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Background: Branched-chain amino acids (BCAAs) regulate protein metabolism and energy homeostasis; however, elevated BCAA exposure is associated with cardiometabolic risk. While overall feeding timing influences metabolic health, the metabolic consequences of circadian phase-dependent BCAA enrichment remain insufficiently defined. Methods: A total of 18 male Sprague-Dawley rats were assigned for 12 weeks to diets designed to be nominally isocaloric and isonitrogenous while redistributing BCAA content across the light-dark cycle: control (Ctrl), D + N - (BCAA-enriched during the inactive/light phase and reduced during the active/dark phase), or D - N + (BCAA-reduced during the inactive phase and enriched during the active phase). Growth trajectories, plasma lipids, liver and skeletal muscle untargeted metabolomes, pathway enrichment networks, and selected hepatic antioxidant indices were evaluated, and skeletal muscle mammalian target of rapamycin complex 1 (mTORC1) signaling was assessed by S6 phosphorylation at the terminal fasted time point. Results: Final body weight and skeletal muscle p-S6/S6 did not differ across the groups. However, D - N + showed more uniform growth trajectories (lower residual variance) compared to Ctrl and D + N-. Plasma LDL-C was higher in D + N - than Ctrl. Untargeted metabolomics demonstrated the strongest group separation in the liver, driven predominantly by lipid-related features including putative bile acid-annotated metabolites, whereas skeletal muscle changes were more heterogeneous. Tissue BCAA and detected branched-chain keto acid (BCKA) abundances were largely unchanged. Pathway-network analysis indicated that inactive-phase BCAA enrichment (D + N-) was associated with hepatic glutathione-pathway enrichment and downregulation of nutrient-handling modules (e.g., protein digestion/absorption), whereas active-phase enrichment (D - N+) showed lower enrichment of stress/immune-adjacent pathways (e.g., necroptosis/sphingolipid signaling). Consistently, hepatic total superoxide dismutase (T-SOD) activity was higher in D - N + than in D + N-, while GSH/GSSG was unchanged. In the skeletal muscle, D - N + was associated with enrichment of energy/biosynthetic support pathways (purine/nucleotide metabolism; pantothenate/coenzyme A CoA biosynthesis) without a sustained endpoint shift in mTORC1 readout. Conclusion: Redistributing BCAA exposure across circadian phases produces measurable, timing-dependent metabolic differences, with the liver exhibiting the most coherent response. Aligning BCAA enrichment to the active phase is associated with a more favorable hepatic antioxidant/stress-signaling profile, whereas inactive-phase enrichment coincides with a mild dyslipidemic signal and redox-adjacent pathway remodeling.
Yu et al. (Thu,) studied this question.