Angiotensin II Type 1 Receptor-associated Protein Inhibits Angiotensin II-induced Insulin Resistance with Suppression of Oxidative Stress in Skeletal Muscle Tissue

Kohji Ohki,Ryu Kobayashi,Kotaro Haruhara,Kengo Azushima,Takahiro Yamaji,Hiromichi Wakui,Atsushi Nakajima,Sona Haku,Sho Kinguchi,Akio Yamashita,Kenichi Ohashi,Ikuo Kato ,Takayuki Yamada,Kazushi Uneda,Shintaro Minegishi,Yoshiyuki Toya,Kento Imajo,Tomoaki Ishigami,Nozomu Kishio,Kouichi Tamura

doi:10.1038/s41598-018-21270-8

Kohji Ohki, Ryu Kobayashi + Show 18 more

Open Access

https://doi.org/10.1038/s41598-018-21270-8

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Abstract

Enhancement of AT1 receptor-associated protein (ATRAP) in adipose tissue improves high fat diet (HFD)-induced visceral obesity and insulin resistance, and suppresses adipose oxidative stress. However, HFD loading is not a direct stimulatory factor for AT1 receptor. In the present study, we investigated the effect of chronic, low-dose angiotensin II (Ang II) stimulation on glucose and lipid metabolism in mice and functional role of ATRAP. ATRAP expression was higher in adipose tissue (5–10-fold) and skeletal muscle tissue (approximately 1.6-fold) in ATRAP transgenic (TG) mice compared with wild-type (WT) mice. After Ang II infusion, insulin sensitivity was impaired in WT mice, but this response was suppressed in TG mice. Unexpectedly, Ang II infusion did not affect the adipose tissue profile in WT or TG mice. However, in skeletal muscle tissue, Ang II stimulus caused an increase in oxidative stress and activation of p38 MAPK, resulting in a decrease in glucose transporter type 4 expression in WT mice. These responses were suppressed in TG mice. Our study suggests that Ang II-induced insulin resistance is suppressed by increased ATRAP expression in skeletal muscle tissue. Hyperactivity of AT1 receptor could be related to formation of insulin resistance related to metabolic syndrome.

Highlights

AT1 receptor-associated protein (ATRAP) directly binds to the AT1 receptor and functions as an endogenous inhibitor, which functionally suppresses hyperactivation of this receptor[11,12,13]
We reconfirmed that ATRAP mRNA expression in white adipose tissue (WAT) and brown adipose tissue (BAT) of TG mice was markedly increased compared with WT mice (Fig. 1a)
Fold induction analysis of mRNA levels in each tissue showed that ATRAP mRNA expression in skeletal muscle tissue of TG mice was slightly, but significantly, higher compared with WT mice

Summary

Introduction

AT1 receptor-associated protein (ATRAP) directly binds to the AT1 receptor and functions as an endogenous inhibitor, which functionally suppresses hyperactivation of this receptor[11,12,13]. We demonstrated that enhancement of ATRAP expression in adipose tissue improved diet-induced visceral obesity and insulin resistance, concomitant with www.nature.com/scientificreports/. Suppression of oxidative stress and inflammation of adipose tissue[15]. We analysed visceral ATRAP mRNA expression levels in TG mice prior to our Ang II administration experiment. We found that ATRAP expression was higher (approximately 1.6-fold) in soleus muscle tissue in TG mice than in WT mice. Our analysis of WAT indicated that an Ang II stimulus had no effect on adipose oxidative stress, inflammation, or adipocyte differentiation marker levels in WT or TG mice. Our analysis of skeletal muscle tissue indicated that an Ang II stimulus caused an increase in oxidative stress, which exacerbated insulin resistance only in WT mice

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