Abstract 8462: A Crucial Role of Semaphorin3E, an Anti-angiogenic Factor, in the Regulation of Insulin Resistance

Abstract

The neurovascular-guiding molecules known as semaphorins and their specific receptors (plexins) regulate vascular pattern formation and play an important role in the development of vascular network during embryogenesis. We have recently reported that semaphorin3E (Sema3E), one of the class 3 semaphorins, and its specific receptor plexinD1 negatively regulate postnatal angiogenesis by suppressing the vascular endothelial growth factor signaling pathway. We also found that Sema3E expression was significantly up-regulated via a p53-dependent pathway under ischemia or diabetic conditions and that this up-regulation accounted for impaired angiogenesis of diabetic mice. Although Sema3E was found to play a critical role in the pathogenesis of impaired angiogenesis of diabetes, it remains unclear whether Sema3E is involved in glucose homeostasis. Here we report that the Sema3E/plexinD1 axis is also involved in the regulation of insulin sensitivity and glucose tolerance. First, we found that expression of Sema3E was markedly up-regulated in skeletal muscle and adipose tissue of diabetic mice compared with non-diabetic mice. To examine the effect of Sema3E inhibition on glucose homeostasis in vivo, we treated diabetic mice with plexinD1-Fc that acts as an inhibitor of Sema3E. The results showed that inhibition of Sema3E significantly improved insulin resistance and glucose intolerance compared with vehicle-treated diabetic mice and that this improvement was associated with decreased body weight and visceral fat mass assessed by computed tomography. Moreover, when fed on a high fat/high sucrose diet, Sema3E-deficient mice showed better insulin sensitivity and glucose tolerance than wild-type mice. Conversely, forced expression of Sema3E by gene transfer resulted in impaired glucose tolerance and insulin sensitivity. These results indicate a crucial role for Sema3E not only in the pathogenesis of impaired angiogenesis, but also in glucose homeostasis of diabetes. Inhibition of Sema3E would be a novel strategy for the treatment of insulin resistance as well as impaired angiogenesis of diabetes.