Imeglimin Exhibits Novel Anti-Inflammatory Effects on High-Glucose-Stimulated Mouse Microglia through ULK1-Mediated Suppression of the TXNIP-NLRP3 Axis.

Type 2 diabetes mellitus (T2DM) is an epidemiological risk factor for dementia and has been implicated in multifactorial pathologies, including neuroinflammation. In the present study, we aimed to elucidate the potential anti-inflammatory effects of imeglimin, a novel antidiabetic agent, on high-glucose (HG)-stimulated microglia. Mouse microglial BV2 cells were stimulated with HG in the presence or absence of imeglimin. We examined the effects of imeglimin on the levels of proinflammatory cytokines, intracellular reactive oxygen species (ROS), mitochondrial integrity, and components related to the inflammasome or autophagy pathways in these cells. Our results showed that imeglimin suppressed the HG-induced production of interleukin-1beta (IL-1ß) by reducing the intracellular ROS levels, ameliorating mitochondrial dysfunction, and inhibiting the activation of the thioredoxin-interacting protein (TXNIP)-NOD-like receptor family pyrin domain containing 3 (NLRP3) axis. Moreover, the inhibitory effects of imeglimin on the TXNIP-NLRP3 axis depended on the imeglimin-induced activation of ULK1, which also exhibited novel anti-inflammatory effects without autophagy induction. These findings suggest that imeglimin exerted novel suppressive effects on HG-stimulated microglia through the ULK1-TXNIP-NLRP3 axis, and may, thereby, contribute to the development of innovative strategies to prevent T2DM-associated cognitive impairment.

3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41.

3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41.

Taxifolin Suppresses Inflammatory Responses of High-Glucose-Stimulated Mouse Microglia by Attenuating the TXNIP-NLRP3 Axis.

Type 2 diabetes mellitus is associated with an increased risk of dementia, potentially through multifactorial pathologies, including neuroinflammation. Therefore, there is a need to identify novel agents that can suppress neuroinflammation and prevent cognitive impairment in diabetes. In the present study, we demonstrated that a high-glucose (HG) environment elevates the intracellular reactive oxygen species (ROS) levels and triggers inflammatory responses in the mouse microglial cell line BV-2. We further found that thioredoxin-interacting protein (TXNIP), a ROS-responsive positive regulator of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, was also upregulated, followed by NLRP3 inflammasome activation and subsequent interleukin-1beta (IL-1ß) production in these cells. Conversely, caspase-1 was not significantly activated, suggesting the involvement of noncanonical pathways in these inflammatory responses. Moreover, our results demonstrated that taxifolin, a natural flavonoid with antioxidant and radical scavenging activities, suppressed IL-1ß production by reducing the intracellular ROS levels and inhibiting the activation of the TXNIP-NLRP3 axis. These findings suggest the novel anti-inflammatory effects of taxifolin on microglia in an HG environment, which could help develop novel strategies for suppressing neuroinflammation in diabetes.

Lactococcus cremoris subsp. cremoris FC-fermented milk activates protein synthesis and increases skeletal muscle mass in middle-aged mice.

Age-related muscle atrophy is associated with decreased protein anabolic capacity. Dietary intervention is an important strategy for the treatment of age-related muscle atrophy. This study examined the effect of Lactococcus cremoris subsp. cremoris FC-fermented milk on muscle mass and protein anabolic signaling in middle-aged mice. Male C57BL/6J mice (18-month-old) were divided into the control and Lactococcus cremoris subsp. cremoris FC-fermented milk supplementation groups. Mice were administered unfermented or fermented milk (300 µL/day) by gavage every alternate day for 8 weeks; thereafter, muscle weight, protein metabolic signaling factors, and inflammatory factors were investigated. Soleus muscle weight was higher in the fermented milk group than in the control group. Expression of insulin growth factor-1, a typical anabolic factor, and phosphorylation levels of anabolic signaling factors (mTOR and p70S6K) were higher after fermented milk supplementation. Levels of tumor necrosis factor-α, an inhibitor of protein anabolism, were lower in the fermented milk group. These data suggest that the daily intake of Lactococcus cremoris subsp. cremoris FC-fermented milk increased skeletal muscle mass as well as protein synthesis in the middle-aged mice, which may be mediated by reduction in the levels of inflammatory factors. Therefore, accelerated protein synthesis, induced by the consumption of fermented milk, has a potential role in counteracting muscle atrophy.

Metabolic functions of flavonoids: From human epidemiology to molecular mechanism.

Dietary flavonoid intake is associated with the regulation of nutrient metabolism in the living body. Observational and cohort studies have reported a negative association between flavonoid intake and the risk of metabolic and cardiovascular diseases. Several intervention trials in humans have also supported the benefits of dietary flavonoids. In experimental studies using animal models, a daily diet rich in typical flavonoids such as catechins, anthocyanin, isoflavone, and quercetin was shown to improve whole-body energy expenditure, mitochondrial activity, and glucose tolerance. For some flavonoids, molecular targets for the metabolic modulations have been suggested. Although the effect of flavonoids on neurons has been unclear, several flavonoids have been shown to regulate thermogenesis and feeding behavior through modulating autonomic and central nervous systems. Based on epidemiological and experimental studies, this review summarizes the evidence on the metabolic benefits of flavonoids and their potential mechanism of action in metabolic regulation.

A milk casein hydrolysate-derived peptide enhances glucose uptake through the AMP-activated protein kinase signalling pathway in skeletal muscle cells.

NEW FINDINGS: What is the central question of this study? How do common active ingredients contained in both Lactobacillus helveticus-fermented milk and milk casein hydrolysate (MCH) enhance glucose metabolism by skeletal muscle? What is the main finding and its importance? MCH enhanced glucose uptake in skeletal muscle cells by stimulating AMP-activated kinase, but not insulin, signalling. Moreover, the MCH-derived specific peptide Ile-Pro-Pro mimicked this effect, suggesting a mechanism for MCH-induced metabolic improvement. ABSTRACT: Improvement of glucose metabolism in the skeletal muscle has a key role in exercise performance and prevention of metabolic diseases. In our previous study, we showed that intake of milk casein hydrolysate improves glucose metabolism in humans, but the mechanism of action was not elucidated. In this study, we aimed to investigate the mechanism of action of milk casein hydrolysate and its derived peptides on glucose uptake and glucose metabolic signalling in cultured skeletal muscle cells. Differentiated C2C12 myotubes were used for the experiments. The differentiated cells were incubated with milk casein hydrolysate, valine-proline-proline and isoleucine-proline-proline. Subsequently, the rate of 2-deoxy-glucose uptake and the phosphorylation levels of insulin-dependent and -independent signalling factors were examined. We found that the rate of 2-deoxy-glucose uptake in both milk casein hydrolysate and isoleucine-proline-proline-treated cells was higher than that in the control cells. Immunoblotting assays showed that the phosphorylation levels of AMP-activated protein kinase, a rate-limiting factor in insulin-independent signalling, and of liver kinase B1, an upstream factor of AMP-activated protein kinase, in both milk casein hydrolysate and isoleucine-proline-proline-treated cells were higher than those in the control cells. Such significant effects were not observed after treatment with valine-proline-proline. Moreover, the insulin-dependent signalling was not significantly affected under the different conditions. The findings of our study suggest that milk casein hydrolysate enhances glucose uptake by activating insulin-independent AMP-activated protein kinase signalling in skeletal muscle cells, which might be mediated by a milk casein hydrolysate-derived peptide, namely, isoleucine-proline-proline.

Erratum to: The effect of Katsura-uri (Japanese pickling melon, Cucumis melo var. conomon) and its derived ingredient methylthioacetic acid on energy metabolism during aerobic exercise.

[This corrects the article DOI: 10.1186/s40064-015-1144-y.].

The effect of Katsura-uri (Japanese pickling melon, Cucumis melo var. conomon) and its derived ingredient methylthioacetic acid on energy metabolism during aerobic exercise.

PURPOSE: We investigated the effect of Katsura-uri (Japanese pickling melon; Cucumis melo var. conomon) on energy metabolism during exercise in human and animal studies. METHODS: Eight healthy men (mean age, 21.4 ± 0.7 years) participated in a single-blind, crossover study. Thirty minutes after ingesting the Katsura-uri drink or placebo drink, they exercised on a cycle ergometer at 40% maximal heart rate for 30 min. Respiratory gas analysis was performed during exercise to examine oxygen consumption and substrate utilization. Blood biochemical parameters were evaluated during exercise. In the animal study, the effect of methylthioacetic acid (MTA), a Katsura-uri derived component was examined in mice. Immediately after running at 25 m/min for 30 min, biochemical parameters in the hind limb muscle and blood of mice were measured. RESULTS: Oxygen consumption during exercise was higher in the Katsura-uri condition (19.8 ± 3.5 mL/kg/min) than the placebo condition (18.6 ± 3.0 mL/kg/min) (P < 0.05). The elevation of blood lactate was lower in the Katsura-uri condition (1.7 ± 0.4 mM) than the placebo condition (2.2 ± 0.6 mM) 15 min after beginning exercise (P < 0.05). There was a higher positive correlation between lactate concentration and carbohydrate oxidation during exercise in the Katsura-uri condition (R(2) = 0.86) compared to the placebo condition (R(2) = 0.47). The decrease in intermuscular pH and the increase in blood lactate following exercise were prevented by MTA supplementation (250 ppm) with significant differences in the MTA-supplemented group compared to the control group. CONCLUSIONS: These results suggest that the ingestion of Katsura-uri and/or MTA improves glucose metabolism and acidification in skeletal muscles during exercise in human and animal studies.

Fermented milk improves glucose metabolism in exercise-induced muscle damage in young healthy men.

BACKGROUND: This study investigated the effect of fermented milk supplementation on glucose metabolism associated with muscle damage after acute exercise in humans. METHODS: Eighteen healthy young men participated in each of the three trials of the study: rest, exercise with placebo, and exercise with fermented milk. In the exercise trials, subjects carried out resistance exercise consisting of five sets of leg and bench presses at 70-100% 12 repetition maximum. Examination beverage (fermented milk or placebo) was taken before and after exercise in double-blind method. On the following day, we conducted an analysis of respiratory metabolic performance, blood collection, and evaluation of muscle soreness. RESULTS: Muscle soreness was significantly suppressed by the consumption of fermented milk compared with placebo (placebo, 14.2 ± 1.2 score vs. fermented milk, 12.6 ± 1.1 score, p < 0.05). Serum creatine phosphokinase was significantly increased by exercise, but this increase showed a tendency of suppression after the consumption of fermented milk. Exercise significantly decreased the respiratory quotient (rest, 0.88 ± 0.01 vs. placebo, 0.84 ± 0.02, p < 0.05), although this decrease was negated by the consumption of fermented milk (0.88 ± 0.01, p < 0.05). Furthermore, exercise significantly reduced the absorption capacity of serum oxygen radical (rest, 6.9 ± 0.4 µmol TE/g vs. placebo, 6.0 ± 0.3 µmol TE/g, p < 0.05), although this reduction was not observed with the consumption of fermented milk (6.2 ± 0.3 µmol TE/g). CONCLUSION: These results suggest that fermented milk supplementation improves glucose metabolism and alleviates the effects of muscle soreness after high-intensity exercise, possibly associated with the regulation of antioxidant capacity.

Combined light exercise after meal intake suppresses postprandial serum triglyceride.

PURPOSE: The effect of exercise performed on the day of meal intake on postprandial triglyceride concentration, which is an independent risk factor for cardiovascular disease, is unclear. The present study investigated the effects of combined low-intensity exercise before and after a high-fat meal on serum triglyceride concentrations. METHODS: Ten healthy young subjects (four men and six women) consumed a relatively high-fat diet (fat energy ratio: men = 37.8%, women = 39.1%). In the exercise trials, subjects performed brisk walking (2.0 km) after light resistance exercise, either 60 min before or after meal intake. Blood samples were collected before and 2, 4, and 6 h after meal intake. RESULTS: Exercise resulted in a reduction in the transient elevation in serum triglyceride concentration observed 2 h after meal intake in the postmeal trial (131 ± 67 mg·dL) when compared with the sedentary trial (172 ± 71 mg·dL; 95% confidence interval = 7.2-79.4, d = -1.00). This was also observed in the premeal trial, although the effect was less pronounced (148 ± 66 mg·dL; 95% confidence interval = -9.0 to 59.0, d = -0.57). The triglyceride concentrations in the VLDL, LDL, and HDL fractions, but not the chylomicron fraction, were also decreased 2 h after meal intake in both exercise trials, whereas the integrated triglyceride values after meal intake showed a greater decrease when exercise was performed after meal intake (d = -1.23) than before (d = -0.47). The concentration of serum growth hormone was drastically increased after exercise in both trials. CONCLUSIONS: Low-intensity exercise on the day of meal intake, particular after intake, can prevent the elevation of postprandial triglyceride concentration in healthy young subjects.