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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp191
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice

Ayumu Hirata, Norikazu Maeda*, Aki Hiuge, Toshiyuki Hibuse, Koichi Fujita, Takuya Okada, Shinji Kihara, Tohru Funahashi and Iichiro Shimomura

Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan

* Corresponding author: Norikazu Maeda, MD, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5, Yamada-oka, Suita, Osaka 565-0871, Japan, Telephone; +81-6-6879-3732, Fax; +81-6-6879-3739, E-mail; nmaeda{at}imed2.med.osaka-u.ac.jp

Aims: In obesity, chronic low-grade inflammation and overproduction of reactive oxygen species (ROS) in fat contribute to the development of metabolic syndrome. Suppression of inflammation and ROS production in fat may attenuate the metabolic syndrome. Activation of mineralocorticoid receptor (MR) promotes inflammation in heart, kidney, and vasculature via ROS generation. However, the significance of MR in fat remains elusive. Here we investigated whether MR blockade attenuates obesity-related insulin resistance and improves adipocyte dysfunction.

Methods: Obese ob/ob and db/db mice were treated with eplerenone, a MR antagonist, for 3 weeks. 3T3-L1 adipocytes were treated with aldosterone or H2O2, with and without eplerenone or MR-siRNA.

Results: High levels of MR mRNA were detected in adipose tissue of obese ob/ob and db/db mice. Eplerenone treatment significantly reduced insulin resistance, suppressed macrophage infiltration and ROS production in adipose tissues, and corrected the mRNA levels of obesity-related genes in obese mice. In 3T3-L1 adipocytes, aldosterone and H2O2 increased intracellular ROS levels and MR blockade inhibited such increases. H2O2 and aldosterone resulted in dysregulation of mRNAs of various genes related to ROS and cytokines, while MR blockade corrected such changes.

Conclusion: MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.

KEYWORDS Adipose tissue; Inflammation; Insulin resistance; Oxidative stress; Mineralocorticoid receptor

Time for primary review: 20 Days

Abbreviations: MR, mineralocorticoid receptor, ROS, reactive oxygen species


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