Effects of the Angiotensin receptor blocker olmesartan on adipocyte hypertrophy and function in mice with metabolic disorders

Akinobu Maeda, Kouichi Tamura, Hiromichi Wakui, Masato Ohsawa, Kengo Azushima, Kazushi Uneda, Tomohiko Kanaoka, Ryu Kobayashi, Kohji Ohki, Miyuki Matsuda, Yuko Tsurumi-Ikeya, Akio Yamashita, Yasuo Tokita, Satoshi Umemura, Akinobu Maeda, Kouichi Tamura, Hiromichi Wakui, Masato Ohsawa, Kengo Azushima, Kazushi Uneda, Tomohiko Kanaoka, Ryu Kobayashi, Kohji Ohki, Miyuki Matsuda, Yuko Tsurumi-Ikeya, Akio Yamashita, Yasuo Tokita, Satoshi Umemura

Abstract

In the present study, we examined the therapeutic effects of olmesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders with visceral obesity, with a focus on an olmesartan effect on the adipose tissue. Olmesartan treatment (3 mg/kg per day) for 4 weeks significantly lowered systolic blood pressure but did not affect body weight during the study period in KKAy mice. However, there were three interesting findings possibly related to the pleiotropic effects of olmesartan on adipose tissue in KKAy mice: (1) an inhibitory effect on adipocyte hypertrophy, (2) a suppressive effect on IL-6 gene expression, and (3) an ameliorating effect on oxidative stress. On the other hand, olmesartan exerted no evident influence on the adipose tissue expression of AT1R-associated protein (ATRAP), which is a molecule interacting with AT1R so as to inhibit pathological AT1R activation and is suggested to be an emerging molecular target in metabolic disorders with visceral obesity. Collectively, these results suggest that the blood pressure lowering effect of olmesartan in KKAy mice is associated with an improvement in adipocyte, including suppression of adipocyte hypertrophy and inhibition of the adipose IL-6-oxidative stress axis. Further study is needed to clarify the functional role of adipose ATRAP in the pleiotropic effects of olmesartan.

Figures

Figure 1
Figure 1
Effects of olmesartan (olm) on systolic blood pressure (a), heart rate (b), and body weight (c) in KKAy mice. Individual values are shown in the graphs and the values are also shown as the mean ± SEM (n = 8). B, before treatment; A, after treatment. *P < 0.05, **P < 0.01 versus before treatment; ##P < 0.01 versus KKAy + vehicle; ‡P < 0.01 versus C57BL/6 (ANOVA).
Figure 2
Figure 2
Effects of olmesartan (olm) on daily food intake in KKAy mice. The values are the mean ± SEM (n = 8). **P < 0.01 versus C57BL/6 (ANOVA).
Figure 3
Figure 3
Effects of olmesartan (olm) on adipocyte hypertrophy in KKAy mice. Upper panel: histological analysis of epididymal adipose tissue sections ((a) C57BL/6; (b) KKAy + vehicle; (c) KKAy + olmesartan) stained with hematoxylin and eosin in each experimental group. Original magnification: ×200. Lower panel: adipocyte diameter (d) and area (e). The values are the mean ± SEM (n = 8). **P < 0.01 versus C57BL/6; ##P < 0.01 versus KKAy + vehicle (ANOVA). Olm indicates olmesartan.
Figure 4
Figure 4
Effects of olmesartan (olm) on the adipose tissue mRNA expression of adiponectin (a) and PPARγ (b) in KKAy mice. The values are the mean ± SEM (n = 8). **P < 0.01 versus C57BL/6 (ANOVA). Olm indicates olmesartan.
Figure 5
Figure 5
Effects of olmesartan (olm) on the adipose tissue mRNA expression of angiotensinogen (a), ATRAP (b), and AT1R (c) (AT1a receptor) in KKAy mice. The values are the mean ± SEM (n = 8). **P < 0.01 versus C57BL/6 (ANOVA). Olm indicates olmesartan.
Figure 6
Figure 6
Effects of olmesartan (olm) on the adipose tissue mRNA expression of proinflammatory cytokines ((a) MCP-1; (b) TNF-α; (c) IL-6; and (d) PAI-1) in KKAy mice. The values are the mean ± SEM (n = 8). *P < 0.05, **P < 0.01 versus C57BL/6 (ANOVA). Olm indicates olmesartan.
Figure 7
Figure 7
Effects of olmesartan (olm) on the adipose tissue mRNA expression of NADPH oxidase components ((a) p22phox; (b) gp91phox; (c) p47phox; and (d) p40phox) in KKAy mice. The values are the mean ± SEM (n = 8). **P < 0.01 versus C57BL/6; #P < 0.05, ##P < 0.01 versus KKAy + vehicle (ANOVA). Olm indicates olmesartan.

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