Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4wks HFD), hepatocytes secrete exosomes which enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal miRNA miR-3075 which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and siRNA depletion of FA2H in adipocytes, myocytes, and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16–18wks HFD), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signaling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes which express high levels of the insulin sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.