Valsartan, independently of AT1 receptor or PPAR γ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes

Misaki Iwashita, Hideyuki Sakoda, Akifumi Kushiyama, Midori Fujishiro, Haruya Ohno, Yusuke Nakatsu, Toshiaki Fukushima, Sonoko Kumamoto, Yoshihiro Tsuchiya, Takako Kikuchi, Hiroki Kurihara, Hiroshi Akazawa, Issei Komuro, Hideaki Kamata, Fusanori Nishimura, Tomoichiro Asano

研究成果: Contribution to journalArticle査読

26 被引用数 (Scopus)

抄録

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-α (TNFα) 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)-1β, IL-6, and TNFα with nuclear factor-κB activation and c-Jun NH 2-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-γ (PPARγ) antagonist as well as macrophages from AT1a receptor-knockout mice. We conclude that valsartan suppresses the inflammatory response of macrophages, albeit not via PPARγ or the AT1a receptor. This suppression appears to secondarily improve adipose insulin resistance.

本文言語英語
ページ(範囲)286-296
ページ数11
ジャーナルAmerican Journal of Physiology - Endocrinology and Metabolism
302
3
DOI
出版ステータス出版済み - 2 2012
外部発表はい

All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 生理学
  • 生理学(医学)

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