Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes
Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes
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DOI：
10.1152/ajpendo.00324.2011
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发表时间：
2012-02-01
影响因子：
5.1
通讯作者：
Asano, Tomoichiro
中科院分区：
文献类型：
--
作者：
Iwashita, Misaki;Sakoda, Hideyuki;Asano, Tomoichiro
岩下M、Sakoda H、Kushiyama A、Fujishiro M、Ohno H、Nakatsu Y、Fukushima T、熊本S、土屋Y、菊池T、栗原H、赤泽H、小室一号、Kamata H、西村F、Asano T.Valsartan独立于AT1受体或PPAR伽马，抑制脂多糖诱导的巨噬细胞激活，并改善共培养脂肪细胞的胰岛素抵抗。AM J生理学内分泌代谢酶302：E286-E296,2012。2011年11月1日首次出版；DOI：10.1152/ajpeno.00324.2011。-巨噬细胞整合到脂肪组织中，并与肥胖受试者的脂肪细胞相互作用，从而加剧脂肪胰岛素抵抗。本研究旨在阐明血管紧张素II受体阻滞剂(ARB)valsartan的胰岛素增敏作用的分子机制。肿瘤坏死因子-α或脂多糖刺激的RAW-264.7小鼠巨噬细胞培养液中的胰岛素信号转导，即胰岛素受体底物-1和Akt磷酸化均显著受损，而Valsartan对此无影响。然而，相反，当使用Transwell系统与RAW 264.7细胞共同培养时，加入Valsartan后，内毒素诱导的3T3-L1脂肪细胞的胰岛素信号损伤几乎完全正常化。此外，在RAW 264.7和原代小鼠巨噬细胞中，valsartan通过核因子-kappaB的激活和c-jun NH2末端激酶的磷酸化，强烈抑制内毒素诱导的细胞因子的产生，如IL-1β、IL-6和肿瘤坏死因子α。非常有趣的是，在用血管紧张素II 1型(AT1)siRNA或过氧化物酶体增殖物激活受体-伽马(PPAR-γ)拮抗剂处理的THP-1细胞以及AT1a受体敲除小鼠的巨噬细胞中，也观察到了valsartan的这种作用。我们得出结论，valsartan抑制巨噬细胞的炎症反应，尽管不是通过PPARγ或AT1a受体。这种抑制似乎继而改善了脂肪胰岛素抵抗。
Iwashita M, Sakoda H, Kushiyama A, Fujishiro M, Ohno H, Nakatsu Y, Fukushima T, Kumamoto S, Tsuchiya Y, Kikuchi T, Kurihara H, Akazawa H, Komuro I, Kamata H, Nishimura F, Asano T. Valsartan, independently of AT1 receptor or PPAR gamma, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. Am J Physiol Endocrinol Metab 302: E286-E296, 2012. First published November 1, 2011; doi: 10.1152/ajpendo.00324.2011.-Macrophages are integrated into adipose tissues and interact with adipocytes in obese subjects, thereby exacerbating adipose insulin resistance. This study aimed to elucidate the molecular mechanism underlying the insulin-sensitizing effect of the angiotensin II receptor blocker (ARB) valsartan, as demonstrated in clinical studies. Insulin signaling, i.e., insulin receptor substrate-1 and Akt phosphorylations, in 3T3-L1 adipocytes was impaired markedly by treatment with tumor necrosis factor-alpha (TNF alpha) or in the culture medium of lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages, and valsartan had no effects on these impairments. However, in contrast, when cocultured with RAW 264.7 cells using a transwell system, the LPS-induced insulin signaling impairment in 3T3-L1 adipocytes showed almost complete normalization with coaddition of valsartan. Furthermore, valsartan strongly suppressed LPS-induced productions of cytokines such as interleukin (IL)-1 beta, IL-6, and TNF alpha with nuclear factor-kappa B activation and c-Jun NH2-terminal kinase phosphorylation in RAW 264.7 and primary murine macrophages. Very interestingly, this effect of valsartan was also observed in THP-1 cells treated with angiotensin II type 1 (AT1) siRNA or a peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist as well as macrophages from AT1a receptor-knockout mice. We conclude that valsartan suppresses the inflammatory response of macrophages, albeit not via PPAR gamma or the AT1a receptor. This suppression appears to secondarily improve adipose insulin resistance.