Central resistin overexposure induces insulin resistance through Toll-like receptor 4.
Central resistin overexposure induces insulin resistance through Toll-like receptor 4.
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作者：
Benomar Y;Gertler A;De Lacy P;Crépin D;Ould Hamouda H;Riffault L;Taouis M
抵抗素会促进与能量稳态受损相关的炎症和胰岛素抵抗。然而，抵抗素受体及其在下丘脑（对于能量稳态控制至关重要）和关键胰岛素敏感组织中介导其作用的分子机制仍然未知。在当前的研究中，我们报告正常大鼠侧脑室的慢性抵抗素输注显着影响下丘脑和外周胰岛素反应性。中枢抵抗素治疗可抑制胰岛素受体 (IR)、AKT 和细胞外信号相关激酶 1/2 的胰岛素依赖性磷酸化，该磷酸化与 IR 表达减少以及细胞因子信号传导 3 和磷酸酪氨酸磷酸酶 1B（胰岛素信号传导的两种负调节因子）抑制因子的上调相关。此外，中枢抵抗素促进丝氨酸激酶Jun NH2末端激酶和p38丝裂原激活蛋白激酶的激活，增强胰岛素受体底物1的丝氨酸磷酸化，并增加下丘脑和关键外周胰岛素敏感组织中促炎细胞因子白细胞介素6的表达。有趣的是，据我们所知，我们还首次报道了抵抗素与下丘脑中 Toll 样受体 (TLR) 4 受体的直接结合，导致相关促炎途径的激活。总而言之，我们的研究结果清楚地确定了 TLR4 是下丘脑中抵抗素的结合位点，并为整个动物中抵抗素诱导的炎症和胰岛素抵抗的分子机制带来了新的见解。
Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. However, the resistin receptor and the molecular mechanisms mediating its effects in the hypothalamus, crucial for energy homeostasis control, and key insulin-sensitive tissues are still unknown. In the current study, we report that chronic resistin infusion in the lateral cerebral ventricle of normal rats markedly affects both hypothalamic and peripheral insulin responsiveness. Central resistin treatment inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and extracellular signal–related kinase 1/2 associated with reduced IR expression and with upregulation of suppressor of cytokine signaling-3 and phosphotyrosine phosphatase 1B, two negative regulators of insulin signaling. Additionally, central resistin promotes the activation of the serine kinases Jun NH2-terminal kinase and p38 mitogen-activated protein kinase, enhances the serine phosphorylation of insulin receptor substrate-1, and increases the expression of the proinflammatory cytokine interleukin-6 in the hypothalamus and key peripheral insulin-sensitive tissues. Interestingly, we also report for the first time, to our knowledge, the direct binding of resistin to Toll-like receptor (TLR) 4 receptors in the hypothalamus, leading to the activation of the associated proinflammatory pathways. Taken together, our findings clearly identify TLR4 as the binding site for resistin in the hypothalamus and bring new insight into the molecular mechanisms involved in resistin-induced inflammation and insulin resistance in the whole animal.
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影响因子：
15.9
作者：
Kahn, BB;Flier, JS
通讯作者：
Flier, JS
影响因子：
7.7
作者：
Hemi R;Yochananov Y;Barhod E;Kasher-Meron M;Karasik A;Tirosh A;Kanety H
通讯作者：
Kanety H
影响因子：
11.4
作者：
Holcomb, IN;Kabakoff, RC;Hébert, CC
通讯作者：
Hébert, CC
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
DOI：
10.1080/00365510601032532
发表时间：
2007-01-01
影响因子：
2.1
作者：
Mojiminiyi, O. A.;Abdella, N. A.
通讯作者：
Abdella, N. A.