Regular exercise reduces adipose tissue inflammation and improves glycemic control in Western diet‐fed mice despite hyperendothelinemia

The upregulation of endothelin‐1 (ET‐1), a peptide primarily expressed and secreted into the circulation from endothelial cells, is a key molecular signature in obesity and type 2 diabetes. Given its potent pro‐oxidant and inflammatory effects, ET‐1 is thought to be implicated in the etiology of metabolic dysfunction. Based on previous evidence that regular exercise decreases ET‐1 expression and signaling, it is conceivable that the well‐established exercise‐induced anti‐inflammatory effects and associated improvement in glycemic control is, in part, mediated by a reduction in ET‐1 actions; however, this remains unknown. Accordingly, we tested the hypothesis that overproduction of ET‐1 from endothelial cells and resulting hyperendothelinemia limits the beneficial metabolic adaptations of exercise. Six‐week‐old male transgenic mice overexpressing human preproET‐1 selectively in the endothelium (eET‐1) and non‐transgenic (i.e., wild‐type) littermates were fed a Western diet (46% Kcal fat, 36% Kcal carbohydrate) to induce obesity, while they either remained sedentary or had free access to a running wheel for 12 weeks, creating four groups (n=7–12/group): wild‐type sedentary, wild‐type exercise, eET‐1 sedentary, eET‐1 exercise. Plasma ET‐1 was significantly elevated in eET‐1 mice (sedentary: 15.12±3.77 pg/ml; exercise 14.90±2.30 pg/ml) versus wild‐type (sedentary: 0.02±0.02 pg/ml; exercise: 0.29±0.14 pg/ml) in both sedentary and exercise‐trained mice. Exercise reduced final body weight, adiposity, fasting plasma insulin, HOMA‐IR, cholesterol and triglycerides compared to sedentary mice, and these effects were independent of genotype. Also independent of genotype, exercise reduced visceral adipocyte hypertrophy, immune cell infiltration, inflammatory gene expression (e.g., IL‐1β and CD11c), as well as enhanced visceral adipose tissue insulin signaling (i.e., increased ex vivo insulin‐stimulated pAkt/Akt). Furthermore, exercise improved glucose tolerance and this improvement was mildly enhanced in eET‐1 mice (i.e., significant genotype × exercise interaction). In summary, contrary to our hypothesis, we find that experimentally‐induced hyperendothelinemia does not impede exercise‐induced improvements in metabolic function, supporting the notion that reduced ET‐1 signaling is not required for the beneficial metabolic adaptations of exercise to manifest. Support or Funding Information National Institute of Health This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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