Vitamin D (VD) deficiency has been associated with cognitive impairment; however, the mechanisms underlying this relationship remain unclear. In this study, we examined the impact of dietary VD deficiency on cognitive function and explored the potential involvement of gastrointestinal signaling pathways independently of changes in circulating VD levels. Mice fed a VD-deficient (VD-Def) diet exhibited impaired cognitive performance in behavioral tests, including the novel object recognition test and the object location test, despite unchanged circulating 25-hydroxyvitamin D [25(OH)D] levels. Notably, this cognitive impairment was ameliorated by oral, but not intraperitoneal, administration of VD, indicating a route-dependent effect. Furthermore, the cognitive improvement induced by oral VD was abolished by oral administration of methyllycaconitine, an α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, whereas intraperitoneal administration had no effect. These findings suggest that α7nAChRs via the gastrointestinal tract are required for the cognitive benefits of orally administered VD. Collectively, our results demonstrate that VD deficiency can impair cognitive function independently of systemic VD depletion and metabolic changes, and highlight a previously unrecognized role of gastrointestinal cholinergic signaling in mediating the cognitive effects of VD.

Seafood, which is rich in omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is reported to be associated with sleep. Animal studies have suggested that these fatty acids influence circadian clock system. People can be classified into morning, intermediate, and evening types based on their chronotype. Social jetlag, defined as the discrepancy in sleep schedule between workdays and free days, is more pronounced in individuals with an evening chronotype. However, the association between the timing of seafood and EPA and or DHA consumption and sleep phase in humans remains unclear. This cross-sectional study aimed to examine the relationship between seafood, EPA, and DHA intake at three different mealtimes and from snacks and sleep patterns among Japanese adults. Dietary and sleep data were collected from 5,975 adults aged 18–75. Generalized estimating equations were used to assess the associations between sleep patterns and seafood, EPA, and DHA intake at breakfast, lunch, dinner, and snack times—measured using a mobile food-logging application—taking chronotype and social jetlag into consideration. Higher total daily intake of seafood, EPA, and DHA was associated with a morning chronotype and less social jetlag. Intake at breakfast and lunch related to morningness and less social jetlag, with breakfast showing the strongest association. These findings suggest that both the quantity and timing of seafood, EPA, and DHA intake may be related to sleep patterns; however, causal relationships cannot be inferred due to the cross-sectional design.

Creatine supplementation can improve muscle outcomes in older adults, particularly when combined with resistance exercise; however, its efficacy without exercise is less consistent. Guanidinoacetic acid (GAA), the immediate precursor of creatine, may bypass age-related limitations in creatine synthesis and transport and exert distinct effects on muscle energetics and protein metabolism. The main aim of the study was compare the effects of 8 wk of GAA versus creatine supplementation on muscle strength, body composition, and selected protein metabolism biomarkers in older adults. In this randomized, double-blind, exploratory pilot trial, 25 apparently healthy adults aged ≥65 y were assigned to receive GAA (2.0 g/d) or an equimolar dose of creatine monohydrate for 8 wk. Twenty-one participants completed the study (GAA, n=11; creatine, n=10). Handgrip strength, body composition and fluid compartments (via multifrequency bioelectrical impedance analysis), and circulating myostatin, insulin-like growth factor-1, mammalian target of rapamycin, total homocysteine, albumin, and total protein were assessed at baseline and follow-up. Intervention effects were evaluated using repeated-measures ANOVA, and between-group effect sizes for change scores were estimated using Hedges’ g with 95% confidence intervals. Handgrip strength increased significantly with GAA (p=0.01) but not with creatine, with a significant time-by-treatment interaction (p=0.04) and a large between-group effect favoring GAA (g=0.91, 95% CI: 0.00 to 1.81). GAA supplementation was associated with significant within-group increases in fat-free mass, body cell mass, muscle mass, and total body water, whereas creatine supplementation did not produce comparable changes. Effect size analyses generally favored GAA for strength, muscle-related indices, and hydration-related compartments, although confidence intervals were wide. Both supplements reduced circulating myostatin, with greater suppression observed with GAA. Creatine supplementation produced a modest reduction in serum albumin that remained within physiological reference ranges. Serum IGF-1 concentrations were below the assay detection limit in most participants, precluding evaluation of the GH-IGF-1 axis. No adverse events were reported, and compliance exceeded 97% in both groups. In this exploratory pilot trial conducted without structured exercise, GAA supplementation was associated with numerically greater improvements in muscle strength and several muscle-related indices compared with creatine; however, these findings are preliminary and hypothesis-generating and require confirmation in adequately powered trials targeting sarcopenia.

A balanced diet has been associated with a lower risk of total and cardiovascular mortality. One intermediate function linking a balanced diet and lower mortality may be optimal insulin secretion. We examined the association between adherence to the Japanese Food Guide Spinning Top (JFGST) and serum C-peptide concentration, an indicator of basal insulin secretion, in a cross-sectional study in a Japanese population, in whom rice (refined grains) is the staple food. A blood sample was collected in November 2012 and a 12-d weighed food record was collected over the subsequent year. A total of 210 healthy residents aged 35–80 y (83 men, 127 women) were included in the analysis. Multiple regression analysis was performed with log-transformed serum C-peptide concentration as dependent variable and total JFGST score or each score by category of dish as independent variable, with adjustment for age and BMI. In both men and women, total JFGST score was inversely associated with serum C-peptide concentration. Slope in the percentage of differences for every 1-point score addition based the regression coefficients was −2.3% (p<0.001) in men and −1.6% (p<0.001) in women. For specified categories of dishes, scores for grain dishes, snacks and alcoholic beverages, and total energy were inversely associated with serum C-peptide concentrations among men. Among women, in contrast, scores for milk and for fruit were inversely associated with serum C-peptide concentrations. A balanced diet consistent with the JFGST was inversely associated with serum C-peptide concentration among middle-aged Japanese.

This study investigated the relationship between masticatory behaviors, masticatory ability, and body mass index (BMI) in healthy adult males and females using a newly developed wearable mastication counter. A total of 106 healthy dentulous participants were included. Assessments during rice ball consumption evaluated mastication frequency, meal duration, mastication speed, masticatory ability, and the presence of fast-eating habits. Statistical analyses compared factors by sex and fast-eating habits and examined the relationships between BMI and these factors, with a 5% significance level. The results showed that BMI was significantly associated with sex, fast-eating habits, and mastication frequency. Females had higher mastication frequency and longer meal durations but mastication speed and lower masticatory ability compared with males. Additionally, participants in the fast-eating group exhibited higher BMI, lower mastication frequency, and shorter meal durations than those in the non-fast-eating group. In conclusion, BMI was associated with sex, fast-eating habit, and mastication frequency in this cross-sectional sample. Further longitudinal or interventional studies are needed to clarify causality.

A number of studies have suggested that tannins improve lipid metabolism disorders. Based on the close relationship between liver and the gut microbiota through the gut-liver axis, we hypothesized that tannins may reduce lipid accumulation in the liver by modulating the gut microbiota. To test this hypothesis, we administered persimmon-derived tannins to rats fed a high-fat diet for 11 wk. Blood parameters and cholesterol, TG, and lipid droplet areas in the liver tissues were measured, and the gut microbiota of the cecal contents was analyzed using 16S rDNA sequencing. The results showed that persimmon-derived tannins significantly suppressed high-fat diet-induced increases in hepatic cholesterol levels. We also observed significant changes in the gut microbiota, including increased α- and β-diversity, a decreased Bacillota/Bacteroidota ratio, and an increased relative abundance of 15 genera, including Akkermansia, Bacteroides, Alloprevotella, and Alistipes. Collectively, these results suggest that persimmon-derived tannins may reduce lipid accumulation in the liver tissues, at least in part, through modulating the gut microbiota, indicating their potential as a functional food component for the prevention of liver diseases. Moreover, these findings provide new insights into the role of plant-derived polyphenols in the regulation of lipid metabolism through gut microbiota modulation. This study is significant because it revealed a relationship between the functionality of persimmon-derived tannins and the gut microbiota.

Equol (Eq), produced by intestinal bacteria, is a more active metabolite than its precursor, daidzein; however, its production varies greatly among individuals. Bile acids (BAs) influence the balance of intestinal microbiota and may affect Eq production. Therefore, this study aimed to investigate the effects of BAs on Eq production in humans. Twenty-four-hour urine and feces were collected simultaneously from 23 participants after a 3-d soy challenge. Fecal samples from three participants with confirmed Eq-production ability, as determined by urinary analysis and in vitro fecal incubation, were used for incubation with BAs. Furthermore, the effects of co-addition of substances with BA-binding ability were examined. Fecal incubation from the three Eq producers showed distinctive daidzin (D) metabolic patterns, and the inhibitory concentrations of BAs on Eq production differed among individual samples. These differences were thought to be due to variations in individual microbiota. However, in all samples, cholic, chenodeoxycholic, and deoxycholic acids (CA, CDCA, and DCA, respectively), the major human BAs, inhibited D metabolism to Eq in a concentration-dependent manner at physiological concentrations. CDCA and DCA had approximately 10 times stronger inhibitory effects than CA. Co-addition of cholestyramine attenuated the inhibitory effects of BAs; therefore, ingestion of substances with BA-binding ability was expected to improve Eq production. However, the addition of sodium alginate, which has BA-binding ability and may affect the microbiota, showed variable response among individual samples. These results strongly suggest that BAs secreted into the intestinal tract are significant factors affecting Eq production in humans.

Regulation of skeletal muscle glucose uptake is an effective strategy for reducing postprandial hyperglycemia and improving whole-body glucose homeostasis in the management of type 2 diabetes. The present study investigated that cardamom enhances glucose uptake in skeletal muscle in vitro and improves glucose tolerance in vivo. Bioactivity-guided fractionation of cardamom identified an ethyl acetate fraction (Fr. A) and its subfraction (Fr. A-i) as potent stimulators of glucose uptake in L6 myotubes. Both fractions significantly promoted glucose uptake by enhancing glucose transporter type 4 (GLUT4) translocation to the plasma membrane. Mechanistic investigations revealed activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, accompanied by increased phosphorylation of Akt substrate of 160 kDa (AS160), a key regulator of GLUT4 vesicle trafficking, while no significant changes were observed in insulin receptor substrate-1 (IRS-1) or AMP-activated protein kinase (AMPK) phosphorylation. Fr. A induced a more pronounced effect on AS160 phosphorylation and was therefore selected for further evaluation. The antihyperglycemic potential of Fr. A was assessed in ICR mice using an oral glucose tolerance test. Oral administration of Fr. A (1 and 10 mg/kg body weight) significantly improved glucose tolerance and alleviated postprandial hyperglycemia. Cardamom in skeletal muscle and highlights its potential as a natural therapeutic candidate for the management of postprandial hyperglycemia.

Obesity is a global health concern, prompting extensive research to identify food components with potential anti-obesity properties. Agaro-oligosaccharides (AOS) have been reported to have anti-obesity effects; however, the precise mechanisms underlying these effects, particularly in relation to the gut microbial metabolites, remain unclear. This study investigated the anti-obesity effects of AOS using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an established animal model of obesity. Seven-week-old Long-Evans Tokushima Otsuka (LETO) and OLETF rats were fed a control diet or a diet supplemented with AOS for 13 wk. Blood parameters, liver lipids, and gene expression in the liver and ileum were analyzed. Bile acids were evaluated using liquid chromatography-mass spectrometry, and the cecal microbiota was analyzed using 16S rRNA sequencing. AOS supplementation suppressed body weight gain, improved metabolic parameters, and reduced hepatic triglycerides in OLETF rats. AOS supplementation altered bile acids and gut microbiota composition, increasing Akkermansia muciniphila abundance in the cecum. In addition, AOS intake downregulated the expression of lipid synthesis-related genes in the liver and ceramide synthesis-related genes in the ileum. AOS supplementation influences obesity and lipid metabolism by modulating the gut microbiota and bile acid metabolism. Therefore, AOS may help prevent various diseases by improving lipid metabolism.

Retinoic acid (RA), a biologically active metabolite of vitamin A, regulates gene expression through retinoic acid receptor/retinoid X receptor (RAR/RXR)-dependent transcription and is important for various biological phenomena. To understand the role of forebrain RA signaling in synaptic plasticity and memory, we generated transgenic mice expressing a dominant-negative form of retinoic acid receptor α (dnRARα) in adult forebrain. We previously showed that dnRARα expression in the adult forebrain impairs α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission and long-term potentiation (LTP) in hippocampal CA1 neurons and hippocampus-dependent memory. To investigate the molecular basis of these impairments, we here examined expressions of synaptic plasticity-related molecules in the hippocampus of dnRARα mice. We found that protein levels of GluA1 and postsynaptic density protein 95 (PSD-95) were significantly reduced in the hippocampus of dnRARα mice in a dnRARα expression-dependent manner. To further examine protein expression changes in dnRARα mice, we performed proteome analysis and found that expression of actin-related protein 3 (ARP3), a molecule implicated in activity-dependent spine enlargement and maturation, was also reduced. Combined with our previous findings, these results suggest that forebrain RAR/RXR signaling is crucial for maintaining synaptic transmission, plasticity, and memory formation by upregulating GluA1, PSD-95, and ARP3.

To elucidate mechanisms governing gene expression regulation in the liver in response to choline deficiency, we sought to identify genes responsive to choline-deficient conditions by conducting gene expression analysis in the livers of rats fed a choline-deficient diet. These rats exhibited reduced choline and betaine levels in their livers, and a group of genes linked to inflammatory responses and lipid metabolism was upregulated. Primary rat hepatocytes were cultured in choline-deficient medium to identify genes upregulated as intracellular choline and betaine levels decrease. Comparative analysis of gene expression profiles to identify regulated genes revealed that ubiquitin D (Ubd) expression is commonly upregulated under choline-deficient conditions in vivo and in cultured hepatocytes.