Abstract 17114: ARIA (Apoptosis Regulator Through Modulating Iap Expression) Regulates Insulin Sensitivity and Predisposition to Obesity Through a Modification of Endothelial Cell Functions

Abstract

Energy metabolism and glucose homeostasis are intricately regulated, failure of which causes type 2 diabetes and predisposition to obesity. Recently, emerging roles of endothelial cells (ECs) in the pathogenesis for insulin resistance through the regulation in insulin delivery and adipose tissue angiogenesis has been revealed, yet the underlying mechanisms remain to be elucidated. Here we show that ARIA, a gene that we recently identified as a regulator of angiogenesis, is highly expressed in white and brown adipose tissues, and it regulates systemic insulin sensitivity and predisposition to obesity. ARIA deficient (ARIA^-/-) mice showed similar body weight and body fat mass comparing with wildtype (WT) mice. Nevertheless, ARIA^-/- mice showed reduced fasting blood glucose and lower serum insulin levels relative to WT mice. Of note, glucose and insulin tolerance test revealed the improved glucose tolerance and enhanced insulin sensitivity in ARIA^-/- mice. Mechanistically, ARIA-deletion enhanced the insulin-mediated Akt/eNOS activation in ECs, resulting in the increased insulin delivery into skeletal muscle. In contrast, targeted activation of ARIA in ECs under the control of Tie2-promoter (TIE2-ARIA-Tg) impeded insulin-mediated Akt/eNOS activation in ECs. Moreover, TIE2-ARIA-Tg mice showed modestly but significantly impaired glucose tolerance and reduced insulin sensitivity relative to WT mice. When fed a high-fat diet (HFD), ARIA^-/- mice showed significant resistance to obesity, accompanied by the substantial improvement in obesity-related metabolic disorders. Blood vessel density was significantly increased in white and brown adipose tissues of ARIA^-/- mice fed a HFD, leading to ameliorated hypoxia and inflammation in white adipose tissue and increased thermogenesis and energy expenditure in ARIA^-/- mice. Conversely, TIE2-ARIA-Tg mice fed a HFD were predisposed to obesity, and they developed aggravated glucose intolerance and insulin resistance. Together, inactivation of ARIA enhances insulin sensitivity and concurrently counteracts obesity, and thus ARIA offers a unique therapeutic potential.