Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants

Jacqueline K. Limberg, Sarah E. Baker, Humphrey G. Petersen-Jones, Winston Guo, An Huang, Michael D. Jensen, Prachi Singh

Research output: Contribution to journalArticlepeer-review

Abstract

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. 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 ± 5 yr, 26 ± 2 kg/m2) 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 < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 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.

Original languageEnglish (US)
Pages (from-to)R351-R362
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume323
Issue number3
DOIs
StatePublished - Sep 2022

Keywords

  • adipose tissue
  • bosentan
  • epinephrine
  • fatty acids
  • intermittent hypoxia

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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