RESUMEN
OBJECTIVES: Supplementation with 6 g/day of medium-chain triglycerides (MCTs) at dinnertime increases muscle function and cognition in frail elderly adults relative to supplementation with long-chain triglycerides. However, suitable timing of MCT supplementation during the day is unknown. DESIGN: We enrolled 40 elderly nursing home residents (85.9 ± 7.7 years) in a 1.5-month randomized intervention trial. Participants were randomly allocated to two groups: one received 6 g/day of MCTs at breakfast (breakfast group) as a test group and the other at dinnertime (dinner group) as a positive control group. MEASUREMENTS: Muscle mass, strength, function, and cognition were monitored at baseline and 1.5 months after initiation of intervention. RESULTS: Thirty-seven participants completed the study and were included in the analysis. MCT supplementation in breakfast and dinner groups respectively increased right arm muscle area from baseline by 1.1 ± 0.8 cm2 (P<0.001) and 1.6 ± 2.5 cm2 (P<0.001), left arm muscle area by 1.1 ± 0.7 cm2 (P<0.001) and 0.9 ± 1.0 cm2 (P<0.01), right knee extension time by 39 ± 42 s (P<0.01) and 20 ± 32 s (P<0.05), leg open and close test time by 1.74 ± 2.00 n/10 s (P<0.01) and 1.67 ± 2.01 n/10 s (P<0.01), and Mini-Mental State Examination score by 1.5 ± 3.0 points (P=0.06) and 1.0 ± 2.1 points (P=0.06). These increases between two groups did not differ statistically significantly. CONCLUSION: Supplementation with 6 g MCTs/day for 1.5 months, irrespective of ingestion at breakfast or dinnertime, could increase muscle mass and function, and cognition in frail elderly adults.
Asunto(s)
Cognición , Anciano Frágil , Anciano , Suplementos Dietéticos , Humanos , Fuerza Muscular , Músculos , TriglicéridosRESUMEN
OBJECTIVE: Isomerized hop extract (IHE), which consists mainly of isohumulones and is required in the beer brewing process, was investigated for its effects on diet-induced obesity in two strains of mice. DESIGN: C57BL/6N and KK-A(y) mice were fed a standard or high-fat diet containing IHE and their body and tissue weights were measured at various time points. Oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT) were carried out in high-fat diet-fed C57BL/6N mice. The effects of IHE on intestinal lipid absorption were examined in Wistar rats using a plasma triacylglycerol assay after oral administration of a lipid emulsion. Fecal lipid levels were also measured in these animals after they were fed a high-fat diet containing IHE for 15 days. The effects of IHE on pancreatic lipase activity and the expression of genes involved in hepatic lipid metabolism were also examined using an in vitro assay and quantitative RT-PCR, respectively. RESULTS: Supplementation of high-fat-containing chow with IHE reduced body weight gain and improved glucose tolerance in our experimental mice. A reduction in body weight gain was also observed in C57BL/6N mice fed a standard diet containing IHE. Wistar rats fed a high-fat diet containing IHE showed reduced plasma triacylglycerol levels and an increase in their fecal lipid excretion. Similarly, their pancreatic lipase activity was inhibited and their elevation in plasma triacylglycerol levels seen after the oral administration of lipid emulsion was significantly suppressed. IHE-fed mice showed an increased expression in their lipid oxidation genes and a decreased expression in genes involved in triacylglycerol biosynthesis. CONCLUSION: The inhibition of intestinal dietary fat absorption may be the mechanism by which IHE induces its weight-lowering effects in high-fat diet-fed mice. The modulatory effect of IHE on lipid metabolism may also, at least partly, be responsible for its beneficial effects on body weight gain. These results suggest that IHE may be helpful in humans in preventing diet-induced obesity and perhaps even metabolic syndrome, the latter of which is known to be associated with obesity.
Asunto(s)
Ciclopentanos/uso terapéutico , Dieta , Obesidad/prevención & control , Fitoterapia , Animales , Secuencia de Bases , Suplementos Dietéticos , Heces/química , Expresión Génica , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Lipasa/análisis , Metabolismo de los Lípidos , Lípidos/análisis , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Datos de Secuencia Molecular , Obesidad/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la Especie , Triglicéridos/biosíntesis , Triglicéridos/sangreRESUMEN
PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Obesidad/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores de Ácido Retinoico/antagonistas & inhibidores , Tiazolidinedionas , Factores de Transcripción/antagonistas & inhibidores , Células 3T3 , Tejido Adiposo/metabolismo , Animales , Compuestos de Bencidrilo , Benzoatos/metabolismo , Benzoatos/farmacología , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/farmacología , Compuestos Epoxi/metabolismo , Compuestos Epoxi/farmacología , Ácidos Grasos/metabolismo , Hiperglucemia/etiología , Hiperglucemia/metabolismo , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Leptina/metabolismo , Ratones , Ratones Noqueados , Ácidos Nicotínicos/metabolismo , Ácidos Nicotínicos/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Rosiglitazona , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/farmacología , Tiazoles/metabolismo , Tiazoles/farmacología , Factores de Transcripción/agonistas , Factores de Transcripción/metabolismoRESUMEN
In vivo and in vitro experiments show that polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) inhibit mitogen- or antigen-stimulated proliferation of T cells in rodents and humans. However, the exact manner and mechanisms by which PUFA inhibits T cell proliferation is not clear. In the present study, we investigated the suppressive effects of EPA, an n-3 PUFA, on PHA stimulated human peripheral blood T cells. Our results showed that EPA suppresses mitogen- or antigen-stimulated human T cell proliferation by at least 2 steps; step 1) EPA suppresses T cell proliferation by inhibiting IL-2R alpha expression and IL-2 production; step 2) EPA induces cell death of blast T cells without reducing the expression of IL-2R alpha. We also showed that EPA selectively stimulates the cell death of blast T cells but not resting T cells. The suppressive effect of EPA was mediated via the production of reactive oxygen products, because EPA-stimulated H2O2 production and the suppressive effect of EPA was restored by addition of catalase or NAC. These results taken together suggest that such immunosuppressive effects of EPA may explain the apparent benefits of EPA-enriched diets for patients with inflammatory disorders.
Asunto(s)
Ácido Eicosapentaenoico/farmacología , Activación de Linfocitos/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Muerte Celular , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Humanos , Peróxido de Hidrógeno/metabolismo , Interleucina-2/análisis , Fitohemaglutininas , Receptores de Interleucina-2/análisis , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.
Asunto(s)
Tejido Adiposo/fisiopatología , Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intercelular , Obesidad/fisiopatología , Proteínas/fisiología , Adiponectina , Tejido Adiposo/metabolismo , Secuencia de Aminoácidos , Animales , Leptina/metabolismo , Ratones , Datos de Secuencia Molecular , Oxidación-Reducción , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/fisiología , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Triglicéridos/metabolismoRESUMEN
This study was performed to assess the effects of short-term, extremely high-intensity intermittent exercise training on the GLUT-4 content of rat skeletal muscle. Three- to four-week-old male Sprague-Dawley rats with an initial body weight ranging from 45 to 55 g were used for this study. These rats were randomly assigned to an 8-day period of high-intensity intermittent exercise training (HIT), relatively high-intensity intermittent prolonged exercise training (RHT), or low-intensity prolonged exercise training (LIT). Age-matched sedentary rats were used as a control. In the HIT group, the rats repeated fourteen 20-s swimming bouts with a weight equivalent to 14, 15, and 16% of body weight for the first 2, the next 4, and the last 2 days, respectively. Between exercise bouts, a 10-s pause was allowed. RHT consisted of five 17-min swimming bouts with a 3-min rest between bouts. During the first bout, the rat swam without weight, whereas during the following four bouts, the rat was attached to a weight equivalent to 4 and 5% of its body weight for the first 5 days and the following 3 days, respectively. Rats in the LIT group swam 6 h/day for 8 days in two 3-h bouts separated by 45 min of rest. In the first experiment, the HIT, LIT, and control rats were compared. GLUT-4 content in the epitrochlearis muscle in the HIT and LIT groups after training was significantly higher than that in the control rats by 83 and 91%, respectively. Furthermore, glucose transport activity, stimulated maximally by both insulin (2 mU/ml) (HIT: 48%, LIT: 75%) and contractions (25 10-s tetani) (HIT: 55%, LIT: 69%), was higher in the training groups than in the control rats. However, no significant differences in GLUT-4 content or in maximal glucose transport activity in response to both insulin and contractions were observed between the two training groups. The second experiment demonstrated that GLUT-4 content after HIT did not differ from that after RHT (66% higher in trained rats than in control). In conclusion, the present investigation demonstrated that 8 days of HIT lasting only 280 s elevated both GLUT-4 content and maximal glucose transport activity in rat skeletal muscle to a level similar to that attained after LIT, which has been considered a tool to increase GLUT-4 content maximally.
Asunto(s)
Glucosa/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Natación/fisiología , Animales , Transporte Biológico Activo/fisiología , Peso Corporal/fisiología , Citrato (si)-Sintasa/metabolismo , Desoxiglucosa/metabolismo , Estimulación Eléctrica , Transportador de Glucosa de Tipo 4 , Glucógeno/metabolismo , Insulina/farmacología , Masculino , Músculo Esquelético/enzimología , Ratas , Ratas Sprague-DawleyRESUMEN
Mitochondrial uncoupling protein (UCP), mitochondrial transporters, function as a proton channel and increase thermogenesis. UCP1 is expressed in brown adipose tissues (BAT), UCP2 is widely expressed in multiple tissues, while UCP3 is expressed in skeletal muscle. Thus, UCPs, especially UCP3, in skeletal muscles is a good candidates for prevention of obesity and diabetes. However, the role of UCP3 in skeletal muscle for energy expenditure and obesity has been controversial. There is some evidence that the UCP3 is possibly regulated by energy substrate, such as lipid and glucose. These observations suggest that increased energy substrate entry in muscle results in an increase in UCP3 expression which leads to an increase in energy expenditure.
Asunto(s)
Proteínas Portadoras/fisiología , Músculo Esquelético/fisiología , Animales , Humanos , Canales Iónicos , Proteínas Mitocondriales , Proteína Desacopladora 3RESUMEN
The effect of dietary Platycodon grandiflorum on the improvement of insulin resistance and lipid profile was investigated in lean (Fa/-) and obese (fa/fa) Zucker rats, a model for noninsulin dependent diabetes mellitus. Dietary Platycodon grandiflorum feeding for 4 weeks resulted in a significant decrease in the concentration of plasma triglyceride in both lean and obese Zucker rats. Furthermore, dietary Platycodon grandiflorum markedly decreased both plasma cholesterol and fasting plasma insulin levels, and significantly decreased the postprandial glucose level at 30 min during oral glucose tolerance test in obese Zucker rats. Although there was no statistical significance, the crude glucose transporter 4 protein level of obese rats fed Platycodon grandiflorum tended to increase when compared with that of obese control rats. Therefore, the present results suggested that dietary Platycodon grandiflorum may be useful in prevention and improvement of metabolic disorders characterized by hyperinsulinemia states such as noninsulin dependent diabetes mellitus, syndrome X, and coronary artery disease.
RESUMEN
Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in beef and dairy products. CLA has been reported to reduce body fat. To examine the mechanism(s) of CLA reduction of fat mass, female C57BL/6J mice were fed standard semipurified diets (10% fat of total energy) with or without CLA (1% wt/wt). Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endlabeling (TUNEL) and DNA fragmentation analysis revealed that fat-mass decrease by CLA was mainly due to apoptosis. Tumor necrosis factor (TNF)-alpha and uncoupling protein (UCP)-2 mRNA levels increased 12- and 6-fold, respectively, in isolated adipocytes from CLA-fed mice compared with control mice. Because it is known that TNF-alpha induces apoptosis of adipocytes and upregulates UCP2 mRNA, a marked increase of TNF-alpha mRNA with an increase of UCP2 in adipocytes caused CLA-induced apoptosis. However, with a decrease of fat mass, CLA supplementation resulted in a state resembling lipoatrophic diabetes: ablation of brown adipose tissue, a marked reduction of white adipose tissue, marked hepatomegaly, and marked insulin resistance. CLA supplementation decreased blood leptin levels, but continuous leptin infusion reversed hyperinsulinemia, indicating that leptin depletion contributes to the development of insulin resistance. These results demonstrate that intake of CLA reduces adipose tissue by apoptosis and results in lipodystrophy, but hyperinsulinemia by CLA can be normalized by leptin administration.
Asunto(s)
Tejido Adiposo/patología , Apoptosis/efectos de los fármacos , Ácidos Linoleicos/farmacología , Ácidos Linoleicos/toxicidad , Lipodistrofia/inducido químicamente , Proteínas de Transporte de Membrana , Proteínas Mitocondriales , Proteínas/genética , Tejido Adiposo/citología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/patología , Animales , Peso Corporal , Suplementos Dietéticos , Femenino , Canales Iónicos , Ácidos Linoleicos/administración & dosificación , Lipodistrofia/patología , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Tamaño de los Órganos/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Proteína Desacopladora 2RESUMEN
Exercise training increases the expression of GLUT4 in skeletal muscle. Previous studies demonstrated that the exercise-responsive element(s) of the murine GLUT4 gene are located between bases -1001 and -442 relative to the transcription start site. To further characterize the regulatory elements in the GLUT4 gene, the regulation of GLUT4 minigenes containing -701, -551, -442, or -423 bp of the 5'-flanking region was studied in transgenic mice. All minigenes studied showed significant expression in skeletal muscle and heart, including the -423 GLUT4 minigene that lacked the myocyte enhancer factor 2 (MEF2)-binding domain (-CTAAAAATAG-) located between bases -437 and -428. The -701- and -551-bp constructs were expressed in brown adipose tissues while the -442 and -423 constructs were not. In skeletal muscle, either swimming or treadmill running up-regulated GLUT4 minigene mRNA levels in -701 and -551 transgenic mice, but not in the -442 and -423 transgenic mice. Denervation of the gastrocnemius muscle by sectioning of the sciatic nerve down-regulated minigene and endogenous GLUT4 mRNAs in all -701, -551, -442, and -423 transgenic mice. These data indicate that exercise-responsive element(s) and brown adipocyte specific element(s) are located within 109 bp between bases -551 and -442 of the GLUT4 gene, but that the cis-element for denervation-induced down-regulation of the GLUT4 gene is located downstream of base -423. Finally, the MEF2 binding site between bases -437 and -428 is not necessary for expression of GLUT4 in skeletal muscles and heart; the cis-element mediating this effect is also located downstream of base -423.
Asunto(s)
Regulación de la Expresión Génica , Proteínas de Transporte de Monosacáridos/genética , Desnervación Muscular , Proteínas Musculares , Músculo Esquelético/fisiología , Condicionamiento Físico Animal/fisiología , Transcripción Genética , Regiones no Traducidas 5'/genética , Animales , Transportador de Glucosa de Tipo 4 , Ratones , Ratones Transgénicos , Músculo Esquelético/inervación , Especificidad de Órganos , ARN Mensajero/genética , Secuencias Reguladoras de Ácidos Nucleicos , Nervio Ciático/fisiología , Eliminación de SecuenciaRESUMEN
Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.
Asunto(s)
Adipocitos/metabolismo , Tamaño de la Célula/genética , Grasas/farmacología , Resistencia a la Insulina/genética , Receptores Citoplasmáticos y Nucleares/genética , Tiazolidinedionas , Factores de Transcripción/genética , Animales , Glucemia/metabolismo , Peso Corporal/genética , Diferenciación Celular/genética , Dieta , Ingestión de Alimentos , Metabolismo Energético , Viabilidad Fetal/genética , Hipoglucemiantes/farmacología , Leptina/metabolismo , Ratones , Ratones Noqueados , Miocardio/patología , Pioglitazona , Placenta/patología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Tiazoles/farmacología , Factores de Transcripción/agonistas , Factores de Transcripción/metabolismoRESUMEN
Dietary fish oil induces hepatic peroxisomal and microsomal fatty acid oxidation by peroxisome proliferator-activator receptor alpha activation, whereas it down-regulates lipogenic gene expression by unknown mechanism(s). Because sterol regulatory element-binding proteins (SREBPs) up-regulated lipogenic genes, investigation was made on the effects of fish oil feeding on SREBPs and sterol regulatory element (SRE)-dependent gene expression in C57BL/6J mice. Three forms of SREBPs, SREBP-1a, -1c, and -2, are expressed in liver, and their truncated mature forms activate transcription of sterol-regulated genes. C57BL/6J mice were divided into three groups; the first group was given a high carbohydrate diet, and the other two groups were given a high fat diet (60% of total energy), with the fat in the form of safflower oil or fish oil, for 5 months. Compared with safflower oil feeding, fish oil feeding decreased triglyceride and cholesterol concentrations in liver. There were no differences in amount of SREBP-1 and -2 in both precursor and mature forms between carbohydrate- and safflower oil-fed mice. However, compared with safflower oil feeding, fish oil feeding reduced the amounts of precursor SREBP-1 in membrane fraction by 90% and of mature SREBP-1 in liver nuclei by 57%. Fish oil feeding also reduced precursor SREBP-2 by 65% but did not alter the amount of mature SREBP-2. Compared with safflower oil feeding, fish oil feeding decreased liver SREBP-1c mRNA level by 86% but did not alter SERBP-1a mRNA. Consistent with decrease of mature SREBP-1, compared with safflower oil feeding, fish oil feeding down-regulated the expression of liver SRE-dependent genes, such as low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA synthase, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1. These data suggested that in liver, fish oil feeding down-regulates the mature form of SREBP-1 by decreasing SREBP-1c mRNA expression, with corresponding decreases of mRNAs of cholesterologenic and lipogenic enzymes.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Proteínas de Unión al ADN/metabolismo , Aceites de Pescado/administración & dosificación , Hígado/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción , Animales , Dieta , Regulación hacia Abajo , Femenino , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/biosíntesis , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , AtúnRESUMEN
Mitochondrial uncoupling protein 3 (UCP3) is expressed in skeletal muscles. We have hypothesized that increased glucose flux in skeletal muscles may lead to increased UCP3 expression. Male transgenic mice harboring insulin-responsive glucose transporter (GLUT4) minigenes with differing lengths of 5'-flanking sequence (-3237, -2000, -1000 and -442 bp) express different levels of GLUT4 protein in various skeletal muscles. Expression of the GLUT4 transgenes caused an increase in UCP3 mRNA that paralleled the increase of GLUT4 protein in gastrocnemius muscle. The effects of increased intracellular GLUT4 level on the expression of UCP1, UCP2 and UCP3 were compared in several tissues of male 4 month-old mice harboring the -1000 GLUT4 minigene transgene. In the -1000 GLUT4 transgenic mice, expression of GLUT4 mRNA and protein in skeletal muscles, brown adipose tissue (BAT), and white adipose tissue (WAT) was increased by 1.4 to 4.0-fold. Compared with non-transgenic littermates, the -1000 GLUT4 mice exhibited about 4- and 1.8-fold increases of UCP3 mRNA in skeletal muscle and WAT, respectively, and a 38% decrease of UCP1 mRNA in BAT. The transgenic mice had a 16% increase in oxygen consumption and a 14% decrease in blood glucose and a 68% increase in blood lactate, but no change in FFA or beta-OHB levels. T3 and leptin concentrations were decreased in transgenic mice. Expression of UCP1 in BAT of the -442 GLUT4 mice, which did not overexpress GLUT4 in this tissue, was not altered. These findings indicate that overexpression of GLUT4 up-regulates UCP3 expression in skeletal muscle and down-regulates UCP1 expression in BAT, possibly by increasing the rate of glucose uptake into these tissues.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Monosacáridos/genética , Proteínas Musculares , Músculo Esquelético/metabolismo , ARN Mensajero/genética , Regulación hacia Arriba , Tejido Adiposo Pardo/metabolismo , Animales , Glucagón/sangre , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4 , Insulina/sangre , Insulina/metabolismo , Canales Iónicos , Masculino , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Proteínas Mitocondriales , Proteína Desacopladora 3RESUMEN
Fish oil feeding showed less obesity in rodents, relative to other dietary oils. N-3 fatty acids rich in fish oil and fibrate compounds are peroxisome proliferator-activated receptor alpha (PPARalpha) ligands that stimulate beta-oxidation of fatty acids in liver and are used for treatment of hypertriglycemic patients. Since UCP-2, a member of an uncoupling protein family, has been shown to express in hepatocytes, the effects of these agents on the expression of UCP2 mRNA were investigated. C57BL/6J mice were divided into three groups; the first group was given a high-carbohydrate diet, and the other two groups were given a high-fat diet (60% of total energy) as safflower oil or fish oil for 5 months. Safflower oil diet fed mice developed obesity, but those fed fish oil diet did not. Therefore, the effects of fish oil feeding on the expression of UCP1, UCP2 and UCP3 in liver, skeletal muscle (gastrocnemius), white adipose tissue (WAT) and brown adipose tissue (BAT) were assessed by Northern blotting. Compared with safflower oil feeding, fish oil feeding up-regulated liver UCP2, BAT UCP2 and skeletal muscle UCP3 mRNA, while down-regulated WAT UCP2 and BAT UCP3 mRNA. Among these alterations, 5-fold up-regulation of liver UCP2 mRNA, relative to carbohydrate feeding, was noteworthy. Fenofibrate administration (about 500 mg/kg BW/d) for 2 wks also induced liver UCP2 expression by 9-fold. These data indicated that fish oil feeding and fibrate administration each up-regulated UCP2 mRNA expression in liver possibly via PPARalpha and hence each has the potential of increasing energy expenditure for prevention of obesity.
Asunto(s)
Fenofibrato/farmacología , Aceites de Pescado/farmacología , Hígado/metabolismo , Proteínas de Transporte de Membrana , Proteínas Mitocondriales , Proteínas/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia , Proteínas Portadoras/genética , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/farmacología , Femenino , Fenofibrato/administración & dosificación , Aceites de Pescado/administración & dosificación , Hormonas/sangre , Canales Iónicos , Hígado/efectos de los fármacos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Oxígeno/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/fisiología , Aceite de Cártamo/administración & dosificación , Aceite de Cártamo/farmacología , Factores de Transcripción/agonistas , Factores de Transcripción/fisiología , Triglicéridos/sangre , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3 , Regulación hacia ArribaRESUMEN
To study whether consumed dietary fat has a linear relationship or a threshold with glycemic controls, female C57BL/6J mice were fed different levels of a safflower oil (10, 20, 30, 40, 50, and 60% of total energy) diet ad libitum for 15 wk. Food intake, body weight, parametrial white adipose tissue (WAT) and liver weight were measured, and oral glucose tolerance tests were conducted. Although there was no significant difference in average energy intake, graded increments of safflower oil resulted in graded deterioration of glucose tolerance during 5 and 12-wk feeding, and deterioration of glucose tolerance was more manifested after 12-wk feeding as compared to 5-wk feeding. After 12-wk feeding, a significant deterioration of glucose tolerance was observed in diets of more than 40% fat. Graded increments of body weight and WAT weight were observed, and their weight increases were manifested in diets of more than 30% fat. These data indicated that the amount of dietary fat had an almost linear relationship with glucose tolerance, and significant differences were observed in mice fed diets more of than 40% fat.
Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Prueba de Tolerancia a la Glucosa , Obesidad/etiología , Tejido Adiposo/anatomía & histología , Animales , Glucemia/metabolismo , Ingestión de Energía , Femenino , Insulina , Cinética , Hígado/anatomía & histología , Ratones , Ratones Endogámicos C57BL , Obesidad/sangre , Tamaño de los Órganos , Aumento de PesoRESUMEN
Although important roles of dietary n-3 fatty acids in the prevention of coronary heart disease (CHD) have been suggested, long-term effects of dietary alpha-linolenic acid (ALA, 18:3n-3) have not yet been established under controlled conditions. We tested whether a moderate increase of dietary ALA affects fatty acids composition in serum and the risk factors of CHD. Oxidized LDL (OxLDL) was directly measured by ELISA using antibody specific to OxLDL. By merely replacing soybean cooking oil (SO) with perilla oil (PO) (i.e., increasing 3 g/d of ALA), the n-6/n-3 ratio in the diet was changed from 4:1 to 1:1. Twenty Japanese elderly subjects were initially given a SO diet for at least 6 mo (baseline period), a PO diet for 10 mo (intervention period), and then returned to the previous SO diet (washout period). ALA in the total serum lipid increased from 0.8 to 1.6% after 3 mo on the PO diet, but EPA and DHA increased in a later time, at 10 mo after the PO diet, from 2.5 to 3.6% and 5.3 to 6.4%, respectively (p<0.05), and then returned to baseline in the washout period. In spite of increases of serum n-3 fatty acids, the OxLDL concentration did not change significantly when given the PO diet. Body weight, total serum cholesterol, triacylglycerol, glucose, insulin and HbA1c concentrations, platelet count and aggregation function, prothrombin time, partial thromboplastin time, fibrinogen and PAI-1 concentration, and other routine blood analysis did not change significantly when given the PO diet. These data indicate that, even in elderly subjects, a 3 g/d increase of dietary ALA could increase serum EPA and DHA in 10 mo without any major adverse effects.
Asunto(s)
Enfermedad Coronaria/etiología , Grasas de la Dieta/farmacología , Ácidos Grasos/sangre , Aceites de Plantas/farmacología , Ácido alfa-Linolénico/farmacología , Anciano , Anciano de 80 o más Años , Culinaria , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Lipoproteínas LDL/sangre , Masculino , Factores de RiesgoRESUMEN
We examined the function of putative sensory fibers that are contained in intercostal nerves and innervate interscapular brown adipose tissue (IBAT) in urethane-anesthetized rats. Warming the IBAT to 40-44 degrees C with two small heaters placed bilaterally on the skin above it attenuated the subsequent noradrenaline-induced thermogenesis (NIT) of the IBAT. In this range of warming, higher IBAT temperatures resulted in more attenuation. Denervation of IBAT blocked the effect of thermal stimulation on the NIT. Thus, activation of nerve fibers in IBAT that are sensitive to warmth or to the nociceptive effects of heat probably attenuated the NIT. Since the putative sensory fibers in the IBAT contain calcitonin gene-related peptide (CGRP) and substance P, which are thought to act in peripheral tissues, we tested the effects of injection of these neuropeptides into the IBAT. Administration of 5.2 nmol CGRP but not substance P or vehicle saline mimicked the effect of thermal stimulation of IBAT. As the neuropeptide-containing primary sensory neurons are characterized by their sensitivity to capsaicin, we also tested its effects (1 mg/kg, s.c.) and found that it also attenuated the NIT. Denervation of the IBAT or pretreatment with capsazepine, a capsaicin receptor antagonist, blocked the effect of capsaicin. We propose that temperature- and capsaicin-sensitive nerve fibers release CGRP to attenuate the NIT of brown adipocytes.
Asunto(s)
Tejido Adiposo Pardo/inervación , Regulación de la Temperatura Corporal/fisiología , Capsaicina/farmacología , Calor , Fibras Nerviosas/efectos de los fármacos , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Desnervación , Femenino , Fibras Nerviosas/fisiología , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Sustancia P/farmacologíaRESUMEN
In skeletal muscles, increased utilization of lipids and carbohydrates accompanied with increased energy expenditure has been observed during and after exercise. UCP3, mitochondrial uncoupling protein, is expressed in skeletal muscles. We investigated UCP3 mRNA levels in exercise training mice which increased energy expenditure and in sciatic nerve-denervated mice which decreased energy expenditure. Mice exercised by 2 wk swimming had 14- to 18-fold increases of UCP3 mRNA in skeletal muscles 3 h after the last swimming, but no increases of UCP1 mRNA in BAT and of UCP2 mRNA in WAT. However, 22 h after exercise, UCP3 mRNA increases observed in skeletal muscles 3 h after exercise returned to sedentary levels. Similar transient increases of UCP3 mRNA were observed in 1 wk treadmill running training or a single exercise bout. In denerved gastrocnemius, GLUT4 and UCP3 mRNA decreased by 58 and 45%, respectively. These data indicate that UCP3 may have a role for fine adjustments of energy expenditure and that up-regulation of UCP3 mRNA may be a defense mechanism against extra energy supply to consume extra energy in skeletal muscles.
Asunto(s)
Proteínas Portadoras/genética , Proteínas Musculares , Músculo Esquelético/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Secuencia de Bases , Cartilla de ADN/genética , Desnervación , Regulación hacia Abajo , Metabolismo Energético , Femenino , Transportador de Glucosa de Tipo 4 , Canales Iónicos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Mitocondriales , Proteínas de Transporte de Monosacáridos/genética , Músculo Esquelético/inervación , Condicionamiento Físico Animal/fisiología , Reacción en Cadena de la Polimerasa , Nervio Ciático , Natación , Proteína Desacopladora 3 , Regulación hacia ArribaRESUMEN
A high-monounsaturated fat diet has been proposed as a palatable alternative to a high-carbohydrate diet in diabetic patients, but it is unknown whether a higher intake of monounsaturated fat induces obesity and diabetes, as usually observed with other types of fat. To answer this question, C57BL/6J mice were divided into three groups: the first group was given a high-carbohydrate diet, and the other two groups were given a high-monounsaturated fat diet (60% of total energy) as olive oil or synthetic triolein for 4 months. It has been previously reported that the C57BL/6J mouse has a genetic predisposition for intraabdominal obesity and non-insulin-dependent diabetes mellitus (NIDDM) by high-polyunsaturated fat (n-6) feeding. Although there were no significant differences in energy intake and fat absorption among these three groups, compared with the high-carbohydrate diet, both high-monounsaturated fat diets produced hyperglycemia, obesity, and triglyceride accumulation in the liver and skeletal muscle. These data indicate that the recently recommended high-monounsaturated fat diet might induce obesity and diabetes.
Asunto(s)
Diabetes Mellitus/etiología , Grasas Insaturadas en la Dieta/administración & dosificación , Obesidad/etiología , Animales , Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/farmacología , Grasas Insaturadas en la Dieta/farmacología , Femenino , Hiperglucemia/etiología , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Triglicéridos/metabolismoRESUMEN
A rapid, highly sensitive method to determine the mRNA level of muscle-specific markers using TaqMan PCR analysis was developed and used to study sequential gene regulation of myoblasts during induced differentiation of C2C12 cells. mRNA levels of muscle regulatory factor (MRF) myogenin, alpha-actin, thermoregulatory uncoupling protein UCP2 and glucose transporter isotype glut4 increased rapidly during early stage differentiation. In contrast, myf5, beta-actin, UCP1 and glut1 mRNA levels gradually decreased during 8 days. However, the mRNA level of other genes such as MyoD, glyceraldehyde-3-phosphate dehydrogenase and hexokinase II changed only slightly in comparison. Muscle-specific uncoupling protein UCP3 mRNA was detected during differentiation and increased rapidly within 8 days. These data clearly show the sequential and the differential regulation of muscle-specific genes in C2C12 cells during multinucleate myotube formation.