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1.
Proteomics ; 17(1-2)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27928909

RESUMO

Over activity of cannabinoid receptor type 1 (CB1R) plays a key role in increasing the incidence of obesity-induced non-alcoholic fatty liver disease. Tissue proteome analysis has been applied to investigate the bioinformatics regarding the mode of action and therapeutic mechanism. The aim of this study was to explore the potential pathways altered with CB1R in obesity-induced fatty liver. Male C57BL/6 mice were fed either a standard chow diet (STD) or a high-fat diet (HFD) with or without 1-week treatment of CB1R inverse agonist AM251 at 5 mg/kg. Then, liver tissues were harvested for 2DE analysis and protein profiles were identified by using MALDI-MS. Results showed that eight of significantly altered protein spots at the level of changes > twofold were overlapped among the three groups, naming major urinary protein 1, ATP synthase subunit ß, glucosamine-fructose-6-phosphate aminotransferase 1, zine finger protein 2, s-adenosylmethionine synthase isoform type-1, isocitrate dehydrogenase subunit α, epoxide hydrolase 2 and 60S acidic ribosomal protein P0. These identified proteins were involved in glucose/lipid metabolic process, xenobiotic metabolic system, and ATP synthesized process in mitochondria. Based on the findings, we speculated that CB1R blockade might exert its anti-metabolic disorder effect via improvement of mitochondrial function in hepatic steatosis in HFD condition.


Assuntos
Biomarcadores/sangue , Antagonistas de Receptores de Canabinoides/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/sangue , Piperidinas/uso terapêutico , Proteômica/métodos , Pirazóis/uso terapêutico , Receptores de Canabinoides/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
2.
Int J Mol Med ; 37(3): 743-54, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26847930

RESUMO

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA­IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/metabolismo , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Citrato (si)-Sintase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 Relacionado a NF-E2/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia
3.
Biochem Biophys Res Commun ; 460(4): 1063-8, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25843798

RESUMO

Hepatic insulin resistance (HIR) is a metabolic abnormality characterized by increased gluconeogenesis which usually contributes from an elevation of free fatty acids. Cannabinoid receptor type 1 (CB1R) and major urinary protein 1 (MUP1) are thought to play pivotal roles in mitochondrial dysfunction, liver steatosis and insulin resistance. The aim of this study was to explore the role of MUP1 in CB1R-mediated HIR through the dysregulation of mitochondrial function in AML12 mouse hepatocytes challenged with high concentration of free fatty acids (HFFA). Firstly we observed that treatment of AM251, a selective CB1R antagonist, obviously reversed the HFFA-induced reduction of MUP1 protein expression both in vivo and in vitro. Additionally, our results revealed that AM251 also reverted HFFA-mediated decrease of the mRNA level of mitochondrial biogenesis-related factors, mtDNA amount, ATP production, mitochondrial respiratory complexes-I and -III, and mitochondrial membrane potential, thus consequently might correlate with a parallel reduction of ROS production. Meanwhile, AM251 attenuated HFFA-induced impairment of insulin signaling phosphorylation and elevation of phosphoenolpyrvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key enzymes of gluconeogenesis. Silence of MUP1 gene abolished the inhibitory effect of AM251 on HFFA-mediated elevation of PEPCK and G6Pase expression, whereas the suppression of insulin signaling and mRNA level of mitochondrial biogenesis-related factors were only partially recovered. Altogether, these findings suggest that the anti-HIR effect of AM251 via improvement of mitochondrial functions might occur in a MUP1-dependent manner.


Assuntos
Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina , Fígado/metabolismo , Proteínas/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Western Blotting , Dieta Hiperlipídica , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Piperidinas/farmacologia , Proteínas/genética , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor CB1 de Canabinoide/antagonistas & inibidores
4.
Biochem Biophys Res Commun ; 460(3): 497-503, 2015 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-25824048

RESUMO

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ETAR during insulin resistance, ETAR expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ETAR pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ETAR/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ETAR are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ETAR expression, and ET-1-induced mitogenic actions in aortic VSMCs.


Assuntos
Aterosclerose/etiologia , Endotelina-1/fisiologia , Hipertensão/etiologia , Resistência à Insulina , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Endotelina-1/metabolismo , Hipertensão/fisiopatologia , Insulina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley
5.
Biochem Biophys Res Commun ; 451(2): 263-9, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25088996

RESUMO

Endothelin-1 (ET-1) is the most potent vasoconstrictor by binding to endothelin receptors (ETAR) in vascular smooth muscle cells (VSMCs). The complex of angiotensin II (Ang II) and Ang II type one receptor (AT1R) acts as a transient constrictor of VSMCs. The synergistic effect of ET-1 and Ang II on blood pressure has been observed in rats; however, the underlying mechanism remains unclear. We hypothesize that Ang II leads to enhancing ET-1-mediated vasoconstriction through the activation of endothelin receptor in VSMCs. The ET-1-induced vasoconstriction, ET-1 binding, and endothelin receptor expression were explored in the isolated endothelium-denuded aortae and A-10 VSMCs. Ang II pretreatment enhanced ET-1-induced vasoconstriction and ET-1 binding to the aorta. Ang II enhanced ETAR expression, but not ETBR, in aorta and increased ET-1 binding, mainly to ETAR in A-10 VSMCs. Moreover, Ang II-enhanced ETAR expression was blunted and ET-1 binding was reduced by AT1R antagonism or by inhibitors of PKC or ERK individually. In conclusion, Ang II enhances ET-1-induced vasoconstriction by upregulating ETAR expression and ET-1/ETAR binding, which may be because of the AngII/Ang II receptor pathways and the activation of PKC or ERK. These findings suggest the synergistic effect of Ang II and ET-1 on the pathogenic development of hypertension.


Assuntos
Angiotensina II/metabolismo , Endotelina-1/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Vasoconstrição/fisiologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Linhagem Celular , Imidazóis/farmacologia , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteína Quinase C/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Vasoconstrição/efeitos dos fármacos
6.
Artigo em Inglês | MEDLINE | ID: mdl-24348460

RESUMO

Co-heritability of hypertension and insulin resistance (IR) within families not only implies genetic susceptibility may be responsible for these complex traits but also suggests a rational that biological candidate genes for hypertension may serve as markers for features of the metabolic syndrome (MetS). Thus we determined whether the T323C polymorphism (rs5333) of endothelin type A (ETA) receptor, a predominant receptor evoking potent vasoconstrictive action of endothelin-1, contributes to susceptibility to IR-associated hypertension in 1694 subjects of Chinese and Japanese origins. Blood pressures (BPs) and biochemistries were measured. Fasting insulin level, insulin-resistance homeostasis model assessment (HOMAIR) score, and area under curve of insulin concentration (AUCINS) were selected for assessing insulin sensitivity. Genotypes were obtained by methods of polymerase chain reaction-restriction fragment length polymorphism. Foremost findings were that minor allele frequency of the T323C polymorphism was noticeable lower in our overall Asian subjects compared to multi-national population reported in gene database; moreover both the genotypic and allelic frequencies of the polymorphism were significantly different between the two ethnic groups we studied. The genotype distributions at TT/TC/CC were 65, 31, 4% in Chinese and 51, 41, 8% in Japanese, respectively (p < 0.0001). Additionally, carriers of the C homozygote revealed characteristics of IR, namely significantly higher levels of fasting insulin, HOMAIR score, and AUCINS at 29.3, 35.3, and 39.3%, respectively, when compared to their counterparts with TT/TC genotypes in Chinese. Meanwhile, the CC genotype was associated with a higher level of high density lipoprotein cholesterol in Japanese. No association of the polymorphism with BP was observed. This study demonstrated for the first time that T323C polymorphism of ETA receptor gene was associated with an adverse insulin response in Chinese and a favorite atherogenic index in Japanese.

7.
J Cell Physiol ; 226(8): 2198-205, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21520072

RESUMO

Endothelin-1 (ET-1), a potent proatherogenic vasoconstrictive peptide, is known to promote macrophage foam cell formation via mechanisms that are not fully understood. Excessive lipid accumulation in macrophages is a major hallmark during the early stages of atherosclerotic lesions. Cholesterol homeostasis is tightly regulated by scavenger receptors (SRs) and ATP-binding cassette (ABC) transporters during the transformation of macrophage foam cells. The aim of this study was to investigate the possible mechanisms by which ET-1 affects lipid accumulation in macrophages. Our results demonstrate that oxidized low-density lipoprotein (oxLDL) treatment increases lipid accumulation in rat bone marrow-derived macrophages. Combined treatment with ET-1 and oxLDL significantly exacerbated lipid accumulation in macrophages as compared to treatment with oxLDL alone. The results of Western blotting show that ET-1 markedly decreased the ABCG1 levels via ET type A and B receptors and activation of the phosphatidylinositol 3-kinase pathway; however, ET-1 had no effect on the protein expression of CD36, SR-BI, SR-A, or ABCA1. In addition, real-time PCR analysis showed that ET-1 treatment did not affect ABCG1 mRNA expression. We also found that ET-1 decreases ABCG1 possibly due to the enhancement of the proteosome/calpain pathway-dependent degradation of ABCG1. Moreover, ET-1 significantly reduced the efficiency of the cholesterol efflux in macrophages. Taken together, these findings suggest that ET-1 may impair cholesterol efflux and further exacerbate lipid accumulation during the transformation of macrophage foam cells.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Endotelina-1/metabolismo , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Calpaína/metabolismo , Endotelina-1/farmacologia , Regulação da Expressão Gênica , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Macrófagos/química , Macrófagos/citologia , Fosfatidilinositol 3-Quinase/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo
8.
J Physiol Biochem ; 67(3): 297-305, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21347724

RESUMO

Past studies have suggested that the stress-induced GLUT4 localization pathway is damaged in fast-twitch muscles (white muscles) of obese subjects. In this study, we used obese rodents in an attempt to determine whether the stress-induced GLUT4 localization pathway is abnormal in slow-twitch muscles (red muscles), which are responsible for most daily activities. Protein expression levels of the intracellular stress sensor AMP-activated protein kinase (AMPK), its upstream kinase LKB1, its downstream protein AS160 and the glucose transporter protein 4 (GLUT4) in the red gastrocnemius muscle were measured under either resting or stress conditions (1 h of swimming or 14% hypoxia) in both lean and obese Zucker rats (n = 7 for each group). At rest, obese rats displayed higher fasting plasma insulin levels and increased muscle AMPK and AS160 phosphorylation levels compared with lean controls. No significant difference was found in the protein levels of LKB1, total GLUT4, or membrane GLUT4 between the obese and lean control groups. After one hour of swimming, AMPK and AS160 phosphorylation levels and the amount of GLUT4 translocated to the plasma membrane were significantly elevated in lean rats but remained unchanged in obese rats relative to their resting conditions. One hour 14% hypoxia did not cause significant changes in the LKB1-AMPK-AS160-GLUT4 pathway in either lean or obese rats. This study demonstrated that the AMPK-AS160-GLUT4 pathway was altered at basal levels and after exercise stimulation in the slow-twitch muscle of obese Zucker rats.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Obesidade/metabolismo , Estresse Fisiológico , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Animais , Glicemia , Peso Corporal , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Transportador de Glucose Tipo 4/genética , Glicogênio/metabolismo , Hipóxia/metabolismo , Insulina/sangue , Masculino , Fosforilação , Esforço Físico , Transporte Proteico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Zucker
9.
Life Sci ; 84(3-4): 97-104, 2009 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-19041881

RESUMO

AIMS: Resistin promotes macrophage-foam cell formation, but the mechanisms are unclear. In macrophages, lipid uptake is regulated by scavenger receptors (SR-A and CD36), while the cholesterol efflux is regulated by SR-BI, ATP-binding cassette transporter-A1 (ABCA1) and ABCG1. We investigated the mechanisms underlying the dysregulation by resistin of these regulators leading to promotion of lipid accumulation in bone marrow-derived macrophages. MAIN METHODS: Western blotting, real-time PCR and oil red O staining were performed. KEY FINDINGS: Resistin exacerbated lipid accumulation in oxLDL-treated macrophages. Resistin treatment of oxLDL-untreated macrophages showed increased SR-A and CD36 mRNA and protein levels, and decreased ABCA1 protein level, while having no effect on SR-BI or ABCG1 expression. Up-regulation of SR-A and CD36 by resistin resulted from activation of AP-1 and PPARgamma, respectively, and this was confirmed by the lack of activation of either after AP-1 inhibition using curcumin or SP600125, or PPARgamma inhibition using GW9662, respectively. The down-regulation of ABCA1 by resistin was not accompanied by a reduced mRNA level or an activation of LXRalpha/RXR, but resulted from enhanced protein degradation as revealed by the abolition of the down-regulation after inhibition of the proteasome pathway using ALLN or MG-132. A combined inhibition by SP600125, GW9662 and ALLN prevented resistin-induced exacerbation of lipid accumulation in oxLDL-treated macrophages. SIGNIFICANCE: Resistin promotes foam cell formation via dysregulation of SR-A, CD36 and ABCA1. SR-A and CD36 are transcriptionally up-regulated by resistin through AP-1 and PPARgamma, respectively, whereas ABCA1 is down-regulated by resistin through proteasome-mediated enhancement of protein degradation.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Antígenos CD36/fisiologia , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Resistina/fisiologia , Receptores Depuradores Classe A/fisiologia , Transportador 1 de Cassete de Ligação de ATP , Animais , Colesterol/metabolismo , Lipoproteínas LDL/fisiologia , PPAR gama/fisiologia , Complexo de Endopeptidases do Proteassoma/fisiologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição AP-1/fisiologia
10.
Chin J Physiol ; 50(2): 69-76, 2007 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-17608144

RESUMO

Diurnal variation of glucose tolerance and insulin action was studied in male Sprague-Dawley rats with a normal or reversed light-dark cycle. A series of experiments conducted was at 12 AM and 12 PM in the two groups. All measurements were separated by a recovery period of at least 3 days and preceded by a 16-hour fast. Glucose tolerance and insulin action were measured by both an oral glucose tolerance test and intraperitoneal insulin tolerance test. Normal light-dark cycle rats had significantly (P < 0.05) greater insulin sensitivity at 12 PM than at 12 AM, whereas reversed light-dark cycle rats had the opposite results (P < 0.05). Rats in the normal light-dark cycle group had a significantly higher growth hormone concentration at 12 AM than at 12 PM, whereas rats in the reversed group had the opposite results. Measurement of insulin-stimulated glucose uptake of isolated adipocytes preincubated with or without 100 ng/ml growth hormone at 37 degrees C for 5 hours revealed that approximately 30% of insulin-stimulated glucose uptake was suppressed when adipocytes were treated with growth hormone. These results indicate that male rats exhibit significant diurnal variation of glucose tolerance and insulin sensitivity, and suggest that the concomitant diurnal variation of growth hormone may have a superimposed and amplifying effects on this variation.


Assuntos
Glicemia/metabolismo , Ritmo Circadiano/fisiologia , Resistência à Insulina/fisiologia , Fotoperíodo , Adipócitos/metabolismo , Animais , Corticosterona/sangue , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/fisiologia , Ácidos Graxos não Esterificados/sangue , Hormônio do Crescimento/sangue , Hormônio do Crescimento/fisiologia , Insulina/sangue , Masculino , Ratos , Ratos Sprague-Dawley
11.
Hum Reprod ; 22(4): 1003-10, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17204522

RESUMO

BACKGROUND: Increased Ser(312) phosphorylation of insulin receptor substrate (IRS)-1 is one possible molecular mechanism of insulin resistance in polycystic ovary syndrome (PCOS). We investigated whether laparoscopic ovarian electrocautery (LOE) improved insulin sensitivity in women with PCOS and examined the underlying molecular mechanism of LOE. METHODS: Adipose tissue and blood samples from 12 women with PCOS before, and 3 months after, LOE were analysed. RESULTS: Before LOE, women with PCOS were found to have significantly higher 2 h glucose, fasting and 2 h insulin levels, homeostasis model insulin resistance index and lower fasting glucose-to-insulin ratio (G(0)/I(0)) than healthy, lean, age-matched controls. Serum levels of glucose and insulin were significantly decreased, and G(0)/I(0) ratio was significantly increased 3 months after LOE. Levels of activated extracellular signal-regulated kinase 1/2 in PCOS women were higher than in controls, but were significantly decreased after LOE. Levels of insulin receptor, glucose transporter-4 and phosphatidylinositol 3-kinase were lower in PCOS patients before LOE than in controls and increased after LOE. Levels of Ser(312)-phosphorylated IRS-1 in PCOS women before LOE were higher than in controls and decreased significantly after LOE, whereas IRS-1 tyrosine phosphorylation in PCOS women before LOE was lower than in controls and increased significantly after LOE. CONCLUSION: Over the short observation period of this study, our results demonstrated that LOE effectively ameliorated insulin resistance in women with PCOS via decreased IRS-1 Ser(312) phosphorylation.


Assuntos
Eletrocoagulação/métodos , Resistência à Insulina , Ovário/patologia , Fosfoproteínas/metabolismo , Síndrome do Ovário Policístico/terapia , Serina/química , Índice de Massa Corporal , Feminino , Teste de Tolerância a Glucose , Humanos , Proteínas Substratos do Receptor de Insulina , Laparoscopia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Risco , Transdução de Sinais
12.
Hum Reprod ; 22(4): 1100-6, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17208941

RESUMO

BACKGROUND: The aim of this study was to investigate serum and adipocyte mRNA expression of resistin in lean and obese women with polycystic ovary syndrome (PCOS) before and 3 months after laparoscopic ovarian electrocauterization (LOE). METHODS: Adipose tissue obtained from 12 women with PCOS (six obese and six lean, body mass index > 27 kg m(-1) as threshold point) before and after LOE was analysed. Gene expression of resistin was measured by semi-quantitative RT-PCR. Ten lean, age-matched healthy women served as controls. RESULTS: Both lean and obese women with PCOS had significantly higher fasting and 2 h insulin and homeostasis model insulin resistance index (HOMA(IR)) values and lower fasting glucose-to-insulin ratios (G(0)/I(0)) than did the controls. The serum levels of glucose and insulin and HOMA(IR) were significantly decreased, and the G(0)/I(0) ratio was significantly increased 3 months after LOE. No difference was found in serum resistin levels between controls and either obese or lean women with PCOS before LOE, nor between PCOS patients before and after LOE. However, resistin mRNA expression levels in both lean and obese women with PCOS before LOE were significantly higher than that in controls and were decreased significantly after LOE back to control levels. CONCLUSION: Local resistin activity may be actively involved in the pathogenesis of PCOS. LOE reduces insulin resistance and down-regulates resistin mRNA expression in lean and obese women with PCOS.


Assuntos
Adipócitos/citologia , Ovário/patologia , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/terapia , RNA Mensageiro/metabolismo , Resistina/biossíntese , Índice de Massa Corporal , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Laparoscopia , Obesidade/complicações
13.
Obesity (Silver Spring) ; 14(3): 398-404, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16648610

RESUMO

OBJECTIVE: To explore the role of endothelin-1 (ET-1) on lipid metabolism, we examined the effect of ET-1 on lipolysis in rat adipocytes. RESEARCH METHODS AND PROCEDURE: Adipocytes isolated from male Sprague-Dawley rats, weighing 400 to 450 grams, were incubated in Krebs-Ringer buffer with or without 10(-7) M ET-1 for various times or with various concentrations of ET-1 for 4 hours; then glycerol release into the incubation medium was measured. In addition, selective ET(A)R and ET(B)R blockers were used to identify the ET receptor subtype involved. We also explored the involvement of cyclic adenosine monophosphate (cAMP) in ET-1-stimulated lipolysis using an adenylyl cyclase inhibitor and by measuring changes in intracellular cAMP levels in response to ET-1 treatment. To further explore the underlying mechanism of ET-1 action, we examined the involvement of the extracellular signal-regulated kinase (ERK)-mediated pathways. RESULTS: Our results showed that ET-1 caused lipolysis in rat adipocytes in a time- and dose-dependent manner. BQ610, a selective ET(A)R blocker, blocked this effect. The adenylyl cyclase inhibitor, 2',5'-dideoxyadenosine, had no effect on ET-1-stimulated lipolysis. ET-1 did not induce an increase in intracellular cAMP levels. In addition, ET-1-induced lipolysis was blocked by inhibition of ERK activation using PD98059. Coincubation of cells with ET-1 and insulin suppressed ET-1-stimulated lipolysis. DISCUSSION: These findings show that ET-1 stimulates lipolysis in rat adipocytes through the ET(A)R and activation of the ERK pathway. The underlying mechanism is cAMP-independent. However, this non-conventional lipolytic effect of ET-1 is inhibited by the anti-lipolytic effect of insulin.


Assuntos
Adipócitos/efeitos dos fármacos , Endotelina-1/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Células Cultivadas , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/fisiologia , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Flavonoides/farmacologia , Insulina/farmacologia , Masculino , Oligopeptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Endotelina/efeitos dos fármacos , Fatores de Tempo
14.
Life Sci ; 78(11): 1155-62, 2006 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-16436285

RESUMO

The aim of this study was to compare the postprandial leptin response in rats with and without metabolic syndrome induced by a fructose-enriched diet. The effect of aging and the association between variations in metabolic substrates was also evaluated. Oral glucose tolerance test (OGTT) and fasting/re-feeding test were used to evaluate the responses of leptin and to explore the dynamic relationship between endogenous leptin and metabolic substrates, including glucose, insulin and triglycerides (TG). At the 7th week, plasma leptin was unchanged in control rats after oral glucose loading. However, plasma leptin levels increased in fructose-fed rats with insulin resistant OGTT curves. At the 11th month, plasma leptin level was reduced during starvation and returned to the level prior to starvation during re-feeding in control rats. In contrast, the starvation-induced reduction in leptin showed a potentially larger rebound effect during re-feeding in fructose-fed rats. Analysis of covariance demonstrated that there alone was no interactive effect of dietary manipulation between leptin and TG, suggesting that fructose diet-induced insulin resistance-related metabolic syndrome may concomitantly elevate leptin and TG. Furthermore, multiple regression analysis suggests TG was the primary correlative determinant of endogenous leptin concentration. Our data showed that there are different patterns of leptin response to OGTT and fasting/re-feeding tests in rats with and without metabolic syndrome. The results suggest that these effects may be related to a TG-mediated impairment of leptin function and a protective mechanism to reduce lipid-induced tissue damage in patients with metabolic syndrome.


Assuntos
Envelhecimento/metabolismo , Frutose/administração & dosagem , Leptina/sangue , Inanição/metabolismo , Envelhecimento/sangue , Animais , Glicemia/análise , Pressão Sanguínea , Ingestão de Alimentos , Teste de Tolerância a Glucose , Insulina/sangue , Masculino , Período Pós-Prandial , Ratos , Ratos Sprague-Dawley , Inanição/sangue , Triglicerídeos/sangue
15.
Hum Reprod ; 20(1): 117-21, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15513972

RESUMO

BACKGROUND: Resistin is a hormone linking obesity and insulin resistance. The aim of this study was to compare resistin levels in serum or follicular fluid from women with polycystic ovarian syndrome (PCOS) and controls, both of whom were undergoing IVF. METHODS: We compared serum and follicular resistin levels in 21 PCOS women and in 18 healthy, normal ovulation, age- and body mass index (BMI)-matched non-PCOS women undergoing IVF. Correlations between serum or follicular fluid resistin levels and reproductive outcome were evaluated. RESULTS: There was no significant difference in either serum or follicular resistin levels between the control group and the PCOS group as a whole or those with insulin resistance [homeostasis model assessment of insulin resistance index applied to oral glucose tolerance test (HOMA(OGTT)) <4.7]. However, resistin levels in follicular fluid were unexpectedly significantly lower than serum levels (P<0.0001) in both the PCOS and control groups. No significant correlation was found between resistin levels and BMI, estradiol, LH, or fasting or 2 h glucose or insulin levels or between follicular resistin levels and fertilization rate, implantation rate, clinical pregnancy rate, or early miscarriage rate in PCOS. CONCLUSION: Resistin is unlikely to be a major determining factor in the growth and maturation of oocytes during IVF-stimulated cycles in PCOS.


Assuntos
Líquido Folicular/metabolismo , Hormônios Ectópicos/sangue , Hormônios Ectópicos/metabolismo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/metabolismo , Infertilidade Feminina/terapia , Resistência à Insulina , Síndrome do Ovário Policístico/terapia , Gravidez , Resultado da Gravidez , Resistina
16.
Eur J Nutr ; 43(2): 116-24, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15083319

RESUMO

BACKGROUND: Sprague-Dawley rats fed a fructose-rich diet exhibit insulin resistance and hypertension, a pathologic status resembling human type II diabetes mellitus, and are an excellent laboratory animal model for research on insulin action and the development of hypertension. Since green tea has numerous beneficial effects, we tested its effect on fructose-fed rats. AIM: The present study was therefore designed to further evaluate the effects of green tea supplementation on insulin resistance, hypertension, and the glucose transporters I and IV contents in adipose tissue in the fructose-fed rat model. METHODS: The animals were divided into three groups and fed for 12 weeks with standard chow and water (control group), a high fructose diet and water (fructose group), or the same high fructose diet, but with green tea (0.5 g of lyophilized green tea powder dissolved in 100 mL of deionized distilled water) instead of water (fructose/green tea group). During the 12 weeks study period, fresh water or green tea was provided daily at 6:00 PM. Blood pressure was measured twice a week, and an oral glucose tolerance test performed after 12 weeks of diet supplementation. At the end of the experiment, plasma triglyceride (TG), free fatty acid (FFA), glucose, and insulin were assayed. The epididymal fat pads from all rats in the same group were pooled and adipocytes isolated and tested for insulin binding, glucose uptake, and their content of glucose transporters I (GLUT I) and IV (GLUT IV). RESULT: Compared to the control group, the fructose group developed fasting hyperglycemia, hyperinsulinemia, and elevated blood pressure. Insulin-stimulated glucose uptake and insulin binding of adipocytes were significantly reduced, and the glucose transporter IV content of adipocytes also decreased. The fructose/green tea group showed improvement in all of these metabolic defects and in insulin resistance and blood pressure. CONCLUSION: Based on these results, we suggest that the amelioration of insulin resistance by green tea is associated with the increased expression of GLUT IV.


Assuntos
Suplementos Nutricionais , Frutose/administração & dosagem , Hipertensão/dietoterapia , Resistência à Insulina/fisiologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Chá , Tecido Adiposo/metabolismo , Animais , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose , Teste de Tolerância a Glucose , Hipertensão/complicações , Insulina/sangue , Lipídeos/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Resultado do Tratamento
17.
J Agric Food Chem ; 52(3): 643-8, 2004 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-14759162

RESUMO

Epidemiological observations and laboratory studies have shown that green tea has a variety of health effects, including antitumor, antioxidative, and hypolipidemic activities. The aim of this study was to examine whether it had an effect on glucose tolerance and insulin sensitivity in Sprague-Dawley rats. In experiment 1 (in vivo study), rats were divided into two groups: a control group fed standard chow and deionized distilled water and a "green tea" group fed the same chow diet but with green tea instead of water (0.5 g of lyophilized green tea powder dissolved in 100 mL of deionized distilled water). After 12 weeks of green tea supplementation, the green tea group had lower fasting plasma levels of glucose, insulin, triglyceride, and free fatty acid than the control rats. Insulin-stimulated glucose uptake of, and insulin binding to, adipocytes were significantly increased in the green tea group. In experiment 2 (in vitro study), a tea polyphenol extract was used to determine its effect on insulin activity in vitro. Green tea polyphenols (0.075%) significantly increased basal and insulin-stimulated glucose uptake of adipocytes. Results demonstrated that green tea increases insulin sensitivity in Sprague-Dawley rats and that green tea polyphenol is one of the active components.


Assuntos
Resistência à Insulina , Chá , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Flavonoides/farmacologia , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Insulina/metabolismo , Masculino , Fenóis/farmacologia , Polifenóis , Ratos , Ratos Sprague-Dawley , Chá/química
18.
Hum Reprod ; 19(1): 48-53, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14688155

RESUMO

BACKGROUND: The aim of this study was to investigate the relationship between resistin and insulin resistance in patients with polycystic ovary syndrome (PCOS). METHODS: We compared serum resistin levels in 17 PCOS women and 10 lean, healthy, age-matched non-PCOS women and also compared levels of insulin receptor (IR), phosphatidylinositol-3 kinase (PI3-kinase), glucose transporter 4 (GLUT4) protein and resistin mRNA in adipocytes isolated from the omental adipose tissue of five of the PCOS patients and five age- and weight-matched, non-PCOS controls, to look for local defects in insulin action in PCOS. RESULTS: The PCOS group was hyperinsulinaemic and displayed an impaired insulin response in a 75 g oral glucose tolerance test and an abnormal homeostasis model insulin resistance index. Serum resistin levels were similar in PCOS patients and controls; however, resistin mRNA levels were 2-fold higher in adipocytes from PCOS patients. No correlation was found between serum resistin levels and either the BMI or testosterone levels. Western blot analysis showed that adipocyte levels of insulin receptor, PI3-kinase, and GLUT4 were respectively decreased by 56, 39.4 and 54% in PCOS patients compared with controls. CONCLUSIONS: These results suggest that overexpression of the resistin gene in adipocytes may be a local determinant factor in the pathogenesis of PCOS.


Assuntos
Adipócitos/metabolismo , Hormônios Ectópicos/metabolismo , Resistência à Insulina , Síndrome do Ovário Policístico/fisiopatologia , Adulto , Estudos de Casos e Controles , Feminino , Expressão Gênica , Hormônios Esteroides Gonadais/sangue , Gonadotropinas/sangue , Hormônios Ectópicos/sangue , Hormônios Ectópicos/genética , Humanos , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , RNA Mensageiro/metabolismo , Resistina
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