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.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

“…Senescent EC impairs adipocyte functions through SASP. Aging causes impaired metabolic homeostasis 1,2,24 , and the AT contains highly developed vascular networks that play an important role in maintaining adipocyte functions 18,21,22 . We, therefore, hypothesized that EC senescence might directly cause the adipocyte dysfunction and lead to age-related metabolic disorders.…”

“…We have previously reported that adipose tissue (AT) vasculatures are critically involved in fat functions, and consequently play crucial roles in the maintenance of systemic metabolic health [18][19][20] . Adipocytes actively regulate AT angiogenesis by secreting angiogenic factors to maintain AT vasculatures [19][20][21][22][23] .…”

Family with sequence similarity 13, member A modulates adipocyte insulin signaling and preserves systemic metabolic homeostasis

“…Fatty acids activate inflammatory signaling in adipocytes and macrophages via Toll-like receptor 4, leading to chronic adipose tissue inflammation in obesity (6). In addition, excessive adipocyte expansion causes imbalanced vascularization and consequent hypoxia, which also triggers inflammation in adipose tissue (7,8). Chronic inflammation in adipose tissue is closely associated with obesity-related metabolic disorders at least in part through inducing adipocyte insulin resistance (4,5).…”

Loss of Apoptosis Regulator through Modulating IAP Expression (ARIA) Protects Blood Vessels from Atherosclerosis

“…Because the atheroprotective effect of ARIA deletion appeared to be attributed to a reduction in macrophage foam cell formation, inhibition of ARIA might prevent atherosclerosis independent of the control of risk factors such as hyperlipidemia and hyperglycemia. Moreover, we have previously demonstrated that loss of ARIA enhanced insulin sensitivity, as well as protected mice from diet-induced obesity and metabolic disorders by modulating endothelial insulin signaling and adipose tissue angiogenesis (27). Additionally, genetic loss of ARIA ameliorated doxorubicin-induced cardiomyopathy (21).…”