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1.
Nutr Res ; 126: 14-22, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38603978

RESUMO

Hormonal changes during the menopause transition may lead to vasomotor symptoms, including hot flashes (HFs) and neuropsychiatric symptoms such as anxiety and irritability. We hypothesized that the effects of cassis polyphenol (CaP) to improve microcirculation and vasorelaxation may alleviate menopausal symptoms. We performed a randomized, double-blind, parallel-group, placebo-controlled trial involving 59 healthy women (mean [standard deviation] age, 51.3 [4.3] years; body mass index, 20.8 [2.6] kg/m2). Participants experiencing subjective menopausal symptoms consumed CaP tablets (400 mg/d, CaP group) or placebo tablets (placebo group) for 4 weeks. Participants were evaluated using questionnaires at baseline, during the 4-week intervention period, and during a 2-week postinterventional observation period. The primary objective was to evaluate the effects of supplementation with CaP on HFs in healthy Japanese women with menopausal symptoms. Additional assessments included the modified Kupperman menopausal index, World Health Organization-5 Well-Being Index, World Health Organization quality-of-life 26-item index, State-Trait Anxiety Inventory (anxiety and trait components), and Oguri-Shirakawa-Azumi sleep inventory (middle-aged and elderly versions). During the 4-week intervention period, no significant between-group differences were detected in the HF frequency, HF score, sweating frequency, menopausal symptoms, quality of life, anxiety, or sleep. During the 2-week postintervention observational period, the HF score and sweating frequency were significantly decreased in the CaP group compared with the placebo group. These findings suggest that twice daily intake of CaP for 4 weeks does not alleviate menopause symptoms, but the improvement observed in the CaP intake group during the postintervention period warrants confirmation through further large-scale studies.


Assuntos
Suplementos Nutricionais , Fogachos , Menopausa , Polifenóis , Qualidade de Vida , Humanos , Feminino , Método Duplo-Cego , Pessoa de Meia-Idade , Fogachos/tratamento farmacológico , Polifenóis/farmacologia , Polifenóis/administração & dosagem , Menopausa/efeitos dos fármacos , Ansiedade , Inquéritos e Questionários
2.
JMIR Res Protoc ; 12: e47024, 2023 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-37294611

RESUMO

BACKGROUND: Human health status can be measured on the basis of many different parameters. Statistical relationships among these different health parameters will enable several possible health care applications and an approximation of the current health status of individuals, which will allow for more personalized and preventive health care by informing the potential risks and developing personalized interventions. Furthermore, a better understanding of the modifiable risk factors related to lifestyle, diet, and physical activity will facilitate the design of optimal treatment approaches for individuals. OBJECTIVE: This study aims to provide a high-dimensional, cross-sectional data set of comprehensive health care information to construct a combined statistical model as a single joint probability distribution and enable further studies on individual relationships among the multidimensional data obtained. METHODS: In this cross-sectional observational study, data were collected from a population of 1000 adult men and women (aged ≥20 years) matching the age ratio of the typical adult Japanese population. Data include biochemical and metabolic profiles from blood, urine, saliva, and oral glucose tolerance tests; bacterial profiles from feces, facial skin, scalp skin, and saliva; messenger RNA, proteome, and metabolite analyses of facial and scalp skin surface lipids; lifestyle surveys and questionnaires; physical, motor, cognitive, and vascular function analyses; alopecia analysis; and comprehensive analyses of body odor components. Statistical analyses will be performed in 2 modes: one to train a joint probability distribution by combining a commercially available health care data set containing large amounts of relatively low-dimensional data with the cross-sectional data set described in this paper and another to individually investigate the relationships among the variables obtained in this study. RESULTS: Recruitment for this study started in October 2021 and ended in February 2022, with a total of 997 participants enrolled. The collected data will be used to build a joint probability distribution called a Virtual Human Generative Model. Both the model and the collected data are expected to provide information on the relationships between various health statuses. CONCLUSIONS: As different degrees of health status correlations are expected to differentially affect individual health status, this study will contribute to the development of empirically justified interventions based on the population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47024.

3.
Exp Brain Res ; 241(2): 661-675, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36662264

RESUMO

We examined the causes of decreased fingertip dexterity in elderly individuals with an aim to improve their quality of life by improving their activities of daily living. We calculated nerve conduction velocity, absolute error during force adjustment tasks, and fingertip dexterity test scores for 30 young (21-34 years old) and 30 elderly (60-74 years old) participants to identify age-related changes. We also assessed subjective complaints of pain, motor function, and numbness. Motor nerve (young: 55.8 ± 3.7 m/s; elderly: 52.2 ± 5.0 m/s) and sensory nerve (young: 59.4 ± 3.4 m/s; elderly: 55.5 ± 5.3 m/s) conduction velocities decreased in an age-dependent manner. Moreover, the decrease of motor nerve conduction velocity was associated with decreased fingertip dexterity (objective index), while the decrease of sensory nerve conduction velocity was associated with subjective complaints of pain and motor function (subjective index).


Assuntos
Atividades Cotidianas , Condução Nervosa , Humanos , Idoso , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Qualidade de Vida , Dedos/fisiologia , Dor
4.
Nutrients ; 12(2)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075202

RESUMO

The accumulation of amyloid ß (Aß) in the brain is a major pathological feature of Alzheimer's disease (AD). In our previous study, we demonstrated that coffee polyphenols (CPP) prevent cognitive dysfunction and Aß deposition in the brain of an APP/PS2 transgenic mouse AD model. The underlying mechanisms, however, remain to be elucidated. Here, we investigated the effects of the chronic administration of 5-caffeoylquinic acid (5-CQA), the most abundant component of CPP, on cognitive dysfunction in APP/PS2 mice to identify the role of CPP in Aß elimination. Relative to the untreated controls, the mice fed a 5-CQA-supplemented diet showed significant improvements in their cognitive function assessed by Y-maze and novel object recognition tests. Histochemical analysis revealed that 5-CQA substantially reduced Aß plaque formation and neuronal loss in the hippocampi. Moreover, 5-CQA upregulated the gene encoding low-density lipoprotein receptor-related protein 1, an Aß efflux receptor, and normalized the perivascular localization of aquaporin 4, which facilitates Aß clearance along the paravascular pathway. These results suggest that 5-CQA reduces Aß deposition in the brain by modulating the Aß clearance pathways and ameliorating cognitive decline and neuronal loss in APP/PS2 mice. Thus, 5-CQA may be effective in preventing cognitive dysfunction in AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Café , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Fitoterapia , Polifenóis/administração & dosagem , Polifenóis/farmacologia , Ácido Quínico/análogos & derivados , Animais , Modelos Animais de Doenças , Feminino , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Camundongos Transgênicos , Ácido Quínico/administração & dosagem , Ácido Quínico/farmacologia
5.
Neurosci Res ; 154: 35-44, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31121203

RESUMO

Epidemiological studies have found that habitual coffee consumption may reduce the risk of Alzheimer's disease. Coffee contains numerous phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, evidence demonstrating the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer's disease is limited. The present study investigated the effect of chlorogenic acids on the prevention of cognitive dysfunction in APP/PS2 transgenic mouse model of Alzheimer's disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was determined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Immunohistochemical analysis revealed that chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid ß (Aß) plaques in the hippocampus. Furthermore, we determined that 5-caffeoylquinic acid, one of the primary coffee polyphenols, did not inhibit Aß fibrillation; however, degraded Aß fibrils. In conclusion, our results demonstrate that coffee polyphenols prevent cognitive deficits and reduce Aß plaque deposition via disaggregation of Aß in the APP/PS2 mouse.


Assuntos
Doença de Alzheimer/prevenção & controle , Ácido Clorogênico/farmacologia , Café/química , Disfunção Cognitiva/prevenção & controle , Placa Amiloide/prevenção & controle , Polifenóis/farmacologia , Doença de Alzheimer/metabolismo , Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Córtex Cerebral/efeitos dos fármacos , Ácido Clorogênico/metabolismo , Café/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória , Camundongos , Camundongos Transgênicos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Teste de Campo Aberto/efeitos dos fármacos , Placa Amiloide/metabolismo , Polifenóis/metabolismo , Ácido Quínico/análogos & derivados , Ácido Quínico/química , Aprendizagem Espacial/efeitos dos fármacos
6.
J Agric Food Chem ; 67(11): 3118-3124, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30574780

RESUMO

Functional tea beverages have emerged as a novel approach to achieving health benefits associated with tea. The use of metabolomics may improve the evaluation of their consumption and their effects. The current study aimed at exploring the urinary signature of exposure to a functional high-catechin tea (HCT) using untargeted NMR-based metabolomics. Ten volunteers participated in a crossover intervention study. Individuals consumed an HCT or a control beverage over a period of 28 days. Multilevel partial least-squares discriminant analysis (ML-PLS-DA) was used for paired comparisons. A further crossover model was performed to assess the significant changes. The consumption of the HCT resulted in the excretion of theanine, epicatechin, pyrogallol sulfate, and higher levels of 3-methyl-2-oxovalerate and succinate, as well as unknown compounds. In conclusion, the present work established novel urinary signatures of a functional drink. Such signatures may be potential biomarkers and/or reflect certain benefits of functional tea beverages.


Assuntos
Biomarcadores/urina , Catequina/urina , Chá/metabolismo , Adulto , Análise Discriminante , Voluntários Saudáveis , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica
7.
Food Nutr Res ; 622018.
Artigo em Inglês | MEDLINE | ID: mdl-30302087

RESUMO

BACKGROUND: Compared to white rice, brown rice induces a lower glycemic response in healthy and diabetic humans. This effect is partly attributed to the higher amounts of water- or oil-soluble bran components and dietary fiber in brown rice. We hypothesized that dietary supplementation with oil-soluble rice bran triterpenoids (RBTs; triterpene alcohol and sterol prepared from rice bran) might reduce the incidence of postprandial hyperglycemia in healthy humans. OBJECTIVE: We examined the acute effects of a single RBT-supplemented meal on the postprandial blood glucose responses of healthy male adults in a double-blind, randomized, placebo-controlled, crossover trial. DESIGN: Nineteen subjects consumed a test meal containing either placebo- or RBT-supplemented olive oil. Blood biomarkers were evaluated in a fasting state and up to 240 min postprandially. RESULTS: Compared to the placebo-supplemented meal, the RBT-supplemented meal significantly suppressed the increase in postprandial blood glucose level. A subclass analysis revealed that RBT-supplemented oil significantly reduced blood glucose increases in subjects with higher postprandial blood glucose elevations. Postprandial increases in blood insulin, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1) levels did not differ between the groups. CONCLUSION: These results suggest that RBT consumption improves postprandial hyperglycemia in healthy humans, especially those with higher postprandial glucose increases.

8.
J Physiol Sci ; 68(6): 855-864, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29572772

RESUMO

Habitual consumption of chlorogenic acid compounds (CGAs) from coffee increases fat catabolism and reduces body fat; however, the contribution of roasted coffee remains unclear. Hydroxyhydroquinone (HHQ) impairs the vasodilatory and antihypertensive effects of CGAs by reducing nitric oxide (NO) bioavailability. Since HHQ also reduces fat catabolism, we hypothesized that HHQ does so by decreasing NO availability. Therefore, we investigated the effect of HHQ on energy metabolism in KKAy mice. In HHQ-treated mice, fat oxidation was significantly low and dose-dependent, serum and urinary hydrogen peroxide were high, and plasma NO metabolites and S-nitrosylated liver proteins were low. In HHQ-treated mouse hepatocytes, the palmitate-induced increase in cellular oxygen consumption was negatively affected, and HHQ or L-NAME reduced cellular fatty acid utilization. In conclusion, HHQ can impair fat utilization by reducing NO availability in mice. Protein S-nitrosylation reduction in liver cells after HHQ consumption may be associated with impaired fatty acid oxidation.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hidroquinonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Calorimetria Indireta , Hepatócitos/metabolismo , Peróxido de Hidrogênio/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ácido Palmítico/farmacologia
9.
Am J Physiol Endocrinol Metab ; 309(6): E523-33, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26173458

RESUMO

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.


Assuntos
Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Músculo Esquelético/metabolismo , Subunidade p50 de NF-kappa B/genética , Obesidade/genética , Resistência Física/genética , Tecido Adiposo/metabolismo , Animais , Inflamação , Masculino , Camundongos , Camundongos Knockout , Subunidade p50 de NF-kappa B/metabolismo , Oxirredução , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fenótipo , Regulação para Cima
10.
J Nutr Biochem ; 26(10): 1058-67, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26101135

RESUMO

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.


Assuntos
Fármacos Antiobesidade , Dieta Hiperlipídica , Obesidade/prevenção & controle , PPAR delta/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Zingiber officinale/química , Tecido Adiposo/citologia , Animais , Linhagem Celular , Dieta , Metabolismo Energético/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Obesidade/etiologia , PPAR delta/fisiologia , Resistência Física/efeitos dos fármacos
11.
Br J Nutr ; 107(12): 1757-65, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22017960

RESUMO

Postprandial energy metabolism, including postprandial hyperglycaemia, hyperinsulinaemia and hyperlipidaemia, is related to the risk for developing obesity and CVD. In the present study, we examined the effects of polyphenols purified from coffee (coffee polyphenols (CPP)) on postprandial carbohydrate and lipid metabolism, and whole-body substrate oxidation in C57BL/6J mice. In mice that co-ingested CPP with a lipid-carbohydrate (sucrose or starch)-mixed emulsion, the respiratory quotient determined by indirect calorimetry was significantly lower than that in control mice, whereas there was no difference in VO2 (energy expenditure), indicating that CPP modulates postprandial energy partitioning. CPP also suppressed postprandial increases in plasma glucose, insulin, glucose-dependent insulinotropic polypeptide and TAG levels. Inhibition experiments on digestive enzymes revealed that CPP inhibits maltase and sucrase, and, to a lesser extent, pancreatic lipase in a concentration-dependent manner. Among the nine kinds of polyphenols (caffeoyl quinic acids (CQA), di-CQA, feruloyl quinic acids (FQA)) contained in CPP, di-CQA showed more potent inhibitory activity than CQA or FQA on these digestive enzymes, suggesting a predominant role of di-CQA in the regulation of postprandial energy metabolism. These results suggest that CPP modulates whole-body substrate oxidation by suppressing postprandial hyperglycaemia and hyperinsulinaemia, and these effects are mediated by inhibiting digestive enzymes.


Assuntos
Coffea/química , Carboidratos da Dieta/metabolismo , Gorduras na Dieta/metabolismo , Metabolismo Energético , Doenças Metabólicas/tratamento farmacológico , Fitoterapia , Polifenóis/uso terapêutico , Animais , Glicemia/metabolismo , Respiração Celular , Café/química , Digestão/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperinsulinismo/complicações , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/metabolismo , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Insulina/sangue , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/prevenção & controle , Oxirredução , Consumo de Oxigênio , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polifenóis/farmacologia , Período Pós-Prandial , Ácido Quínico/análogos & derivados , Ácido Quínico/farmacologia , Ácido Quínico/uso terapêutico , Triglicerídeos/sangue
12.
Am J Physiol Endocrinol Metab ; 300(1): E122-33, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20943752

RESUMO

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.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Café/química , Gorduras na Dieta/efeitos adversos , Regulação para Baixo , Flavonoides/uso terapêutico , Obesidade/prevenção & controle , Fenóis/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Linhagem Celular , Cinamatos/análise , Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Suplementos Nutricionais , Metabolismo Energético , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Flavonoides/análise , Flavonoides/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/isolamento & purificação , MicroRNAs/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Fenóis/análise , Fenóis/metabolismo , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Polifenóis , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
13.
Am J Physiol Endocrinol Metab ; 299(2): E266-75, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20501876

RESUMO

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.


Assuntos
Fármacos Antiobesidade , Citrus paradisi/química , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta , Metabolismo Energético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Sesquiterpenos/farmacologia , Nucleotídeos de Adenina/metabolismo , Animais , Western Blotting , Calorimetria Indireta , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Oxirredução , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Resistência Física/fisiologia , Sesquiterpenos Policíclicos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estimulação Química , Natação/fisiologia
14.
Biochem Pharmacol ; 78(1): 78-84, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19447226

RESUMO

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.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Catequina/análogos & derivados , Catequina/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Células 3T3-L1/efeitos dos fármacos , Células 3T3-L1/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Neoplasias Hepáticas , Neoplasias Hepáticas Experimentais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
15.
J Biol Chem ; 278(38): 36176-82, 2003 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-12855700

RESUMO

In the course of an effort to identify unknown targets genes for sterol regulatory element-binding proteins (SREBPs) by PCR, the gene for ATP citrate-lyase was determined to be one such gene. (Sato, R., Okamoto, A., Inoue, J., Miyamoto, W., Sakai, Y., Emoto, N., Shimano, H., and Maeda, M. (2000) J. Biol. Chem. 275, 12497-12502). We here report that gene expression of sterol Delta8-isomerase (SI), which catalyzes the conversion of the 8-ene isomer into the 7-ene isomer in the last steps of the cholesterol biosynthetic pathway, is regulated by SREBPs, mainly by SREBP-2. Luciferase assays using the promoter of the human SI gene revealed that a 200-base pair segment upstream region from the transcription start site contains functional elements required for the activity of the SREBPs, Sp1 and NF-Y. Interestingly, SI gene expression was well regulated by sterols in Caco-2 and HepG2 cells, in contrast with HEK293 and HeLa cells. Overexpression of hepatocyte nuclear factor (HNF)-4 in HEK293 cells augmented expression of SREBP-responsive genes including the SI gene, whereas inactivation of HNF-4 by small interfering RNAs in HepG2 cells reduced the SI gene promoter activity. The in vitro pull-down and in vivo co-immunoprecipitation experiments showed the direct interaction between SREBP-2 and HNF-4. These data provide a novel pathway by which HNF-4 potentiates the SREBP functions and stimulates expression of SREBP-responsive genes in enterohepatic cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Fosfoproteínas/metabolismo , Esteroide Isomerases/biossíntese , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Northern Blotting , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Colesterol/metabolismo , Cricetinae , Eletroforese em Gel de Poliacrilamida , Genes Reporter , Glutationa Transferase/metabolismo , Células HeLa , Fator 4 Nuclear de Hepatócito , Humanos , Luciferases/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Plasmídeos/metabolismo , Testes de Precipitina , Regiões Promotoras Genéticas , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Esteroide Isomerases/química , Proteína de Ligação a Elemento Regulador de Esterol 2
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