的变化。值得注意的是，厄贝沙坦抑制应激诱导的脂肪组织重量和游离脂肪酸释放的减少，并通过恢复WAT中IRS-1和GLUT4 mRNA的表达来改善胰岛素耐受性。结果表明，厄贝沙坦可改善应激性脂肪组织炎症和胰岛素抵抗。我们的研究结果表明厄贝沙坦治疗对伴有精神压力的高血压患者的糖代谢有附加的益处。
A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results indicate that irbesartan improves stress-induced adipose tissue inflammation and insulin resistance. Our results suggests that irbesartan treatment exerts additive benefits for glucose metabolism in hypertensive patients with mental stress.
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影响因子：
3
作者：
Benito, Manuel
通讯作者：
Benito, Manuel
影响因子：
7.7
作者：
Uchida Y;Takeshita K;Yamamoto K;Kikuchi R;Nakayama T;Nomura M;Cheng XW;Egashira K;Matsushita T;Nakamura H;Murohara T
通讯作者：
Murohara T
影响因子：
15.1
作者：
Cox, Stewart S.;Speaker, Kristin J.;Fleshner, Monika
通讯作者：
Fleshner, Monika
影响因子：
7.7
作者：
Ruan, H;Miles, PDG;Lodish, HF
通讯作者：
Lodish, HF
影响因子：
7.7
作者：
Schupp, M;Clemenz, M;Kintscher, U
通讯作者：
Kintscher, U