Valsartan ameliorates the constitutive adipokine expression pattern in mature adipocytes: a role for inverse agonism of the angiotensin II type 1 receptor in obesity
Valsartan ameliorates the constitutive adipokine expression pattern in mature adipocytes: a role for inverse agonism of the angiotensin II type 1 receptor in obesity
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DOI：
10.1038/hr.2014.51
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发表时间：
2014-07-01
影响因子：
5.4
通讯作者：
Kohno, Masakazu
中科院分区：
文献类型：
--
作者：
Hasan, Arif U.;Ohmori, Koji;Kohno, Masakazu
血管紧张素 (Ang) II 受体阻滞剂 (ARB) 可减轻肥胖相关的胰岛素抵抗，这表明 Ang II 1 型受体 (AT1R) 在脂肪细胞因子的调节中发挥重要作用。因此，我们用50μmol l(-1)缬沙坦处理成熟3T3-L1脂肪细胞，缬沙坦是一种选择性AT1R阻滞剂，对过氧化物酶体增殖物激活受体(PPAR)-γ没有直接激动作用。在缺乏有效浓度的 Ang II 的情况下，未刺激的成熟脂肪细胞表达并分泌高水平的白细胞介素 (IL)-6。这种组成性促炎活性因缬沙坦抑制细胞外信号调节激酶磷酸化而减弱，但不受 Ang II 2 型受体阻滞剂 PD123319 的影响。共转染 AT1R 和 IL-6 的 COS7 细胞表达 NF-κ B 但缺乏 PPAR-gamma，没有表现出组成型但显着的配体依赖性 IL-6 报告活性，而缬沙坦可以抵消这种活性。缬沙坦保留了胞浆 I kappa B-alpha，随后降低了成熟脂肪细胞中核 NF-kappa B1 蛋白的表达。有趣的是，缬沙坦本身并没有增加 PPAR-γ 信使 RNA 的表达，而是增强了成熟脂肪细胞中 PPAR-γ 的转录活性。这种增强伴随着 PPAR 共激活因子 (PGC)-1 α 的上调。此外，T0090907（一种 PPAR-γ 抑制剂）可增加 IL-6 的表达，并且这种增加可被缬沙坦减弱。事实上，添加缬沙坦而不直接激动 PPAR-γ 会增加成熟脂肪细胞中脂联素的产生。总之，这些研究结果表明，缬沙坦可阻断涉及 NF-κ B 通路的组成型 AT1R 活性，从而限制成熟脂肪细胞中的 PPAR-gamma 活性。因此，AT1R 的反向激动作用会减弱自发的促炎反应，并增强成熟脂肪细胞的组成型胰岛素敏化活性，这可能是 ARB 产生有益代谢影响的基础。
Angiotensin (Ang) II receptor blockers (ARBs) alleviate obesity-related insulin resistance, which suggests an important role for the Ang II type 1 receptor (AT1R) in the regulation of adipocytokines. Therefore, we treated mature 3T3-L1 adipocytes with 50 mu mol l(-1) of valsartan, a selective AT1R blocker without direct agonism to peroxisome proliferator-activated receptor (PPAR)-gamma. In the absence of effective concentrations of Ang II, unstimulated mature adipocytes expressed and secreted high levels of interleukin (IL)-6. This constitutive proinflammatory activity was attenuated by the suppression of extracellular signal-regulated kinase phosphorylation by valsartan but was unaffected by the Ang II type 2 receptor blocker PD123319. COS7 cells co-transfected with AT1R and IL-6, which expressed NF-kappa B but lacked PPAR-gamma, showed no constitutive but substantial ligand-dependent IL-6 reporter activity, which was counteracted by valsartan. Valsartan preserved cytosolic I kappa B-alpha and subsequently reduced nuclear NF-kappa B1 protein expression in mature adipocytes. Interestingly, valsartan did not increase PPAR-gamma messenger RNA expression per se but enhanced the transcriptional activity of PPAR-gamma in mature adipocytes; this enhancement was accompanied by upregulation of the PPAR coactivator (PGC)-1 alpha. Moreover, T0090907, a PPAR-gamma inhibitor, increased IL-6 expression, and this increase was attenuated by valsartan. Indeed, addition of valsartan without direct PPAR-gamma agonism increased adiponectin production in mature adipocytes. Together, the findings indicate that valsartan blocks the constitutive AT1R activity involving the NF-kappa B pathway that limits PPAR-gamma activity in mature adipocytes. Thus, inverse agonism of AT1R attenuates the spontaneous proinflammatory response and enhances the constitutive insulin-sensitizing activities of mature adipocytes, which may underlie the beneficial metabolic impacts of ARBs.