Yoshihiko Minegishi

Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice

The prevalence of obesity is increasing globally, and obesity is a major risk factor for type 2 diabetes and cardiovascular disease. We investigated the effects of coffee polyphenols (CPP), which are abundant in coffee and consumed worldwide, on diet-induced body fat accumulation. C57BL/6J mice were fed either a control diet, a high-fat diet, or a high-fat diet supplemented with 0.5 to 1.0% CPP for 2-15 wk. Supplementation with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, and infiltration of macrophages into adipose tissues. Energy expenditure evaluated by indirect calorimetry was significantly increased in CPP-fed mice. The mRNA levels of sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 in the liver were significantly lower in CPP-fed mice than in high-fat control mice. Similarly, CPP suppressed the expression of these molecules in Hepa 1-6 cells, concomitant with an increase in microRNA-122. Structure-activity relationship studies of nine quinic acid derivatives isolated from CPP in Hepa 1-6 cells suggested that mono- or di-caffeoyl quinic acids (CQA) are active substances in the beneficial effects of CPP. Furthermore, CPP and 5-CQA decreased the nuclear active form of SREBP-1, acetyl-CoA carboxylase activity, and cellular malonyl-CoA levels. These findings indicate that CPP enhances energy metabolism and reduces lipogenesis by downregulating SREBP-1c and related molecules, which leads to the suppression of body fat accumulation.

Ginger extract prevents high-fat diet-induced obesity in mice via activation of the peroxisome proliferator-activated receptor δ pathway ☆

The initiation of obesity entails an imbalance wherein energy intake exceeds expenditure. Obesity is increasing in prevalence and is now a worldwide health problem. Food-derived peroxisome proliferator-activated receptor δ (PPARδ) stimulators represent potential treatment options for obesity. Ginger (Zingiber officinale Roscoe) was previously shown to regulate the PPARγ signaling pathway in adipocytes. In this study, we investigated the antiobesity effects of ginger in vivo and the mechanism of action in vitro. Energy expenditure was increased, and diet-induced obesity was attenuated in C57BL/6J mice treated with dietary ginger extract (GE). GE also increased the number of Type I muscle fibers, improved running endurance capacity and upregulated PPARδ-targeted gene expression in skeletal muscle and the liver. 6-Shogaol and 6-gingerol acted as specific PPARδ ligands and stimulated PPARδ-dependent gene expression in cultured human skeletal muscle myotubes. An analysis of cellular respiration revealed that pretreating cultured skeletal muscle myotubes with GE increased palmitate-induced oxygen consumption rate, which suggested an increase in cellular fatty acid catabolism. These results demonstrated that sustained activation of the PPARδ pathway with GE attenuated diet-induced obesity and improved exercise endurance capacity by increasing skeletal muscle fat catabolism. 6-Shogaol and 6-gingerol may be responsible for the regulatory effects of dietary ginger on PPARδ signaling.

Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK

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 AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(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 performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver.

Effects of Nutritional Supplementation with Milk Fat Globule Membrane on Physical and Muscle Function in Healthy Adults Aged 60 and Over with Semiweekly Light Exercise : A Randomized Double-Blind, Placebo-Controlled Pilot Trial

This study aimed to demonstrate the beneficial effects of nutritional supplementation with dietary milk fat globule membrane (MFGM) on physical performance and skeletal muscle function in healthy adults aged 60 and over with semiweekly light exercise. The study was designed as a randomized double-blind controlled trial. Twenty-two Japanese participants (10 men, 12 women) aged 60-73 y were assigned to one of two groups (11 [5 men, 6 women] in each). One group received MFGM tablets (1 g MFGM/d), and the other received placebo tablets daily for 10 wk. Both groups participated in a twice-weekly light exercise program. Physical function tests and surface electromyography (EMG) were conducted at the baseline and after 5 and 10 wk. Chair stand time significantly shortened in both groups after 10 wk compared with that at the baseline. The average time shortened more considerably in the MFGM group than in the placebo group, although the change was not statistically significant. Both knee extension strength and the cross-sectional area of the quadriceps muscles significantly increased from baseline in the MFGM group but not in the placebo group. Surface EMG showed that muscle fiber conduction velocity increased significantly after 10 wk from the baseline only in the MFGM group. The increase from the baseline was significantly greater in the MFGM group than in the placebo group. Daily supplementation with MFGM increased motor unit action potential conduction and improved muscle strength and physical performance in healthy Japanese adults aged 60 y and over paired with semiweekly light exercise.

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.

Milk fat globule membrane supplementation with voluntary running exercise attenuates age-related motor dysfunction by suppressing neuromuscular junction abnormalities in mice

ABSTRACT Age‐related loss of skeletal muscle mass and function attenuates physical performance, and maintaining fine muscle innervation is known to play an important role in its prevention. We had previously shown that consumption of milk fat globule membrane (MFGM) with habitual exercise improves the muscle mass and motor function in humans and mice. Improvement of neuromuscular junction (NMJ) was suggested as one of the mechanisms underlying these effects. In this study, we evaluated the effect of MFGM intake combined with voluntary running (MFGM‐VR) on morphological changes of NMJ and motor function in aging mice. Seven months following the intervention, the MFGM‐VR group showed a significantly improved motor coordination in the rotarod test and muscle force in the grip strength test compared with the control group at 13 and 14 months of age, respectively. In 14‐month old control mice, the extensor digitorum longus muscle showed increased abnormal NMJs, such as fragmentation and denervation, compared with 6‐month old young mice. However, such age‐related deteriorations of NMJs were significantly suppressed in the MFGM‐VR group. Increase in the expression of NMJ formation‐related genes, such as agrin and LDL Receptor Related Protein 4 (LRP4), might contribute to this beneficial effect. Rotarod performance and grip strength showed significant negative correlation with the status of denervation and fragmentation of NMJs. These results suggest that MFGM intake with voluntary running exercise effectively suppresses age‐related morphological deterioration of NMJ, thus contributing to improvement of motor function. HIGHLIGHTSMilk fat globule membrane (MFGM) with exercise improved motor function in aging mice.MFGM with exercise attenuated age‐related neuromuscular junction (NMJ) abnormalities.The expression of NMJ related genes was upregulated by MFGM with exercise.The status of NMJ correlated with motor function and related gene expression.

Combined Supplementation of Pre-Exercise Carbohydrate, Alanine, and Proline and Continuous Intake of Green Tea Catechins Effectively Boost Endurance Performance in Mice

Continuous intake of green tea catechins (GTC) increases fatty acid utilization as an energy source and improves endurance capacity. Conversely, the single pre-exercise intake of maltodextrin (MD) as a carbohydrate source and the gluconeogenic amino acids alanine (Ala) and proline (Pro) effectively maintain blood glucose levels and increase endurance performance. In this study, we investigated the synergistic combinational effect of these interventions on endurance performance in mice. Male BALB/c mice were fed a 0.5% GTC diet or Control diet for 8 weeks. Maximum running time was measured every 2 weeks. MD (2 g/kg body weight (B.W.)), MD (1 g/kg B.W.) + AlaPro (9:1, 1 g/kg B.W.), and vehicle were orally administrated 60 mins before measurements in each diet group. The GTC + MD + AlaPro group showed significantly higher endurance performance than the Control-Vehicle group at all measurements. Indirect calorimetry analysis during running exercise at 4 weeks in the Control and GTC groups supplemented with pre-exercise MD + AlaPro administration revealed significantly higher fat oxidation in the GTC groups compared to the Control group. The combined increase in fatty acid utilization through continuous GTC intake and pre-exercise MD + AlaPro carbohydrate energy supplementation synergistically improves endurance capacity.