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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)286-296
Number of pages11
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume302
Issue number3
DOIs
Publication statusPublished - Feb 1 2012
Externally publishedYes

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Valsartan
Angiotensin Type 1 Receptor
Peroxisome Proliferator-Activated Receptors
Macrophage Activation
Adipocytes
Lipopolysaccharides
Insulin Resistance
Macrophages
Insulin
Tumor Necrosis Factor-alpha
Phosphorylation
Insulin Receptor Substrate Proteins
Angiotensin Receptor Antagonists
Interleukin-1
Knockout Mice
Angiotensin II
Small Interfering RNA
Culture Media
Adipose Tissue
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Valsartan, independently of AT1 receptor or PPAR γ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. / Iwashita, Misaki; Sakoda, Hideyuki; Kushiyama, Akifumi; Fujishiro, Midori; Ohno, Haruya; Nakatsu, Yusuke; Fukushima, Toshiaki; Kumamoto, Sonoko; Tsuchiya, Yoshihiro; Kikuchi, Takako; Kurihara, Hiroki; Akazawa, Hiroshi; Komuro, Issei; Kamata, Hideaki; Nishimura, Fusanori; Asano, Tomoichiro.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 302, No. 3, 01.02.2012, p. 286-296.

Research output: Contribution to journalArticle

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 2012, 'Valsartan, independently of AT1 receptor or PPAR γ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes', American Journal of Physiology - Endocrinology and Metabolism, vol. 302, no. 3, pp. 286-296. https://doi.org/10.1152/ajpendo.00324.2011
Iwashita, Misaki ; Sakoda, Hideyuki ; Kushiyama, Akifumi ; Fujishiro, Midori ; Ohno, Haruya ; Nakatsu, Yusuke ; Fukushima, Toshiaki ; Kumamoto, Sonoko ; Tsuchiya, Yoshihiro ; Kikuchi, Takako ; Kurihara, Hiroki ; Akazawa, Hiroshi ; Komuro, Issei ; Kamata, Hideaki ; Nishimura, Fusanori ; Asano, Tomoichiro. / Valsartan, independently of AT1 receptor or PPAR γ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. In: American Journal of Physiology - Endocrinology and Metabolism. 2012 ; Vol. 302, No. 3. pp. 286-296.
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AU - Ohno, Haruya

AU - Nakatsu, Yusuke

AU - Fukushima, Toshiaki

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AU - Tsuchiya, Yoshihiro

AU - Kikuchi, Takako

AU - Kurihara, Hiroki

AU - Akazawa, Hiroshi

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