L-serine enhances light-induced circadian phase resetting in mice and humans

Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood. Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans. Methods: Male CBA/N mice were orally administered 1 of 20 L-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before L-serine administration, and light-induced phase shifts were analyzed. In addition, the effect of L-serine on the light-induced phase advance was investigated in healthy male students (mean ± SD age 22.2 ± 1.8 y) by using dim-light melatonin onset (DLMO) determined by saliva samples as an index of the circadian phase. Results: L-Serine administration enhanced light-induced phase shifts inmice (1.86-fold; P < 0.05). Both L-serine and its metabolite D-serine, a coagonist of N-methyl-D-aspartic acid (NMDA) receptors, exerted this effect, but D-serine concentrations in the hypothalamus did not increase after L-serine administration. The effect of L-serine was blocked by picrotoxin, an antagonist of γ-aminobutyric acid A receptors, but not by MK801, an antagonist of NMDA receptors. L-Serine administration altered the long-term expression patterns of clock genes in the suprachiasmatic nuclei. After advancing the light-dark cycle by 6 h, L-serine administration slightly accelerated re-entrainment to the shifted cycle. In humans, L-serine ingestion before bedtime induced significantly larger phase advances of DLMO after bright-light exposure during the morning (means ± SEMs-L-serine: 25.9 ± 6.6 min; placebo: 12.1 ± 7.0 min; P < 0.05). Conclusion: These results suggest that L-serine enhances light-induced phase resetting in mice and humans, and it may be useful for treating circadian disturbances.