Hepatic Expression of Ectodysplasin (ED) A Increases in Obesity and Impairs Insulin Sensitivity in Skeletal Muscle

We screened intronic microRNAs dysregulated in liver of obese mouse models to identify previously uncharacterized coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach identified the expression of Ectodysplasin A (Eda), the causal gene of X-linked hypohidrotic ectodermal dysplasia (XLHED; MIM 305100) was strongly increased in liver of obese mouse models both in rodents and humans.Eda expression in murine liver is controlled via PPAR? activation, increases in circulation and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. Consistently, bi-directional modulation of hepatic Eda expression in mouse models affects systemic glucose metabolism with alterations of muscle insulin signaling, revealing a novel role of EDA as an obesity-associated hepatokine, which impairs insulin sensitivity in skeletal muscle. Overall design: Soleus muscle mRNA profiles of db/db mice at 3 weeks after injection of AAV encoding shRNA targeting mouse Eda or the control scrambled shRNA sequence at the titer of 2-3x10e10 particles/body.