Smooth Muscle Knockout of Endothelin-1 Receptor A Attenuates Insulin Resistance in Mice Fed High Fat Diet

Endothelin-1 (ET-1), a proinflammatory factor, is increased in the circulation of patients with obesity and adipose tissue of high fat diet (HFD) fed mice. Our lab recently has shown that blockade of the ET-1 receptor type A (ETA) attenuates the proinflammatory increase in CD4 and CD8 T cells and reduction in eosinophiles observed in the visceral adipose of obese HFD fed mice and attenuates insulin resistance. We and others have shown that ET-1 increases contributes to cardiovascular and metabolic disease risk in obesity. Obesity causes adipose tissue hypoxia followed by infiltration of pro-inflammatory T cells and macrophages, adipocyte dysfunction (adipokine dysregulation and inability to store excess energy), and eventual peripheral insulin resistance. Considering how the endothelin receptor A (ETA) on smooth muscle causes vasoconstriction, we hypothesized that excess activation of ETA promotes the detrimental inflammation, insulin resistance and adipocyte dysfunction that accompanies metabolic disease. Our lab has developed a smooth muscle knockout of ETA in mice. Mice were given normal or high fat diet for 12 weeks and body mass, fat percentage and lean mass were measured. At the end of the diet period, following a 6-hour fast, mice were tested for glucose (GTT) and insulin tolerance (ITT). Mice were given 2 g/kg of dextrose administered via oral gavage needle for the GTT or insulin (0.75 IU/kg for males and 0.5 IU/kg for females of lean mass) was injected into the peritoneal cavity for ITT. Blood glucose levels were measured from the tail vein at 0, 15, 30, 60, and 120 minutes following administration. In males, the response to glucose in the knockout mice that were given HFD were comparable to mice given normal diet (NMD) in wild type and knockout mice. Likewise in the ITT, male knockout mice given HFD had an improved response to insulin compared to control mice given HFD. Consistent with other reports and results within our lab, knockout and control females did not demonstrate a difference in GTT and unlike the male knockout, the female knockout given HFD responded similarly to control mice given HFD. These data indicate that ETA receptor on smooth muscle is involved in glucose control in the context of diet induced obesity in a sex-dependent manner and hints at a potential target for alleviating symptoms associated with obesity and diabetes. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.