Orexin receptor antagonist increases fat oxidation and suppresses protein catabolism during sleep in humans

Suvorexant is an orexin receptor antagonist that targets the wake-promoting system. Orexin is also known to regulate energy metabolism in rodents, but its role in humans remains largely unknown. Here, we assessed the effect of suvorexant (20 mg) on energy metabolism during sleep and shortly after awakening in a randomized, double-blind, placebo-controlled, crossover study in 14 healthy men. Suvorexant increased rapid eye movement (REM) but decreased nonrapid eye movement (NREM) stage 1. Energy expenditure during wake after sleep onset (WASO) was higher than that during NREM and REM sleep in the placebo but not in the suvorexant trial, suggesting that the increase in energy expenditure during WASO was due to an activation of the orexin system. Fat oxidation during sleep increased, and its effect remained after waking the next morning. Suvorexant decreased protein catabolism but did not affect overall energy expenditure. The orexin system may affect fat oxidation independent of its roles in sleep regulation in humans.