Ecscr regulates insulin sensitivity and predisposition to obesity by modulating endothelial cell functions

Yoshiki Akakabe, Masahiro Koide, Youhei Kitamura, Kiyonari Matsuo, Tomomi Ueyama, Satoaki Matoba, Hiroyuki Yamada, Keishi Miyata, Yuichi Oike and Koji Ikeda ()
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Yoshiki Akakabe: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Masahiro Koide: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Youhei Kitamura: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Kiyonari Matsuo: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Tomomi Ueyama: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Satoaki Matoba: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Hiroyuki Yamada: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Keishi Miyata: Graduate School of Medical Sciences, Kumamoto University
Yuichi Oike: Graduate School of Medical Sciences, Kumamoto University
Koji Ikeda: Graduate School of Medical Science, Kyoto Prefectural University of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract Insulin resistance is closely associated with obesity and is one of the earliest symptoms of type-2 diabetes. Endothelial cells are involved in the pathogenesis of insulin resistance through their role in insulin delivery and adipose tissue angiogenesis. Here we show that Ecscr (endothelial cell surface expressed chemotaxis and apoptosis regulator; also known as ARIA), the transmembrane protein that regulates endothelial cell signalling, is highly expressed in white and brown adipose tissues, and regulates energy metabolism and glucose homeostasis by modulating endothelial cell functions. Ecscr-deficient mice fed a normal chow show improved glucose tolerance and enhanced insulin sensitivity. We demonstrate that Ecscr deletion enhances the insulin-mediated Akt/endothelial nitric oxide synthase activation in endothelial cells, which increases insulin delivery into the skeletal muscle. Ecscr deletion also protects mice on a high-fat diet from obesity and obesity-related metabolic disorders by enhancing adipose tissue angiogenesis. Conversely, targeted activation of Ecscr in endothelial cells impairs glucose tolerance and predisposes mice to diet-induced obesity. Our results suggest that the inactivation of Ecscr enhances insulin sensitivity and may represent a new therapeutic strategy for treating metabolic syndrome.

Date: 2013
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DOI: 10.1038/ncomms3389

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