Abstract
Semaphorins and their receptors (plexins) are the axon-guiding molecules that also regulate the development of vascular network during embryogenesis. Semaphorin3E (Sema3E) is one of the class 3 semaphorins, and plexinD1 is its receptor. Our recent work shows that Sema3E is up-regulated by p53 under diabetic conditions and inhibits neoangiogenesis in ischemic tissues. Here we show a novel role for Sema3E in adipose tissue inflammation and insulin resistance in obesity. Expression of Sema3E and plexinD1 was up-regulated in adipose tissue of diet-induced obesity (DIO) model. Inhibition of the Sema3E-plexinD1 axis with genetic models or soluble form of the receptors markedly improved adipose tissue inflammation (infiltration of macrophages) and systemic insulin resistance. Conversely, forced expression of sema3E in adipose tissues provoked inflammation and systemic insulin resistance. Disruption of adipose tissue p53 down-regulated the expression of Sema3E and improved adipose tissue inflammation in DIO model. Migration assay showed that Sema3E promoted infiltration of macrophages, and this effect was inhibited when plexinD1 expression was disrupted in macrophages. These results indicate that Sema3E functions as a chemoattractant for macrophages and p53-induced increase of Sema3E-plexinD1 signals provokes adipose tissue inflammation and systemic insulin resistance in DIO model. Inhibition of the Sema3E-plexinD1 axis will be a new therapeutic target for lifestyle-related diseases including diabetes.
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