Satoshi Haramizu

Catechin-induced activation of the LKB1/AMP-activated protein kinase pathway.

Catechins are abundant in green tea and induce a variety of biologic actions, including anti-cancer, anti-obesity, and anti-diabetes effects, and their clinical application has been widely investigated. To clarify the underlying molecular mechanisms of these actions, we examined the effect of catechins on AMP-activated protein kinase (AMPK) in cultured cells and in mice. In Hepa 1-6, L6, and 3T3-L1 cells, epigallocatechin gallate (EGCG) induced increases in AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC) phosphorylation, and AMPKalpha activity. Analysis of the molecular specificity of eight naturally occurring catechins revealed that catechins with a gallocatechin moiety or a galloyl residue act as AMPK activators. In addition, phosphorylation of LKB1, which is a tumor-suppressor protein and a major AMPK-kinase, was increased by catechin treatment. EGCG-induced phosphorylation of LKB1 and AMPKalpha was suppressed by treatment with catalase, suggesting that reactive oxygen species are involved in EGCG-induced activation of the LKB1/AMPK pathway. Oral administration of EGCG (200mg/kg body weight) to BALB/c mice induced an increase in AMPKalpha activity in the liver concomitant with a significant increase in AMPKalpha and ACC phosphorylation. EGCG administration also increased oxygen consumption and fat oxidation, as determined by indirect calorimetry. These findings suggest that multiple effects of catechins, including anti-obesity and anti-cancer effects, are mediated, at least in part, by the activation of LKB1/AMPK in various tissues, and that these effects vary according to the catechin structure.

Tea catechin ingestion combined with habitual exercise suppresses the aging-associated decline in physical performance in senescence-accelerated mice

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.

Tea catechins prevent contractile dysfunction in unloaded murine soleus muscle: A pilot study

OBJECTIVE Extended periods of muscle disuse, physical inactivity, immobilization, and bedrest result in a loss of muscle mass and a decrease in muscle force, which are accompanied by an increase in oxidative stress. We investigated the effects of the intake of green tea catechins on unloading-induced muscle dysfunction in tail-suspended mice. METHODS Ten-week-old male BALB/c mice were fed a purified control diet or a diet containing 0.5% tea catechins for 14 d. Thereafter, the mice were subjected to continuous tail suspension for 10 d. On the final day, muscle mass, contractile force production, antioxidant potential, and carbonylated protein levels were evaluated. RESULTS Hind limb unloading caused a loss of soleus muscle weight and muscle force. Intake of tea catechins significantly inhibited the unloading-induced decrease in force in isolated soleus muscle by 19% compared with the control group, although tea catechins did not affect muscle weight. In addition, intake of tea catechins suppressed the decrease in antioxidant potential and the increase in carbonyl myofibrillar protein. CONCLUSION Ingestion of tea catechins minimized contractile dysfunction in skeletal muscle and muscle atrophy in unloaded muscle. This effect might be partly due to the lower oxidative modification of myofibrillar protein through the antioxidant activity of tea catechins.

Aging-Associated Changes in Physical Performance and Energy Metabolism in the Senescence-Accelerated Mouse

The aim of the study was to clarify the aging-associated changes in physical performance and energy metabolism in senescence-accelerated prone mouse (SAMP1). The endurance of aged SAMP1 was significantly lower by 28% than the age-matched senescence-resistant mouse (SAMR1). Oxygen consumption and fat oxidation in aged SAMP1 were lower by 19% and 22%, respectively. Peroxisome proliferator-activated receptor-γ coactivator-1β and medium-chain acyl coenzyme A dehydrogenase messenger RNA expression was significantly lower in aged SAMP1. Aged SAMP1 exhibited higher plasma glucose, insulin, leptin, and lower adiponectin concentrations. Aged SAMP1 also had higher malondialdehyde levels in plasma and tissues and lower peroxisome proliferator-activated receptor-γ messenger RNA and protein levels in adipose tissue. These results indicate that physical performance and energy expenditure decrease earlier with aging in SAMP1, accompanied by decreased fatty acid catabolism in muscle and liver and increased inflammation and oxidative stress in adipose tissue. SAMP1 could thus be a useful accelerated functional depression model for studying physical performance and energy metabolism.

Dietary milk fat globule membrane improves endurance capacity in mice

Milk fat globule membrane (MFGM) comprises carbohydrates, membrane-specific proteins, glycoproteins, phospholipids, and sphingolipids. We evaluated the effects of MFGM consumption over a 12-wk period on endurance capacity and energy metabolism in BALB/c mice. Long-term MFGM intake combined with regular exercise improved endurance capacity, as evidenced by swimming time until fatigue, in a dose-dependent manner. The effect of dietary MFGM plus exercise was accompanied by higher oxygen consumption and lower respiratory quotient, as determined by indirect calorimetry. MFGM intake combined with exercise increased plasma levels of free fatty acids after swimming. After chronic intake of MFGM combined with exercise, the triglyceride content in the gastrocnemius muscle increased significantly. Mice given MFGM combined with exercise had higher mRNA levels of peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc1α) and CPT-1b in the soleus muscle at rest, suggesting that increased lipid metabolism in skeletal muscle contributes, in part, to improved endurance capacity. MFGM treatment with cyclic equibiaxial stretch consisting of 10% elongation at 0.5 Hz with 1 h on and 5 h off increased the Pgc1α mRNA expression of differentiating C2C12 myoblasts in a dose-dependent manner. Supplementation with sphingomyelin increased endurance capacity in mice and Pgc1α mRNA expression in the soleus muscle in vivo and in differentiating myoblasts in vitro. These results indicate that dietary MFGM combined with exercise improves endurance performance via increased lipid metabolism and that sphingomyelin may be one of the components responsible for the beneficial effects of dietary MFGM.

Deletion of nuclear factor-κB p50 upregulates fatty acid utilization and contributes to an anti-obesity and high-endurance phenotype in mice

The transcription factor nuclear factor-κB (NF-κB) plays an important role in regulating physiological processes such as immunity and inflammation. In addition to this primary role, NF-κB interacts physically with peroxisome proliferator-activated receptors regulating lipid metabolism-related gene expression and inhibits their transcriptional activity. Therefore, inhibition of NF-κB may promote fatty acid utilization, which could ameliorate obesity and improve endurance capacity. To test this hypothesis, we attempted to elucidate the energy metabolic status of mice lacking the p50 subunit of NF-κB (p50 KO mice) from the tissue to whole body level. p50 KO mice showed a significantly lower respiratory quotient throughout the day than did wild-type (WT) mice; this decrease was associated with increased fatty acid oxidation activity in liver and gastrocnemius muscle of p50 KO mice. p50 KO mice that were fed a high-fat diet were also resistant to fat accumulation and adipose tissue inflammation. Furthermore, p50 KO mice showed a significantly longer maximum running time compared with WT mice, with a lower respiratory exchange ratio during exercise as well as higher residual muscle glycogen content and lower blood lactate levels after exercise. These results suggest that p50 deletion facilitates fatty acid catabolism, leading to an anti-obesity and high-endurance phenotype of mice and supporting the idea that NF-κB is an important regulator of energy metabolism.

Coffee polyphenols extracted from green coffee beans improve skin properties and microcirculatory function

Coffee polyphenols (CPPs), including chlorogenic acid, exert various physiological activities. The purpose of this study was to investigate the effects of CPPs on skin properties and microcirculatory function in humans. In this double-blind, placebo-controlled study, 49 female subjects with mildly xerotic skin received either a test beverage containing CPPs (270 mg/100 mL/day) or a placebo beverage for 8 weeks. The ingestion of CPPs significantly lowered the clinical scores for skin dryness, decreased transepidermal water loss, skin surface pH, and increased stratum corneum hydration and the responsiveness of skin blood flow during local warming. Moreover, the amounts of free fatty acids and lactic acid in the stratum corneum significantly increased after the ingestion of CPPs. These results suggest that an 8-week intake of CPPs improve skin permeability barrier function and hydration, with a concomitant improvement in microcirculatory function, leading to efficacy in the alleviation of mildly xerotic skin. Eight-Week intake of coffee polyphenols improves skin hydration and permeability barrier function, with a concomitant improvement of microcirculatory function.