Abstract P158: Endothelin Inhibits Adiponectin Production Via ETB Receptor Activation On Adipocytes

Abstract

Endothelin-1 has been implicated in obesity related insulin resistance. Our lab recently demonstrated that ET-1 is elevated in adipose tissue of obese mice, and blockade of ET-1 receptors improves insulin sensitivity in a mouse model of diet induced obesity. One potential mechanism by which ET-1 promotes insulin resistance is through activation of the ET-1 type B receptor (ET B ). Blockade of ET B receptors improves insulin sensitivity and increases circulating adiponectin, an adipokine only released by adipose tissue. Therefore, the current hypothesis is that ET-1 causes insulin resistance and inhibits adiponectin production by adipocytes. Primary mouse adipocytes were cultured and chronically treated with ET-1 for 3 days. ET-1 treated adipocytes had significantly lower peroxisome proliferator activator gamma, a transcription factor that drive adiponectin production, and adiponectin mRNA expression and release into media. This response was attenuated by co-treatment with an ET B receptor antagonist (BQ-788; 57.2±2.0 vehicle, 42.5±4.5 ET-1, 59.8±1.5 ET-1+BQ788, ng/ml; p<0.05) and in adipocytes from adipocyte ET B receptor knockout mice. Further, expression of several genes in the insulin signaling pathway, including Glut4 and insulin receptor substrates 1 and 2 were significantly reduced in adipocytes treated with ET-1, a response that was attenuated with ET B receptor blockade or knockout of the ET B receptor. These data suggest that increased ET-1 production in adipose tissue promotes insulin resistance on adipocytes and inhibits the release of insulin sensitizing adipokines such as adiponectin, a potential mechanism by which ET-1 receptor blockade improves insulin sensitivity in obese mice.