PROJECET SUMMARY Insulin resistance is a major health problem in the U.S. It precludes type II diabetes and is often present in obese patients, both being major risk factors for cardiovascular disease. Currently, mechanisms associated with insulin resistance aren't fully understood. ET-1 is a vasoactive peptide primarily released by endothelial cells that is associated with insulin resistance and increased in obese patients. ET-1 activates two receptors, ETA and ETB. We have previously shown that inhibiting ETB receptors in rodents, either genetically or pharmacologically, improves insulin tolerance and reduces fasting blood glucose. In addition, loss of ETB function reduces adiposity, suggesting the adipose tissue as a possible target for ET-1 induced alteration in insulin signaling. It has been previously shown that activation of ETB receptors on cultured adipocytes inhibits the anti-lipolytic effects of insulin. Furthermore, blockade of ETB receptors reduces fasting blood glucose in the GK rat model of type II diabetes and improves insulin sensitivity in a rodent model of sleep apnea. These data suggest that increased ET-1 observed in obese patients may promote insulin resistance via the ETB receptor. Thus, we hypothesize that activation of the ET-1/ETB receptor promotes IR and impairs glucose metabolism in adipocytes. To test this hypothesis, we will utilize both in vivo and in vitro techniques using two novel mouse models. One will allow us to over-express the ETB receptor, and another that will allow us to knockout the ETB receptor specifically in adipocytes. We will test the following specific aims: Specific aim 1: To test the hypothesis that ETB receptor activation inhibits insulin signaling in cultured adipocytes. Specific aim 2: To test the hypothesis that ETB receptor activation causes insulin resistance in vivo.