RESUMEN
Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.
Asunto(s)
Hígado Graso/metabolismo , Fenretinida/farmacología , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Resistencia a la Insulina , Obesidad/metabolismo , Adiponectina/sangre , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Dieta Alta en Grasa , Hígado Graso/patología , Leptina/sangre , Metabolismo de los Lípidos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/patología , Prealbúmina/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
The defective satiation signaling may contribute to the etiology of obesity. We investigated how dietary modification during maternal (pregnancy and lactation) and post-weaning affects obesity, insulin resistance (IR) and hypothalamic appetite responses in offspring in adulthood. Pregnant female SD rats were randomly allocated to either maternal high-fat diet (43% energy from fat) or control diet (12% energy from fat) until the end of suckling. After weaning for additional 4 weeks, half of the offsprings were continuously fed the same diet as the dam (C-C and H-H groups); the remainder received the counterpart diet (C-H and H-C groups). The long-term high-fat diet during maternal and post-weaning period (H-H group) led to susceptibility to obesity and IR through the significant increases of hypothalamic orexigenic genes compared to the maternal and post-weaning control diet group (C-C group). In contrast, the hypothalamic expression levels of anorexigenic genes, apolipoprotein E, leptin receptor, and activated signal transducer and activator of transcription protein 3 were significantly lower in H-H group with elevations in circulating insulin and leptin and body fat mass. However, dietary changes after weaning (H-C and C-H groups) partially modified these conditions. These results suggest that maternal and post-weaning diet conditions can potentially disrupt hypothalamic neuronal signal irrelevantly, which is essential for leptin's regulation of energy homeostasis and induce the risk of offspring to future metabolic disorders.
RESUMEN
To unravel metabolic determinats of insulin resistance, we performed a targeted metabolomics analysis in Korean Children-Adolescent Cohort Study (KoCAS, n = 430). Sixty-seven metabolites were associated with insulin resistance in adolescents and the association also found in an adult population (KoGES, n = 2,485). Functional interactions of metabolites with gene/proteins using biological pathway with insulin resistance were not identified biological significance and regulatory effects of asymmetric dimethylarginine (ADMA). However, ADMA showed a higher association with adolescent obesity (P < 0.001) and adult diabetes (P = 0.007) and decreased after obesity intervention program. Functional studies in cellular and mouse models demonstrated that an accumulation of ADMA is associated with the regulation of obesity-induced insulin resistance in skeletal muscle. ADMA treatment inhibited dimethylarginine-dimethylaminohydrolase (DDAH) activity and mRNA expression in insulin resistance muscle cell. Moreover, the treatment led to decrease of phosphorylation of insulin receptor (IR), AKT, and GLUT4 but increase of protein-tyrosine phosphatase 1B (PTP1B). Accordingly, increased ADMA significantly inhibited glucose uptake in myotube cell. We suggest that accumulation of ADMA is associated with modulation of insulin signaling and insulin resistance. ADMA might expand the possibilities of new therapeutic target for functional and clinical implications in the control of energy and metabolic homeostasis in humans.
Asunto(s)
Arginina/análogos & derivados , Biomarcadores/metabolismo , Resistencia a la Insulina , Músculo Esquelético/patología , Adolescente , Adulto , Animales , Arginina/metabolismo , Estudios de Cohortes , Humanos , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Transducción de SeñalRESUMEN
Chronic hyperglycemia is toxic to pancreatic beta-cells, impairing cellular functioning as observed in type 2 diabetes; however, the mechanism underlying beta-cell dysfunction and the resulting apoptosis via glucose toxicity are not fully characterized. Here, using MIN6N8 cells, a mouse pancreatic beta-cell line, we show that chronic exposure to high glucose increases cell death mediated by Bax oligomerization, cytochrome C release, and caspase-3 activation. During apoptosis, glucokinase (GCK) expression decreases in high-glucose-treated cells, concomitant with a decrease in cellular ATP production and insulin secretion. Moreover, exposure to a chronically high dose of glucose decreases interactions between GCK and mitochondria with an increase in Bax binding to mitochondria and cytochrome C release. These events are prevented by GCK overexpression, and phosphorylation of proapoptotic Bad proteins in GCK-overexpressing cells is prolonged compared with Neo-transfected cells. Similar results are obtained using primary islet cells. Collectively, these data demonstrate that beta-cell apoptosis from exposure to chronic high glucose occurs in relation to lowered GCK expression and reduced association with mitochondria. Our results show that this may be one mechanism by which glucose is toxic to beta-cells and suggests a novel approach to prevent and treat diabetes by manipulating Bax- and GCK-controlled signaling to promote apoptosis or proliferation.
Asunto(s)
Apoptosis/efectos de los fármacos , Glucoquinasa/metabolismo , Glucosa/fisiología , Islotes Pancreáticos/fisiología , Mitocondrias/fisiología , Animales , Línea Celular Tumoral , Citocromos c/fisiología , Regulación hacia Abajo , Factores de TiempoRESUMEN
OBJECTIVE: Genistein has been suggested to prevent insulin resistance and its related diseases. We investigated the effects of dietary genistein at different levels on hepatic lipid levels and mitochondrial functions in mice fed high-fat diets. METHODS: C57BL/6J mice were randomly divided into four groups and fed a high-fat diet containing genistein at levels of 0%, 0.1%, 0.2%, and 0.4% (HF, HF + 0.1G, HF + 0.2G, and HF + 0.4G) for 12 wk. We measured lipid levels in the blood and liver. We also observed messenger RNA (mRNA) expression of genes encoding proteins related to lipid and energy metabolism and antioxidant defense system and mitochondrial enzyme activities in the liver. RESULTS: The induction of fatty liver by HF was substantially decreased in the HF + 0.2G and HF + 0.4G groups. Peroxisome proliferator-activated receptorgamma coactivator mRNA was increased by HF + 0.4G. Although genistein did not affect peroxisomal acyl-CoA oxidase mRNA expression, it increased medium-chain acyl-CoA dehydrogenase mRNA expression in a dose-dependent manner and HF + 0.2G increased uncoupling protein-2 mRNA expression two-fold relative to HF mice. Genistein decreased malondialdehyde levels and increased glutathione levels in liver homogenates, regardless of dose. The HF + 0.1G diet increased mitochondrial glutathione peroxidase activity and mitochondrial succinate dehydrogenase activity. CONCLUSIONS: Although genistein at higher levels decreased hepatic fat accumulation possibly by increasing fatty acid oxidation and uncoupling protein, low-dose genistein increased mitochondrial enzyme activities in mice with fatty liver and obesity induced by high-fat diets.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Hígado Graso/prevención & control , Genisteína/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Mitocondrias Hepáticas/efectos de los fármacos , ARN Mensajero/metabolismo , Acil-CoA Deshidrogenasa/genética , Acil-CoA Deshidrogenasa/metabolismo , Acil-CoA Oxidasa , Animales , Grasas de la Dieta/efectos adversos , Relación Dosis-Respuesta a Droga , Metabolismo Energético/fisiología , Hígado Graso/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Canales Iónicos/genética , Canales Iónicos/metabolismo , Metabolismo de los Lípidos/fisiología , Hígado/enzimología , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/fisiología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Receptores Activados del Proliferador del Peroxisoma/genética , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Distribución Aleatoria , Succinato Deshidrogenasa/metabolismo , Proteína Desacopladora 2RESUMEN
Excessive tissue iron levels are a risk factor for insulin resistance and type 2 diabetes, which are associated with alterations in iron metabolism. However, the mechanisms underlying this association are not well understood. This study used human liver SK-HEP-1 cells to examine how excess iron induces mitochondrial dysfunction and how hepcidin controls gluconeogenesis. Excess levels of reactive oxygen species (ROS) and accumulated iron due to iron overload induced mitochondrial dysfunction, leading to a decrease in cellular adenosine triphosphate content and cytochrome c oxidase III expression, with an associated increase in gluconeogenesis. Disturbances in mitochondrial function caused excess iron deposition and unbalanced expression of iron metabolism-related proteins such as hepcidin, ferritin H and ferroportin during the activation of p38 mitogen-activated protein kinase (MAPK) and CCAAT/enhancer-binding protein alpha (C/EBPα), which are responsible for increased phosphoenolpyruvate carboxykinase expression. Desferoxamine and n-acetylcysteine ameliorated these deteriorations by inhibiting p38 MAPK and C/EBPα activity through iron chelation and ROS scavenging activity. Based on experiments using hepcidin shRNA and hepcidin overexpression, the activation of hepcidin affects ROS generation and iron deposition, which disturbs mitochondrial function and causes an imbalance in iron metabolism and increased gluconeogenesis. Repression of hepcidin activity can reverse these changes. Our results demonstrate that iron overload is associated with mitochondrial dysfunction and that together they can cause abnormal hepatic gluconeogenesis. Hepcidin expression may modulate this disorder by regulating ROS generation and iron deposition.
Asunto(s)
Gluconeogénesis , Hepcidinas/metabolismo , Hierro/química , Mitocondrias/metabolismo , Estrés Oxidativo , Animales , Proteínas de Transporte de Catión/metabolismo , Línea Celular , Diabetes Mellitus Tipo 2/patología , Complejo IV de Transporte de Electrones/metabolismo , Ferritinas/metabolismo , Humanos , Sobrecarga de Hierro/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Mitocondrias/patología , Oligomicinas/química , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
OBJECTIVE: We investigated the effects of specific conjugated linoleic acid (CLA) isomers on glucose metabolism and insulin resistance and on mRNA levels of genes important in glucose and lipid metabolism. METHODS: Sprague-Dawley rats were fed for 8 wk on a high-fat diet (45% kcal from fat) or one of three CLA-supplemented diets (1% CLA) containing differing isomers of CLA, including a mixture of CLAs (CLA mix), cis-9, trans-11-CLA (C9,T11-CLA), or trans-10, cis-12-CLA (T10,C12-CLA). RESULTS: Compared with the high-fat group, all the CLA groups had enhanced glucose tolerance. Insulin resistance index was significantly lower in the CLA-treated groups. No significant difference could be observed in the level of serum lipids between groups and in the activities of phosphoenolpyruvate carboxylase, glucose-6-phosphatase, and glucokinase. However, C9,T11-CLA and T10,C12-CLA significantly increased acyl coenzyme A oxidase mRNA in skeletal muscle. In addition, C9,T11-CLA increased hepatic acyl coenzyme A oxidase mRNA and skeletal muscle uncoupling protein-2 mRNA. The CLA mix showed intermediate effects on the levels of these genes. CONCLUSIONS: The addition of all types of CLA to Sprague-Dawley rats fed a high-fat diet can decrease insulin resistance. Possible mechanisms are increased fat oxidation and energy expenditure by increasing acyl coenzyme A oxidase and uncoupling protein-2 mRNA in the liver and/or skeletal muscle.
Asunto(s)
Grasas de la Dieta/farmacología , Metabolismo Energético/efectos de los fármacos , Resistencia a la Insulina , Ácidos Linoleicos Conjugados/farmacología , Lípidos/sangre , Hígado/metabolismo , Acil-CoA Oxidasa/metabolismo , Animales , Glucemia/metabolismo , Grasas de la Dieta/administración & dosificación , Metabolismo Energético/fisiología , Canales Iónicos , Ácidos Linoleicos Conjugados/administración & dosificación , Ácidos Linoleicos Conjugados/química , Hígado/efectos de los fármacos , Masculino , Proteínas de Transporte de Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Isoformas de Proteínas , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Proteína Desacopladora 2RESUMEN
Previously, we reported that water-extracted Acanthopanax senticosus exhibited anti-metastatic activity by stimulating the immune system. In this study, we fractionated glycoproteins (EN-SP) from the soluble protein layer (GF-AS) of A. senticosus and determined their basic chemical properties. We also investigated the anti-tumor and immunostimulating activities of the fractionated glycoprotein, EN-SP. We found that intravenous (i.v.) administration of GF-AS dramatically inhibited metastasis of colon26-M3.1 carcinoma cells to the lung in a dose-dependent manner. In vitro analysis showed GF-AS to enhance the proliferation of splenocytes. GF-AS also stimulated peritoneal macrophage, which was followed by the production of various cytokines such as IL-1beta, TNF-alpha, IL-12 and IFN-gamma. Furthermore, the production of these cytokines was partially blocked when peritoneal macrophage was cultured with the polyclonal antibodies against GF-AS. The depletion of NK cells by rabbit anti-asialo GM1 serum partly abolished the inhibitory effect of GF-AS on lung metastasis of colon26-M3.1 cells. Using gel filtration, EN-SP, an active glycoprotein fraction, is isolated from GF-AS. While both GF-AS and EN-SP stimulated the proliferatation of splenocytes of normal mice, EN-SP showed higher anti-metastatic activity and more potently stimulated the proliferation of splenocytes compared to GF-AS. These results suggest the use of EN-SP, the fractionated glycoprotein from A. senticosus, can be used as a therapeutical reagent to prevent or inhibit tumor metastasis.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Eleutherococcus/química , Glicoproteínas/uso terapéutico , Células Asesinas Naturales/fisiología , Activación de Macrófagos/fisiología , Metástasis de la Neoplasia/prevención & control , Adyuvantes Inmunológicos/aislamiento & purificación , Adyuvantes Inmunológicos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Western Blotting , División Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Citocinas/biosíntesis , Electroforesis en Gel de Poliacrilamida , Femenino , Glicoproteínas/química , Glicoproteínas/aislamiento & purificación , Humanos , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Linfocitos/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Mitosis/efectos de los fármacosRESUMEN
PURPOSE: Diets rich in fat and energy are associated with metabolic syndrome (MS). Increased body iron stores have been recognized as a feature of MS. High-fat diets (HFs), excess iron loading and MS are closely associated, but the mechanism linking them has not been clearly defined. We investigated the interaction between dietary fat and dietary Fe in the context of glucose and lipid metabolism in the body. METHODS: C57BL6/J mice were divided into four groups and fed the modified AIN-93G low-fat diet (LF) and HF with adequate or excess Fe for 7 weeks. The Fe contents were increased by adding carbonyl iron (2% of diet weight) (LF+Fe and HF+Fe). RESULTS: High iron levels increased blood glucose levels but decreased high-density lipoprotein cholesterol levels. The HF group showed increases in plasma levels of glucose and insulin and insulin resistance. HF+Fe mice showed greater changes. Representative indices of iron status, such hepatic and plasma Fe levels, were not altered further by the HF. However, both the HF and excess iron loading changed the hepatic expression of hepcidin and ferroportin. The LF+Fe, HF and HF+Fe groups showed greater hepatic fat accumulation compared with the LF group. These changes were paralleled by alterations in the levels of enzymes related to hepatic gluconeogenesis and lipid synthesis, which could be due to increases in mitochondrial dysfunction and oxidative stress. CONCLUSIONS: High-fat diets and iron overload are associated with insulin resistance, modified hepatic lipid and iron metabolism and increased mitochondrial dysfunction and oxidative stress.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/administración & dosificación , Sobrecarga de Hierro/sangre , Hierro de la Dieta/administración & dosificación , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Dieta con Restricción de Grasas , Modelos Animales de Enfermedad , Gluconeogénesis/efectos de los fármacos , Insulina/sangre , Resistencia a la Insulina , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/metabolismoRESUMEN
Postmenopausal women are at higher risk for obesity and insulin resistance due to the decline of estrogen, but genistein, a phytoestrogen, may reduce the risks of these diet-related diseases. In this study, we hypothesized that supplemental genistein has beneficial effects on insulin resistance in an ovariectomized rat model by modulating lipid metabolism. Three weeks after a sham surgery (sham) or an ovariectomy (OVX), ovariectomized Sprague-Dawley rats were placed on a diet containing 0 (OVX group) or 0.1% genistein for 4 weeks. The sham rats were fed a high-fat diet containing 0% genistein and served as the control group (sham group). The ovariectomized rats showed increases in body weight and insulin resistance index, but genistein reduced insulin resistance index and the activity of hepatic fatty acid synthetase. Genistein was also associated with increased activity of succinate dehydrogenase and carnitine palmitoyltransferase and the rate of ß-oxidation in the fat tissue of rats. The ovariectomized rats given genistein had smaller-sized adipocytes. Using gene-set enrichment analysis (GSEA) of microarray data, we found that a number of gene sets of fatty acid metabolism, insulin resistance, and oxidative stress were differentially expressed by OVX and reversed by genistein. This systemic approach of GSEA enables the identification of such consensus between the gene expression changes and phenotypic changes caused by OVX and genistein supplementation. Genistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance.
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Genisteína/uso terapéutico , Glycine max/química , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad/metabolismo , Fitoestrógenos/uso terapéutico , Fitoterapia , Tejido Adiposo/citología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Carnitina O-Palmitoiltransferasa/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Ácido Graso Sintasas/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Genisteína/farmacología , Resistencia a la Insulina/genética , Metabolismo de los Lípidos/genética , Hígado/efectos de los fármacos , Hígado/enzimología , Análisis por Micromatrices , Obesidad/etiología , Obesidad/genética , Ovariectomía , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Fitoestrógenos/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Posmenopausia , Ratas , Ratas Sprague-Dawley , Succinato Deshidrogenasa/metabolismo , Aumento de PesoAsunto(s)
Resistencia a la Insulina , Ácidos Linoleicos Conjugados/administración & dosificación , Obesidad/metabolismo , Animales , Distinciones y Premios , Enfermedad Crónica , Dieta , Modelos Animales de Enfermedad , Humanos , Corea (Geográfico) , Esperanza de Vida , Ácidos Linoleicos Conjugados/metabolismo , Fenómenos Fisiológicos de la Nutrición , Obesidad/complicaciones , Obesidad/etiologíaRESUMEN
Consumption of a diet high in barley beta-glucan (BG) has been shown to prevent insulin resistance. To investigate the mechanism for the effects of barley BG, three groups of male 7-wk-old C57BL/6J mice were fed high-fat diets containing 0, 2, or 4% of barley BG for 12 wk. The 2% BG and 4% BG groups had significantly lower body weights compared with the 0% BG group. The 4% BG group demonstrated improved glucose tolerance and lower levels of insulin-resistance index and glucose-dependent insulinotropic polypeptide. Consumption of the BG diet decreased hepatic lipid content. Mice on the BG diet also demonstrated decreased fatty acid synthase and increased cholesterol 7alpha-hydroxylase gene expression levels. The BG diet promoted hepatic insulin signaling by decreasing serine phosphorylation of insulin receptor substrate 1 and activating Akt, and it decreased mRNA levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. In summary, consumption of BG reduced weight gain, decreased hepatic lipid accumulation, and improved insulin sensitivity in mice fed a high-fat diet. Insulin signaling enhanced due to the expression changes of glucose and lipid metabolism genes by BG consumption. Consumption of barley BG could be an effective strategy for preventing obesity, insulin resistance, and the metabolic syndrome.
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Grasas de la Dieta/administración & dosificación , Hígado Graso/prevención & control , Hordeum/química , Resistencia a la Insulina , beta-Glucanos/administración & dosificación , Animales , Peso Corporal , Hígado Graso/sangre , Hígado Graso/metabolismo , Hígado Graso/patología , Polipéptido Inhibidor Gástrico/sangre , Regulación Enzimológica de la Expresión Génica , Intolerancia a la Glucosa/prevención & control , Proteínas Sustrato del Receptor de Insulina/metabolismo , Metabolismo de los Lípidos/genética , Hígado/enzimología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/prevención & control , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Semillas/química , Transducción de SeñalRESUMEN
It is well established that the IFN-gamma/STAT1 pathway plays an important role in the pancreatic beta-cell apoptosis that is observed in STZ-induced type 1 diabetes; however, the upstream regulatory proteins involved have not been understood. Here, we investigated whether activating transcription factor 3 (ATF3) affects STAT1-mediated beta-cell dysfunction and apoptosis in streptozotocin-treated mice. To this, STZ (80 mg/kg, i.p.) was administered to wild-type and STAT1(-/-) or IFN-gamma(-/-) mice for 5 days and the mice were euthanized after 14 days. STZ-induced beta-cell dysfunction and apoptosis were associated with increased STAT1/IRF-1 and ATF3 expression and were correlated with elevated IFN-gamma levels. Genetic depletion using IFN-gamma(-/-) or STAT1(-/-) mice strongly inhibited the reduction of islet cell mass or insulin synthesis/secretion and the increase of beta-cell apoptosis observed in STZ-treated wild-type mice. ATF3 overexpression, especially the C-terminal domain, strongly enhanced beta-cell dysfunction and apoptosis by enhancing STAT1 activation and its accumulation, which were abolished with an ATF3-specific siRNA or C-terminal-deleted ATF3. The STZ induction of ATF3 was completely depleted in IFN-gamma(-/-) mice, but not in STAT1(-/-) mice. Furthermore, STAT1 did not affect ATF3 expression, but STAT1 depletion or its inactivation inhibited STZ-induced ATF3 nuclear translocation and beta-cell apoptosis. Interestingly, ATF3 also increased STAT1 transcription by directly binding to a putative binding region (-116 to -96 bp) in the STAT1 promoter. Our results suggest that ATF3 functions as a potent upstream regulator of STAT1 and ATF3 may play a role in STZ-induced beta-cell dysfunction by enhancing the steady state abundance of STAT1.
Asunto(s)
Factor de Transcripción Activador 3/metabolismo , Apoptosis , Diabetes Mellitus Tipo 1/genética , Células Secretoras de Insulina/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción Activador 3/genética , Animales , Línea Celular , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/metabolismo , Insulina/metabolismo , Interferón gamma/deficiencia , Interferón gamma/genética , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factor de Transcripción STAT1/deficiencia , Factor de Transcripción STAT1/metabolismo , Transcripción Genética , TransfecciónRESUMEN
OBJECTIVES: Postmenopausal women develop obesity, insulin resistance, and potentially renal dysfunction because of decreased serum estrogen levels. We investigated the effects of genistein, an estrogen-like compound thought to exert antioxidative effects, on insulin resistance, renal lipid accumulation, and oxidative stress in ovariectomized rats. METHODS: Three weeks after an ovariectomy or a sham surgery, rats were put on a high-fat diet containing 0% or 0.1% genistein for 4 wk. We examined the following treatment groups: sham surgery + high-fat diet (sham), ovariectomy + high-fat diet (OVX), and ovariectomy + high-fat diet with 0.1% genistein (OVX + G). RESULTS: The OVX + G group had increased serum estradiol levels and renal expression of estrogen receptors-alpha and -beta compared with the OVX group. OVX + G rats showed decreases in serum insulin levels and the insulin resistance index. OVX + G rats also exhibited decreased renal triacylglycerol and cholesterol levels, which may have been the result of decreased sterol response element binding protein-1 and -2 expressions, and increased adenosine triphosphate-binding cassette transporter-1 and adiponectin receptor expression. The observed increases in renal lipid levels and serum and renal transforming growth factor-beta in OVX rats may be associated with the increased expression of extracellular matrix proteins, such as fibronectin, and the decreased activity of metalloproteinase-2, an extracellular matrix-degrading enzyme. Ovariectomy also induced oxidative stress by the reduction of antioxidative enzymes, whereas genistein reversed these detrimental ovariectomy-induced effects. CONCLUSION: Genistein may help to maintain normal kidney function through the alleviation of many ovariectomy-induced risk factors for renal damage, including an increased insulin resistance index, renal oxidative stress, lipid accumulation, and extracellular matrix protein expression.
Asunto(s)
Genisteína/farmacología , Resistencia a la Insulina , Riñón/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Grasas de la Dieta/administración & dosificación , Estradiol/sangre , Femenino , Glutatión/metabolismo , Riñón/efectos de los fármacos , Riñón/fisiología , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Modelos Animales , Ovariectomía , Oxidación-Reducción , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/metabolismoRESUMEN
OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. This study evaluated the function of macelignan, a natural compound isolated from Myristica fragrans, as a dual agonist for PPARalpha/gamma and investigated its antidiabetes effects in animal models. RESEARCH DESIGN AND METHODS: GAL4/PPAR chimera transactivation was performed and the expression of PPARalpha/gamma target genes was monitored to examine the ability of macelignan to activate PPARalpha/gamma. Additionally, macelignan was administrated to obese diabetic (db/db) mice to investigate antidiabetes effects and elucidate its molecular mechanisms. RESULTS: Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-alpha and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH(2)-terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling. CONCLUSIONS: Macelignan enhanced insulin sensitivity and improved lipid metabolic disorders by activating PPARalpha/gamma and attenuating ER stress, suggesting that it has potential as an antidiabetes agent for the treatment of type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Retículo Endoplásmico/efectos de los fármacos , Lignanos/farmacología , Lignanos/uso terapéutico , PPAR alfa/agonistas , PPAR gamma/agonistas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Línea Celular , Proteínas Sustrato del Receptor de Insulina , Lignanos/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Obesos , Estructura Molecular , Myristica/química , Estrés Fisiológico , TapsigarginaRESUMEN
To investigate the effects of three different conjugated linoleic acid (CLA) preparations containing different ratios of CLA isomers on insulin signalling, fatty acid oxidation and mitochondrial function, Sprague-Dawley rats were fed a high-fat diet either unsupplemented or supplemented with one of three CLA preparations at 1 % of the diet for 8 weeks. The first CLA preparation contained approximately 30 % cis-9, trans-11 (c9, t11)-CLA isomer and 40 % trans-10, cis-12 (t10, c12)-CLA isomer (CLA-mix). The other two preparations were an 80:20 mix (c9, t11-CLA-mix) or a 10:90 mix of two CLA isomers (t10, c12-CLA-mix). Insulin resistance was decreased in all three supplemented groups based on the results of homeostasis model assessment and the revised quantitative insulin-sensitivity check index. The phosphorylation of insulin receptor substrate-1 on serine decreased in the livers of all three supplemented groups, while subsequent Akt phosphorylation increased only in the t10, c12-CLA-mix group. Both the c9, t11-CLA-mix and the t10, c12-CLA-mix increased the expression of hepatic adiponectin receptors R1 and 2, which are thought to enhance insulin sensitivity and fat oxidation. The c9, t11-CLA-mix increased protein and mRNA levels of PPAR alpha, acyl-CoA oxidase and uncoupling protein, which are involved in fatty acid oxidation and energy dissipation. The c9, t11-CLA-mix enhanced mitochondrial function and protection against oxidative stress by increasing the activities of cytochrome c oxidase, manganese-superoxide dismutase, glutathione peroxidase, and glutathione reductase and the level of GSH. In conclusion, all three CLA preparations reduced insulin resistance. Among them, the c9, t11-CLA-mix was the most effective based on the parameters reflecting insulin resistance and fat oxidation, and mitochondrial antioxidative enzyme activity in the liver.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Ácidos Grasos/metabolismo , Insulina/metabolismo , Ácidos Linoleicos Conjugados/administración & dosificación , Mitocondrias/metabolismo , Animales , Antioxidantes/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Metabolismo Energético/genética , Ácidos Grasos/genética , Resistencia a la Insulina/fisiología , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Oxidación-Reducción/efectos de los fármacos , PPAR alfa/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Adiponectina , Receptores de Superficie Celular/sangre , Transducción de Señal/efectos de los fármacos , Succinato Deshidrogenasa/metabolismoRESUMEN
The protective effect of a 30 kDa glycoprotein (GF-AS) isolated from the stem bark of Acanthopanax senticosus against acute and chronic alcohol-induced hepatotoxicity were studied. N-terminal amino acid sequence of GF-AS showed NH(2)-Val-Ala-Tyr-Pro-Trp-Ala-Gly-Phe-Ala-Leu-Ser-Leu-Glx-Pro-Pro-Ala-Gly-Tyr-. GF-AS significantly increases the activities of alcohol-metabolizing enzymes, including alcohol dehydrogenase, microsomal ethanol metabolizing system, and acetaldehyde dehydrogenase in rats acutely treated with alcohol, resulting in decreased plasma alcohol levels. GF-AS also increases the activities of antioxidant enzymes and glutathione level. Markers of liver injury induced by alcohol: elevated serum levels of aspartate aminotransferase, alanine aminotransferase, triglyceride and cholesterol, are reduced by GF-AS in both acutely and chronically treated rats. The activities of lipogenic enzymes including malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphoglucuronic acid dehydrogenase in chronic alcohol-treated rats are significantly decreased by GF-AS. Furthemore, GF-AS improves histological change in fatty liver and hepatic lesions induced by alcohol. Collectively, GF-AS may alleviate alcohol-induced hepatotoxicity through increasing ethanol and lipid metabolism, as well as antioxidant defense systems in livers injured by acute- and chronic-alcohol treatment.
Asunto(s)
Eleutherococcus/química , Glicoproteínas/uso terapéutico , Hepatitis Alcohólica/tratamiento farmacológico , Hígado/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Enfermedad Aguda , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Glicoproteínas/aislamiento & purificación , Lípidos/sangre , Hígado/enzimología , Hígado/patología , Pruebas de Función Hepática , Masculino , Ratones , Sustancias Protectoras/aislamiento & purificación , Ratas , Ratas Sprague-DawleyRESUMEN
Neuronatin (Nnat) is selectively expressed in the neonatal brain and is involved in neuronal differentiation during brain development. However, Nnat also appears to be abundantly expressed in adipose tissue, and is conspicuously elevated in the adipose tissue of obese Zucker diabetic fatty rats compared with control lean Zucker lean control rats shown in our previous report. Here, we examined the expression of Nnat in adipose tissue and demonstrated that the ectopic expression of Nnat mediated by retroviral infection or stable transfection of 3T3-L1 pre-adipocytes stimulated differentiation into mature adipocytes with early induction of adipogenic transcription factors. Moreover, in 3T3-L1 cells overexpressing Nnat, increased intracellular free calcium levels and enhanced phosphorylation of cAMP-response element-binding protein (CREB) were observed, which appears to potentiate CCAAT/enhancer-binding protein (C/EBP)beta, C/EBPdelta, and C/EBPalpha transcriptional activities. Collectively, the data indicate that Nnat enhances CREB phosphorylation through increasing intracellular free calcium levels, which potentiates expression of adipogenic transcription factors resulting in heightened adipocyte differentiation. These findings contribute to a greater fundamental understanding of obesity, a clinically important risk factor in numerous diseases.