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Research Summary

Obesity causes adipose hypoxia and infiltration of pro-inflammatory lymphocytes, adipocyte dysfunction, and insulin resistance. Endothelin-1, a potent vasoconstrictor and pro-inflammatory factor, is increased in adipose tissue in obesity. We have shown that an adipocyte knockout of the ETB receptor attenuated adipose tissue inflammation and insulin resistance in mice. We hypothesized that mice given a dual receptor antagonist, macitentan, would reduce adipose tissue inflammation and hypoxia. Our results indicate that obese mice (high fat diet for 10 weeks) have a 2-fold increase in ET-1 production in visceral adipose. This is associated with a significant increase in hypoxia inducible factor alpha (Hif1a), increased proinflammatory CD4+ and CD8+ T cells and a decrease in eosinophils in visceral adipose. Treatment with macitentan reduced Hif1a by 35% and abolished the pro-inflammatory immune cell profile in the adipose of obese mice compared to lean, and impaired insulin tolerance, and dyslipidemia, were attenuated by treatment with macitentan. These data indicated that ET-1 promotes inflammation and insulin resistance in obesity; however, mechanisms are still unknown. Future studies will utilize cell specific ET-1 receptor knockout models to determine which cell type is the source of ET-1 and which receptors are responsible for causing inflammation and insulin resistance.