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We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32\u2009\u00b1\u20095 yr, 26\u2009\u00b1\u20092 kg\/m<jats:sup>2<\/jats:sup>) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors\/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA ( P &lt; 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA ( P &lt; 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis ( P &gt; 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone. <\/jats:p>","DOI":"10.1152\/ajpregu.00301.2021","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T21:07:01Z","timestamp":1657573621000},"page":"R351-R362","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants"],"prefix":"10.1152","volume":"323","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9982-5851","authenticated-orcid":false,"given":"Jacqueline K.","family":"Limberg","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota"},{"name":"Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, 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