N-methyl-D-aspartate receptor coagonist D-serine suppresses intake of high-preference food

D-Serine is abundant in the forebrain and physiologically important for modulating excitatory gluta-matergic neurotransmission as a coagonist of synaptic N-methyl-D-aspartate (NMDA) receptor. NMDA signaling has been implicated in the control of food intake. However, the role of D-serine on appetite regulation is unknown. To clarify the effects of D-serine on appetite, we investigated the effect of oral D-serine ingestion on food intake in three different feeding paradigms (one-food access, two-food choice, and refeeding after 24-h fasting) using three different strains of male mice (C57Bl/6J, BKS, and ICR). The effect of D-serine was also tested in leptin signaling-deficient db/db mice and sensory-deafferented (capsaicin-treated) mice. The expression of orexigenic neuropeptides [neuropeptide Y (Npy) and agouti-related protein (Agrp)] in the hypothalamus was compared in fast/refed experiments. Conditioned taste aversion for high-fat diet (HFD) was tested in the D-serine-treated mice. Under the one-food-access paradigm, some of the D-serine-treated mice showed starvation, but not when fed normal chow. HFD feeding with D-serine ingestion did not cause aversion. Under the two-food-choice paradigm, D-serine suppressed the intake of high-preference food but not normal chow. D-Serine also effectively suppressed HFD intake but not normal chow in db/db mice and sensory-deafferented mice. In addition, D-serine suppressed normal chow intake after 24-h fasting despite higher orexigenic gene expression in the hypothalamus. D-Serine failed to suppress HFD intake in the presence of L-701,324, the selective and full antagonist at the glycine-binding site of the NMDA receptor. Therefore, D-serine suppresses the intake of high-preference food through coagonism toward NMDA receptors.