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

BACKGROUND
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 inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA.


METHODS
Sixteen healthy male participants (32±5 y, 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 (HWP).


RESULTS
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.


CONCLUSIONS
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.