title: Ecscr regulates insulin sensitivity and predisposition to obesity by modulating endothelial cell functions.
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.
authors.affiliation: Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akakabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koide
authors.forename: Youhei
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Kiyonari
authors.initials: K
authors.lastname: Matsuo
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.forename: Koji
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects; D004032:Diet; D004198:Disease Susceptibility / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020890:Neuregulin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D022722:Thermogenesis / Q000187:drug effects
chemical_list: D007328:Insulin; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D052250:Nitric Oxide Synthase Type III; D005947:Glucose