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

Abstract

d-Serine is abundant in the forebrain and physiologically important for modulating excitatory glutamatergic 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.

Chronic d-serine supplementation impairs insulin secretion

“…We find that d -serine reduces HFD induced weight gain through a reduction in high fat food intake, which seems to depend on altered food preference. These data are in line with Sasaki et al., who described that d -serine suppresses intake of high preference food resulting in blunted weight gain [15] . However, in contrast to this previous study, in our experiments, mice exposed to HFD + d -serine resumed consuming HFD, albeit less than HFD control mice, which could be explained by differences in gut microbiota between and the expansion of obesogenic bacteria facilitating weight gain in our mouse facility.…”

“…One of those genes is serine racemase (SRR) [13] , which catalyzes the conversion from l -serine to d -serine, an important co-agonist of N-methyl- d -aspartate (NMDA) receptors. SRR function was recently suggested to regulate insulin secretion from pancreatic beta cells [3] , [14] , and chronic as well as acute supplementation of the SRR product d -serine reduced food intake and weight gain upon high fat diet (HFD) feeding in mice [15] , [16] . However, dysfunction of SRR, the d -serine degrading d -amino acid oxidase (DAO), and the main d -serine transporter alanine-serine-cysteine transporter 1 (Asc-1) are implicated in the development of schizophrenia, Alzheimer's disease, and depression [17] , [18] , [19] , [20] , [21] .…”

Genome-wide association analysis reveals genetic loci and candidate genes for feeding behavior and eating efficiency in Duroc boars

“…This gene encodes mitogen-activated protein kinase kinase kinase 14, which is a serine/threonine protein-kinase. In mice, D-serine suppresses the intake of high-preference food[ 50 ]. Moreover, MAP3K14 gene knockout mice showed a reduction in the weight of the mammary fat pad.…”

Expanding frontiers in weight-control research explored by young investigators

“…The varying concentration of d -serine water was provided to mice fed either a normal chow diet or a high-fat diet. We found that the increasing dose of d -serine in the drinking water significantly suppressed the intake of high-fat diet, but not the normal chow diet [110]. d -serine water at 1.5 % (weight/volume) concentration also suppressed the intake of a high-sucrose diet and a high-protein diet.…”