![]() ![]() It serves as a precursor of the neuroactive substances L-serine and glycine, and mediates neuroprotective effects ( 25, 26). In addition, L-serine exerts critical functions in the mammalian central nervous system. L-Serine is a precursor of glycine and cysteine, which can be used for the synthesis of glutathione. Recently, dietary supplementation with L-serine has been shown to have antioxidant effects ( 21– 24). L-Serine is traditionally considered a non-essential amino acid. Moreover, NFκB is also a central mediator of stress responses under conditions of oxidative stress and upon exposure to certain chemicals in the central nervous system ( 18). ![]() Importantly, NFκB functions as a central regulator of the immune response and controls the secretion of inflammatory cytokines in many tissues including the hypothalamus ( 18– 20). Additionally, the transcription factor nuclear factor-κB (NFκB) regulates numerous target genes to exert its biological functions. Debate is ongoing as to whether hypothalamic Sirt1 has orexigenic or anorexigenic effects, although most of the evidence shows that inhibition of Sirt1 induces a negative energy balance by regulating the activity of forkhead transcription factor FKHR (FOXO1) ( 13– 15) and the expression of agouti-related protein (AGRP) and neuropeptide Y (NPY) ( 16, 17). Importantly, Sirt1 is also a nutrient sensor and plays critical roles in the energy balance in the hypothalamus. Sirt1 activity in the hypothalamus decreases in association with aging, and its low expression contributes to a low level of antioxidants and increased oxidative damage ( 10). The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (Sirt1) regulates the response to oxidative stress, which correlates with many diseases ( 10– 12). These elevations of oxidative damage and inflammatory responses in the central nervous system are believed to contribute to age-related diseases including obesity and various neurodegenerative disorders ( 7– 9). Low levels of antioxidant enzymes and high levels of lipid peroxidation make the hypothalamus vulnerable to reactive oxygen species (ROS) ( 4– 6). However, in aging mice, increased levels of oxidative stress and inflammatory markers are observed in the hypothalamus ( 1– 3). The hypothalamus is a critical part of the central nervous system that modulates the stress response and senses nutrient-related inputs. Thus, L-serine has the potential to be used in the prevention of age-related obesity. These results indicated that long-term L-serine administration reduces body weight by decreasing orexigenic peptide expression and reduces oxidative stress and inflammation during aging in mice, possibly by modulating the Sirt1/NFκB pathway. The expression of Sirt1 and phosphorylated signal transducers and activators of transcription 3 (pSTAT3) increased, while that of phosphorylated NFκB decreased in the mice treated with 0.5% L-serine. Additionally, the expression of the leptin receptor increased while the levels of neuropeptide Y and agouti-related protein decreased in mice that had been treated with 0.5% L-serine. Reactive oxygen species and the activity of nicotinamide adenine dinucleotide phosphate oxidase were reduced in the hypothalamus of aging mice treated with L-serine as compared with untreated control mice. Moreover, the administration of 0.5% L-serine decreased the concentrations of leptin, malondialdehyde, interleukin-1β, and interleukin-6, while it increased those of superoxide dismutase and glutathione, in both the serum and hypothalamus. The results showed that the administration of 0.5% (w/v) L-serine significantly reduced food intake and body weight gain during the experiment. To explore whether long-term serine administration reduces oxidative stress and body weight in aging mice, various concentrations of L-serine dissolved in water were administered to 18-month-old C57BL/6J mice for 6 months. ![]() Serine has recently been shown to reduce oxidative stress and inflammation, which, when occurring in the hypothalamus, contribute to age-related obesity.
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