Search

Hydroxyhydroquinone (HHQ) is an oxidative component produced by roasting coffee beans and has been reported to generate relatively large amounts of reactive oxygen species (ROS). In this study, we used senescence-accelerated mouse prone 8 (SAMP8) mice to determine whether HHQ consumption increases oxidative-stress-induced injury, because in SAMP8 mice, the activity of 8-oxoguanine DNA glycosylase 1, which repairs oxidative modifications in DNA, is decreased. The results showed that two out of twelve (16.7%) HHQ-treated mice presented polyuria and glucosuria around 2 months after the start of treatment, indicating that HHQ may act as a mutagen against SAMP8 mice, which is sensitive to oxidative damage. No abnormalities were observed in the chlorogenic acid (coffee polyphenol, CPP)-treated group. The concentration of hydrogen peroxide in the serum of SAMP8 mice was significantly higher than that in SAMR1 (senescence-resistant) control mice, and the concentration was further increased in the HHQ-treated group. CPP, when coexisting with HHQ at the rate contained in roasted coffee, decreased the amount of hydrogen peroxide in the serum of SAMP8 mice. Although CPP can act both oxidatively and antioxidatively as a polyphenol, CPP acts more antioxidatively when coexisting with HHQ. Thus, the oxidative effect of HHQ was shown to be counteracted by CPP. [ABSTRACT FROM AUTHOR]

The sodium–glucose cotransporter 2 (SGLT2) mainly carries out glucose reabsorption in the kidney. Familial renal glycosuria, which is a mutation of SGLT2, is known to excrete glucose in the urine, but blood glucose levels are almost normal. Therefore, SGLT2 inhibitors are attracting attention as a new therapeutic drug for diabetes, which is increasing worldwide. In fact, SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases. However, whether long-term SGLT2 inhibition is completely harmless requires further investigation. In this context, mice with mutations in SGLT2 have been generated and detailed studies are being conducted, e.g., the SGLT2−/− mouse, Sweet Pee mouse, Jimbee mouse, and SAMP10-ΔSglt2 mouse. Biological changes associated with SGLT2 mutations have been reported in these model mice, suggesting that SGLT2 is not only responsible for sugar reabsorption but is also related to other functions, such as bone metabolism, longevity, and cognitive functions. In this review, we present the characteristics of these mutant mice. Moreover, because the relationship between diabetes and Alzheimer's disease has been discussed, we examined the relationship between changes in glucose homeostasis and the amyloid precursor protein in SGLT2 mutant mice. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPK[alpha]1 and -[alpha]2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPK[alpha] and the downstream target acetylCoA carboxylase (ACC), in [C.sub.2][C.sub.12] cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and [Ca.sup.2+]/ calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPAR[gamma] coactivator-l[alpha] in [C.sub.2][C.sub.12] cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical pertbrmance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver. AMP-activated protein kinase; exercise; endurance; LKB1; [Ca.sup.2+]/ calmodulin-dependent protein kinase kinase doi: 10.1152/ajpendo.00774.2009.

Chemically modified starches (CMS) are RS4-type resistant starch, which shows a reduced availability, as well as high-amylose corn starch (HACS, RS2 type), compared with the corresponding unmodified starch. Previous studies have shown that RS4 increases fecal excretion of bile acids and reduces zinc and iron absorption in rats. The aim of this study was to investigate the effects of dietary RS4 supplementation on the development of diet-induced obesity in mice. Weight- and age-matched male C57BL/6J mice were fed for 24 wk on a high-fat diet containing unmodified starch, hydroxypropylated distarch phosphate (RS4), or HACS (RS2). Those fed the RS4 diet had significantly lower body weight and visceral fat weight than those fed either unmodified starch or the RS2 diet. Those fed the RS4 diet for 4 wk had a significantly higher hepatic fatty acid oxidation capacity and related gene expression and lower blood insulin than those fed either unmodified starch or the RS2 diet. Indirect calorimetry showed that the RS4 group exhibited higher energy expenditure and fat utilization compared with the RS2 group. When gavaged with fat (trioleate), RS4 stimulated a lower postprandial glucose-dependent insulinotropic polypeptide (GIP; incretin) response than RS2. Higher blood GIP levels induced by chronic GIP administration reduced fat utilization in high-fat diet-fed mice. In conclusion, dietary supplementation with RS4-type resistant starch attenuates high-fat diet-induced obesity more effectively than RS2 in C57BL/6J mice, which may be attributable to lower postprandial GIP and increased fat catabolism in the liver. glucose-dependent insulinotropic polypeptide; insulin doi:10.1152/ajpendo.00468.2009.

Catechins, which are abundant in green tea, possess a variety of biologic actions, and their clinical application has been extensively investigated. In this study, we examined the effects of tea catechins and regular exercise on the aging-associated decline in physical performance in senescence-accelerated prone mice (SAMP1) and age-matched senescence-accelerated resistant mice (SAMR1). The endurance capacity of SAMR1 mice, measured as the running time to exhaustion, tended to increase over the 8-wk experimental period, whereas that of SAMP1 mice decreased by 17%. On the other hand, the endurance capacity of SAMP1 mice fed 0.35% (wt/wt) catechins remained at the initial level and was significantly higher than that of SAMP1 mice not fed catechins. In SAMP1 mice fed catechins and given exercise, oxygen consumption was significantly increased, and there was an increase in skeletal muscle fatty acid [beta]-oxidation. The mRNA levels of mitochondria-related molecules, such as peroxisome proliferator-activated receptor-[gamma] coactivator-1, cytochrome c oxidase-II, III, and IV in skeletal muscle were also higher in SAMP1 mice given both catechins and exercise. Moreover, oxidative stress measured as thiobarbituric reactive substances was lower in SAMP1 groups fed catechins than in the SAMP1 control group. These results suggest that long-term intake of catechins, together with habitual exercise, is beneficial for suppressing the aging-related decline in physical performance and energy metabolism and that these effects are due, at least in part, to improved mitochondrial function in skeletal muscle. energy metabolism; exercise; green tea; mitochondria; oxidative stress

Fish oils (FO) rich in (n-3) PUFA exert hypolipidemic and antiobesity effects in association with modulated hepatic lipid metabolism. We recently demonstrated the possible involvement of intestinal lipid metabolism in the development of obesity. In this study, we examined the effect of FO ingestion on intestinal lipid metabolism in relation to obesity. When dietinduced obesity-prone C57BL/6J mice were fed an 8% FO, high-fat (30%) diet for 5 mo, body weight gain was significantly reduced compared with mice fed a 30% triacylglycerol (TG) diet without FO. In addition to modulating messenger RNA (mRNA) levels in the liver, FO ingestion for 2 wk affected the intestinal mRNA levels of lipid metabolism-related genes; those of carnitine palmitoyltransferase 1 a, cytochrome P450 4A10, and malic enzyme were significantly higher in mice fed the 8% FO diet compared with mice fed the 30% TG diet. Northern blot analysis revealed that the expression levels of most lipid metabolism-related genes in the small intestine of mice fed the 8% FO diet were comparable to those in the liver. Furthermore, reflecting the difference at the mRNA level, FO ingestion affected lipid metabolism-related enzyme activity; fatty acid [beta]-oxidation, [omega]-oxidation, and malic enzyme activities in the small intestine of mice fed the 8% FO diet were 1.2-, 1.6-, and 1.7-fold those in mice fed the 30% TG diet, respectively. These findings suggest that an upregulation of intestinal lipid metabolism is associated with the antiobesity effect of FO. J. Nutr. 137: 2629-2634, 2007.

Recent studies of the relation between serum triacylglycerol concentration and the risk for coronary artery disease suggest that inefficient clearance of postprandial triacylglycerols promotes atherogenesis. We recently demonstrated that dietary diacylglycerol (DAG), rich in the 1,3-species, suppresses the postprandial increase in serum triacylglycerol levels compared with dietary triacylglycerol (TAG). Here, we investigated the effects of dietary DAG on atherosclerosis in rabbits with cholesterol-induced atherosclerosis. New Zealand White rabbits (n = 20) were fed a diet containing 3% lard and 1.3% cholesterol for 50 d to induce atherosclerotic lesions. Thereafter, the rabbits were assigned to 2 groups and fed 90 g/d nonpurified diet and orally administered 5 g DAG or TAG for an additional 34 d. Reference rabbits (n = 5) were fed only the nonpurified diet throughout the 84-d study. The area of atherosclerotic lesions and aortic lipid concentrations were significantly lower in DAG-fed rabbits compared with TAG-fed rabbits. The VLDL receptor and macrophage antigen-1 mRNA expression levels were significantly lower in DAG-fed rabbits than in TAG-fed rabbits. In the liver of DAG-fed rabbits, the triacylglycerol concentration was lower and the carnitine palmitoyltransferase activity higher than in TAG-fed rabbits. Stimulation of hepatic lipid catabolism might be related to the reduced lipid accumulation in the liver and aorta by reducing the release of triacylglycerol into the circulation. Thus, long-term consumption of DAG, which reduces postprandial lipemia, might be useful for the regression of atherosclerosis by stimulating hepatic lipid catabolism and thereby modulating monocyte/macrophage migration and aortic lipid accumulation.

The effects of high-fat (HF) feeding on gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-prone C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF; 5% fat) or HF (30% fat) diets for 2 wk. Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and [NADP.sup.+]-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice. The upregulated gene expression levels were higher in A/J mice than in B6 mice, suggesting more active lipid metabolism in the small intestine of A/J mice. The prominent upregulation of the lipid metabolism-related genes were specific to the small intestine; the expression levels were little or unchanged in the liver, muscle, and white adipose tissue. The increase by HF feeding and predominant expression of the intestinal lipid metabolism-related genes in A/J mice were reflected in the enzyme activities; malic enzyme, CPT, and [beta]-oxidation activities were increased by HF feeding, and the upregulated malic enzyme and CPT activities were significantly higher in obesity-resistant A/J mice compared with those in obesity-prone B6 mice. These findings suggest that intestinal lipid metabolism is associated with susceptibility to obesity. high fat; intestine; [beta]-oxidation; carnitine palmitoyltransferase; nicotinamide adenine dinucleotide [phosphate.sup.+]-dependent cytosolic malic enzyme

A series of polyphenols known as catechins are abundant in green tea, which is consumed mainly in Asian countries. The effects of catechin-rich green tea extract (GTE) on running endurance and energy metabolism during exercise in BALB/c mice were investigated. Mice were divided into four groups: nonexercise control, exercise control (Ex-cont), exercise + 0.2% GTE, and exercise + 0.5% GTE groups. Treadmill running time to exhaustion, plasma biochemical parameters, skeletal muscle glycogen content, [beta]-oxidation activity, and malonyl-CoA content immediately after exercise were measured at 8-10 wk after the initiation of the experiment. Oxygen consumption and respiratory exchange ratio were measured using indirect calorimetry. Running times to exhaustion in mice fed 0.5% GTE were 30% higher than in Ex-cont mice and were accompanied by a lower respiratory exchange ratio, higher muscle [beta]-oxidation activity, and lower malonyl-CoA content. In addition, muscle glycogen content was high in the GTE group compared with the Ex-cont group. Plasma lactate concentrations in mice fed GTE were significantly lower after exercise, concomitant with an increase in free fatty acid concentrations. Catechins, which are the main constituents of GTE, did not show significant effects on peroxisome proliferator-activated receptor-[alpha] or [delta]-dependent luciferase activities. These results suggest that the endurance-improving effects of GTE were mediated, at least partly, by increased metabolic capacity and utilization of fatty acid as a source of energy in skeletal muscle during exercise. catechins; glycogen; malonyl-coenzyme A; lipid metabolism

Mice feed with coffee polyphenols (CPP, chlorogenic acid) and milk fat globule membrane (MFGM) has increased survival rates and helps retain long-term memory. In the cerebral cortex of aged mice, CPP intake decreased the expression of the proinflammatory cytokine TNF-α, and lysosomal enzyme cathepsin B. The suppression of inflammation in the brain during aging was thought to result in the suppression of the repressor element 1-silencing transcription factor (REST) and prevention of brain aging. In contrast, CPP increased the expression of REST, cAMP-responsive element binding (CREB) and transforming growth factor β1 (TGF-β1) in the young hippocampus. The increased expression of these factors may contribute to the induction of neuronal differentiation and the suppression of memory decline with aging. Taken together, these results suggest that CPP increases CREB in the young hippocampus and suppresses inflammation in the old brain, resulting in a preventive effect on brain aging. The endotoxin levels were not elevated in the serum of aged mice. Although the mechanism of action of MFGM has not yet been elucidated, the increase in survival rate with both CPP and MFGM intake suggests that adding milk to coffee may improve not only the taste, but also the function. [ABSTRACT FROM AUTHOR]

The content and distribution of melanin in the epidermis determines the wide variety of skin colors associated with ethnic/racial diversity. Although it was previously reported that qualitative changes in keratinocyte‐derived exosomes regulate melanocyte pigmentation in vitro, their practical involvement, especially in skin color development in vivo, has remained unclear. To address this unexplained scientific concern, the correlation of epidermal exosomes isolated from human skin tissues with melanosomal protein expression levels was demonstrated in this study for the first time. After confirming the quantitative effect of human keratinocyte‐derived exosomes on human melanocyte activation, even in the absence of ultraviolet B (UV‐B) exposure, the impact of exosomes secreted from UV‐B‐irradiated keratinocytes on melanogenesis was consistently detected, which suggests their constitutive role in regulating cutaneous pigmentation. Additionally, both a specific exosome secretion inducer and a suppressor were consistently found to significantly control melanin synthesis in a co‐culture system composed of keratinocytes and melanocytes as well as in an ex vivo skin culture system. These results suggest that quantitative changes, in addition to already known qualitative changes, in exosomes secreted from human epidermal keratinocytes homeostatically regulate melanogenic activity in a paracrine manner, which leads to skin color determination. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of perilla extract on urinary symptoms in spontaneously hypertensive rats as a model of spontaneous overactive bladder. Methods: Spontaneously hypertensive rats were randomly divided into two groups and fed either a control diet or a perilla extract‐containing diet. Cystometry, gene expression and histological analyses were carried out to evaluate the effects of perilla extract after 2‐week feeding of either the control or the perilla extract diet. The expression of inflammation‐related genes in the human urothelial cell line HT‐1376 and the normal human bladder epithelial cell was measured after the treatment with perillaldehyde, the main component of perilla extract, or perillic acid, the final metabolite of perillaldehyde. Results: A significant 27% increase in the micturition interval and decreased expression of nerve growth factor, tumor necrosis factor‐α, interleukin‐1β and transient receptor potential V1 were observed in the perilla group compared with the control group. The level of uroplakin 3A was 40% higher in the perilla group than in the control group. The urothelium in the control group was thin or defective, but it was almost completely intact in the perilla group. Perillaldehyde and perillic acid suppressed the induction of nerve growth factor and tumor necrosis factor‐α by interleukin‐1β in HT‐1376 and normal human bladder epithelial cells. Conclusions: The present findings suggest that perilla extract improves frequent urination, and this improvement seems to be mediated, at least in part, by enhancement of the urothelial presence and by the anti‐inflammatory effects of perilla. [ABSTRACT FROM AUTHOR]

Fat-rich diets not only induce obesity in humans but also make animals obese. Therefore, animals that accumulate body fat in response to a high-fat diet (especially rodents) are commonly used in obesity research. The effect of dietary fat on body fat accumulation is not fully understood in zebrafish, an excellent model of vertebrate lipid metabolism. Here, we explored the effects of dietary fat and green tea extract, which has anti-obesity properties, on body fat accumulation in zebrafish. Adult zebrafish were allocated to four diet groups and over 6 weeks were fed a high-fat diet containing basal diet plus two types of fat or a low-fat diet containing basal diet plus carbohydrate or protein. Another group of adult zebrafish was fed a high-fat diet with or without 5% green tea extract supplementation. Zebrafish fed the high-fat diets had nearly twice the body fat (visceral, subcutaneous, and total fat) volume and body fat volume ratio (body fat volume/body weight) of those fed low-fat diets. There were no differences in body fat accumulation between the two high-fat groups, nor were there any differences between the two low-fat groups. Adding green tea extract to the high-fat diet significantly suppressed body weight, body fat volume, and body fat volume ratio compared with the same diet lacking green tea extract. 3-Hydroxyacyl-coenzyme A dehydrogenase and citrate synthase activity in the liver and skeletal muscle were significantly higher in fish fed the diet supplemented with green tea extract than in those fed the unsupplemented diet. Our results suggest that a diet rich in fat, instead of protein or carbohydrate, induced body fat accumulation in zebrafish with mechanisms that might be similar to those in mammals. Consequently, zebrafish might serve as a good animal model for research into obesity induced by high-fat diets. [ABSTRACT FROM AUTHOR]

Objective: To investigate the combined and separate effects of exercise and milk fat globule membrane (MFGM) supplementation on frailty, physical function, physical activity level, and hematological parameters in community-dwelling elderly Japanese women. Methods: A total of 131 frail, elderly women over 75 years were randomly assigned to one of four groups: exercise and MFGM supplementation (Ex+MFGM), exercise and placebo (Ex+Plac), MFGM supplementation, or the placebo group. The exercise group attended a 60-minute training program twice a week for three months, and the MFGM group ingested 1g of the MFGM supplement in pill form, daily for 3 months. The primary outcome measure was change in frailty status based on Fried’s frailty phenotype. Secondary outcome measures included body composition, physical function and hematological parameters, and interview survey components assessing lifestyle factors. Participants were followed for 4 months post-intervention. Results: Significant group×time interactions were observed for usual walking speed (P = 0.005), timed up & go (P<0.001), and insulin-like growth factor-binding protein 3 / insulin-like growth factor 1 ratio (P = 0.013). The frailty components revealed that weight loss, exhaustion, low physical activity, and slow walking speed were reversed, but low muscle strength did not significantly changed. Frailty reversal rate was significantly higher in the Ex+MFGM (57.6%) than in the MFGM (28.1%) or placebo (30.3%) groups at post-intervention (χ2 = 8.827, P = 0.032), and at the follow-up was also significantly greater in the Ex+MFGM (45.5%) and Ex+Plac (39.4%) groups compared with the placebo (15.2%) group (χ2 = 8.607, P = 0.035). The exercise+MFGM group had the highest odds ratio (OR) for frailty reversal at post-intervention and follow-up (OR = 3.12, 95% confidence interval (CI) = 1.13–8.60; and OR = 4.67, 95% CI = 1.45–15.08, respectively). Conclusion: This study suggests that interventions including exercise and nutrition can improve frailty status. Statistically significant additive effects of MFGM with exercise could not be confirmed in this population, and further investigation in larger samples is necessary. Trial Registration: The Japan Medical Association Clinical Trial Registry (JMACCT) [ABSTRACT FROM AUTHOR]