Endothelin-1 in Obesity and Insulin Resistance

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Project Summary Obesity is an epidemic that affects over 40% of the United States and leads to a high risk of development of diabetes. As adipose tissue expands, several cellular and molecular pathways are altered leading to adipocyte dysfunction and insulin resistance. Black Americans are at an even greater risk of developing cardiovascular disease and type 2 diabetes compared to white counterparts; however, the mechanisms are not understood. Our lab has shown that the peptide endothelin-1 (ET-1) is elevated in obesity and treatment with ET-1 antagonists improve glucose and lipid homeostasis in obese mice. Adipocyte specific knockout of the ET-1 type B receptor attenuates obesity induced dyslipidemia and insulin resistance in mice. Interestingly, black Americans have higher circulating ET-1 compared to white Americans suggesting a potential mechanism and target to improve metabolic syndrome in black Americans. This administrative supplement will support the career development of Ms. Haley Murphy as she aims to determine the intracellular pathways by which ET-1 causes adipocyte dysfunction in obese mice in pre-clinical experiments. Second, she will establish a pathway to clinical research by performing single nuclear RNA sequencing on de-identified visceral adipose tissue samples to determine differences in the cellular makeup of adipose tissue from obese black and white Americans.