Neural Regeneration Research (May 2025)
Decoding the nexus: branched-chain amino acids and their connection with sleep, circadian rhythms, and cardiometabolic health
Abstract
The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and, either directly or indirectly, overall body health, encompassing metabolic and cardiovascular well-being. Given the heightened metabolic activity of the brain, there exists a considerable demand for nutrients in comparison to other organs. Among these, the branched-chain amino acids, comprising leucine, isoleucine, and valine, display distinctive significance, from their contribution to protein structure to their involvement in overall metabolism, especially in cerebral processes. Among the first amino acids that are released into circulation post-food intake, branched-chain amino acids assume a pivotal role in the regulation of protein synthesis, modulating insulin secretion and the amino acid sensing pathway of target of rapamycin. Branched-chain amino acids are key players in influencing the brain’s uptake of monoamine precursors, competing for a shared transporter. Beyond their involvement in protein synthesis, these amino acids contribute to the metabolic cycles of γ-aminobutyric acid and glutamate, as well as energy metabolism. Notably, they impact GABAergic neurons and the excitation/inhibition balance. The rhythmicity of branched-chain amino acids in plasma concentrations, observed over a 24-hour cycle and conserved in rodent models, is under circadian clock control. The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood. Disturbed sleep, obesity, diabetes, and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics. The mechanisms driving these effects are currently the focal point of ongoing research efforts, since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies. In this context, the Drosophila model, though underutilized, holds promise in shedding new light on these mechanisms. Initial findings indicate its potential to introduce novel concepts, particularly in elucidating the intricate connections between the circadian clock, sleep/wake, and metabolism. Consequently, the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle. They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health, paving the way for potential therapeutic interventions.
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