The sleep-wake cycle: molecular mechanisms, disorders, and therapeutic targets in the context of energy metabolism.

A close interconnection exists between the sleep-wake cycle and energy metabolism. During non-rapid eye movement (NREM) sleep, the body experiences a significant decline in basal metabolic rate and overall energy expenditure, coupled with a concurrent acceleration in the clearance of cerebral metabolic wastes. Sleep deprivation or insufficiency can disrupt metabolic homeostasis, compromising the clearance of metabolic waste from the brain and thereby elevating the risk for a range of adverse outcomes, including type 2 diabetes, obesity, and dementia. However, the converse relationship, whereby perturbations in energy metabolism disrupt the sleep-wake cycle and lead to sleep disorders, remains an area lacking detailed investigation. Accordingly, this review synthesizes established evidence on the neural substrates and regulatory mechanisms of the sleep-wake cycle. Central to our discussion is the role of energy metabolism in these processes, with special consideration given to the impact of cell type-specific metabolic profiles on sleep-wake regulation, such as their roles in ATP surge during the early stage of sleep. We also summarize the sleep disorders observed in conditions of energy metabolic disruption and those with impaired energy generation. Complementing this, a compelling body of evidence indicates that pharmacological enhancement of metabolism frequently results in improved sleep. In short, this review advances the perspective that rectifying underlying metabolic deficiencies offers a paradigm shift in sleep therapy.