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1.
Biol Res ; 53(1): 45, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023658

RESUMO

BACKGROUND: Skeletal muscle has an important role in regulating whole-body energy homeostasis, and energy production depends on the efficient function of mitochondria. We demonstrated previously that AT-rich interactive domain 5b (Arid5b) knockout (Arid5b-/-) mice were lean and resistant to high-fat diet (HFD)-induced obesity. While a potential role of Arid5b in energy metabolism has been suggested in adipocytes and hepatocytes, the role of Arid5b in skeletal muscle metabolism has not been studied. Therefore, we investigated whether energy metabolism is altered in Arid5b-/- skeletal muscle. RESULTS: Arid5b-/- skeletal muscles showed increased basal glucose uptake, glycogen content, glucose oxidation and ATP content. Additionally, glucose clearance and oxygen consumption were upregulated in Arid5b-/- mice. The expression of glucose transporter 1 (GLUT1) and 4 (GLUT4) in the gastrocnemius (GC) muscle remained unchanged. Intriguingly, the expression of TBC domain family member 1 (TBC1D1), which negatively regulates GLUT4 translocation to the plasma membrane, was suppressed in Arid5b-/- skeletal muscle. Coimmunofluorescence staining of the GC muscle sections for GLUT4 and dystrophin revealed increased GLUT4 localization at the plasma membrane in Arid5b-/- muscle. CONCLUSIONS: The current study showed that the knockout of Arid5b enhanced glucose metabolism through the downregulation of TBC1D1 and increased GLUT4 membrane translocation in skeletal muscle.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Ativadoras de GTPase/genética , Glucose , Músculo Esquelético , Fatores de Transcrição/genética , Animais , Transporte Biológico , Regulação para Baixo , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Camundongos Knockout , Músculo Esquelético/metabolismo
2.
Chem Biol Interact ; 330: 109198, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692981

RESUMO

Quercetin 3-O-beta-d-glucopyranoside (isoquercetin) is one of the most frequent metabolites of the Passiflora ligularis Juss. The purpose of this study was to investigate the effect of the aqueous extract and ethanol fraction from P. ligularis Juss leaves on glycaemia and the mechanism of action of isoquercetin on glucose uptake. In the glucose tolerance test, the aqueous extract and ethanol fraction from P. ligularis Juss (125 mg/kg to 500 mg/kg o. g.) reduced glycaemia and increased the hepatic and muscular glycogen content. Phytochemical analysis evidenced the dominant presence of isoquercetin in the extract and fraction from leaves of P. ligularis Juss. Isoquercetin mediates the stimulatory effect on glucose uptake independent of insulin receptor activation but, involve PI3K, MAPK, MEK/ERK pathways and de novo protein synthesis to GLUT-4 translocation. Overall findings revealed that isoquercetin and aqueous extract and ethanol fraction of P. ligularis Juss leaves might be a promising functional food or medicine for the treatment or prevention of diabetes.


Assuntos
Glucose/farmacocinética , Músculo Esquelético/metabolismo , Passiflora/química , Quercetina/análogos & derivados , Animais , Transporte Biológico , Diabetes Mellitus/prevenção & controle , Transportador de Glucose Tipo 4/metabolismo , Compostos Fitoquímicos/análise , Extratos Vegetais/química , Folhas de Planta/química , Quercetina/isolamento & purificação , Quercetina/farmacologia , Ratos
3.
Am J Chin Med ; 48(5): 1073-1090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668968

RESUMO

Pro-inflammatory cytokines interfere with blood glucose homeostasis, which leads to hyperglycemia. Andrographis paniculata (AP) has been shown to possess anti-inflammatory activity and to reduce blood glucose levels in diabetes. The two major bioactive diterpenoids in AP, andrographolide (AND) and 14-deoxy-11,12-didehydroandrographolide (deAND), have potent anti-inflammatory activity. We studied whether APE (an ethanolic extract of AP), AND, and deAND could improve a high-fat diet (HFD)-induced hyperglycemia in vivo and TNF[Formula: see text]-induced impairment of insulin signaling in vitro. Male C57BL/6JNarl mice were fed a normal diet (ND) or the HFD, and the fatty mice were treated with APE, deAND, or AND for 16 weeks. 3T3-L1 cells were used to study the underlying mechanisms by which APE, deAND, or AND attenuated TNF[Formula: see text]-induced insulin resistance. The HFD significantly induced obesity, hyperglycemia, insulin resistance, and inflammation, whereas APE and deAND significantly ameliorated HFD-induced obesity, hyperglycemia, insulin resistance, and TNF[Formula: see text] production. The HFD significantly impaired insulin signaling by decreasing the protein expression of p-IRS1 tyr632 and p-AKT ser473, as well as the membrane translocation of GLUT4 in response to insulin stimulation in epididymal adipose tissue. HFD-impaired the membrane translocation of GLUT4 was significantly reversed by deAND and APE. In addition, deAND and APE markedly reversed the detrimental effect of TNF[Formula: see text] on the insulin signaling pathway and glucose uptake in 3T3-L1 cells. Despite no significant positive effect on p-AS160, a trend for recovery by deAND and APE was observed. These results suggest that deAND and APE protect against HFD-induced insulin resistance by ameliorating inflammation-driven impairment of insulin sensitivity.


Assuntos
Andrographis/química , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Células 3T3 , Animais , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Fitoterapia , Extratos Vegetais/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
4.
Exerc Sport Sci Rev ; 48(3): 110-118, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568924

RESUMO

The glucose transporter GLUT4 is critical for skeletal muscle glucose uptake in response to insulin and muscle contraction/exercise. Exercise increases GLUT4 translocation to the sarcolemma and t-tubule and, over the longer term, total GLUT4 protein content. Here, we review key aspects of GLUT4 biology in relation to exercise, with a focus on exercise-induced GLUT4 translocation, postexercise metabolism and muscle insulin sensitivity, and exercise effects on GLUT4 expression.


Assuntos
Exercício Físico/fisiologia , Transportador de Glucose Tipo 4/metabolismo , Músculo Esquelético/metabolismo , Animais , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Humanos , Resistência à Insulina/fisiologia , Contração Muscular/fisiologia , Transporte Proteico , Sarcolema/metabolismo , Transcrição Genética
5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 12-16, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476367

RESUMO

OBJECTIVE: To study the effects of acute and chronic exercise on phosphatidylinositol 3-hydroxy kinase(PI3K)/protein kinase B(AKT)/glucose transporter 4(GLUT4)signaling pathway in adipose tissue of rats with type 2 diabetes mellitus (T2DM) induced by high-fat diet and low-dose streptozotocin (STZ). METHODS: A total of 52 SD male rats aged 15 months were randomly divided into normal control group (13) and high-fat group (39), and fed normal and high fat diets. After 8 weeks, the body weight of the high-fat group was higher 20% than that of the normal control group. After a small dose of STZ, the blood glucose level was >16.7 mmol/l, and the model was successfully established. The diabetic model group was randomly divided into a diabetic control group (DC, n=13), a diabetic chronic exercise group (DCE, n=13), and a diabetic acute exercise group (DAE, n=13). The DCE group underwent an 8-week swimming exercise and the DAE group performed a one-time swimming exercise. Blood lipids, blood glucose and serum insulin levels were measured, and the contents of fat PI3K, AKT and GLUT4 proteins were determined by Western blot method. RESULTS: The levels of body weight, blood lipids, blood glucose and insulin in the diabetic group were significantly higher than those in the normal control group (P<0.01); high density liptein cholesterol(HDL-C) levels were decreased (P<0.05), and the expressions of PI3K, AKT and GLUT4 protein in adipose tissue were decreased (P<0.01). After 8 weeks of swimming training, the levels of body weight, blood lipids, blood glucose and insulin all were decreased significantly (P<0.01); while the level of HDL-C was increased (P<0.05), and the expressions of PI3K, AKT and GLUT4 protein were increased (P<0.01). After acute exercise, the levels of blood lipids, blood glucose and insulin were decreased (P<0.05); the level of HDL-C was increased (P<0.05), and the expression levels of fat PI3K, AKT and GLUT4 were increased significantly (P<0.05). CONCLUSION: ①High fat diet combined with low-dose STZ induced damage to the PI3K/AKT pathway in adipose tissue of T2DM rats reduced insulin sensitivity. ②Acute and chronic aerobic exercise can improve the disorder of glucose and lipid metabolism through PI3K/AKT pathway, and the chronic exercise is better than acute exercise.


Assuntos
Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/terapia , Resistência à Insulina , Condicionamento Físico Animal , Transdução de Sinais , Animais , Glicemia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Lipídeos/sangue , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Chemosphere ; 253: 126772, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32464760

RESUMO

Zeranol is an approved but controversial growth-promoting agent for livestock in North America. It is a mycotoxin metabolite secreted by the Fusarium family fungi. The regulatory bodies in this region have established the acceptable daily intake and exposure below the level would not significantly increase the health risk for humans. However, their European counterparts have yet to establish an acceptable level and do not permit the use of this agent in farm animals. Given the growth-promoting ability of zeranol, its effect on energy metabolism was investigated in the current study. Our results indicated that zeranol could induce glucose transporter type 4 (GLUT4) expression in 3T3 L1 cells at 10 µM and initiate the translocation of the glucose transporter to the membrane as assayed by confocal microscopy. The translocation was likely triggered by the increase of GLUT4 and p-Akt. The insulin signal transduction pathway of glucose translocation was analyzed by Western blot analysis. Since no increase in the phosphorylated insulin receptor substrate in zeranol-treated cells was evidenced, the increased p-Akt and GLUT4 amount should be the mechanism dictating the GLUT4 translocation. In summary, this study showed that zeranol could perturb glucose metabolism in differentiated 3T3 L1 adipocytes. Determining the growth-promoting mechanism is crucial to uncover an accepted alternative to the general public.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Reguladores de Crescimento de Planta/toxicidade , Zeranol/toxicidade , Células 3T3-L1 , Adipócitos , Animais , Antígenos CD , Metabolismo dos Carboidratos , Glucose/metabolismo , Insulina/metabolismo , Gado , Camundongos , América do Norte , Fosforilação , Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Clin Sci (Lond) ; 134(10): 1167-1180, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32458968

RESUMO

In the present study, we evaluated the metabolic effects of green tea polyphenols (GTPs) in high-fat diet (HFD) fed Zucker fatty (ZF) rats, in particular the effects of GTP on skeletal muscle insulin sensitivity. Body weight, visceral fat, glucose tolerance, lipid profiles and whole-body insulin sensitivity were measured in HFD-fed ZF rats after 8-week-treatment with GTP (200 mg/kg of body weight) or saline (5 ml/kg of body weight). Zucker lean rats were studied as controls. Ex vivo insulin-mediated muscle glucose uptake was assessed. Immunoblotting was used to evaluate the expression of key insulin signalling proteins in skeletal muscle. GTP treatment attenuated weight gain (P<0.05) and visceral fat accumulation (27.6%, P<0.05), and significantly reduced fasting serum glucose (P<0.05) and insulin (P<0.01) levels. Homoeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, was lower (P<0.01) in GTP-treated animals compared with ZF controls. Moreover, insulin-stimulated glucose uptake by isolated soleus muscle was increased (P<0.05) in GTP-ZF rats compared with ZF-controls. GTP treatment attenuated the accumulation of ectopic lipids (triacyl- and diacyl-glycerols), enhanced the expression and translocation of glucose transporter-4, and decreased pSer612IRS-1 and increased pSer473Akt2 expression in skeletal muscle. These molecular changes were also associated with significantly decreased activation of the inhibitory (muscle-specific) protein kinase (PKC) isoform, PKC-θ. Taken together, the present study has shown that regular ingestion of GTP exerts a number of favourable metabolic and molecular effects in an established animal model of obesity and insulin resistance. The benefits of GTP are mediated in part by inhibiting PKC-θ and improving muscle insulin sensitivity.


Assuntos
Resistência à Insulina , Insulina/metabolismo , Músculo Esquelético/metabolismo , Polifenóis/farmacologia , Transdução de Sinais , Chá/química , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Glucose/metabolismo , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 4/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Isoenzimas/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Transporte Proteico/efeitos dos fármacos , Ratos Zucker
8.
Arch Biochem Biophys ; 686: 108365, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315651

RESUMO

Pelargonidin is a natural compound that exists widely in fruits, and exerts antioxidant, anti-atherosclerotic, anti-inflammatory, anti-hyperglycemic, and anti-diabetic activities. However, there have not been any studies concerning its anti-obesity potential to date. Therefore, we evaluated the anti-obesity potential of pelargonidin via inhibition of adipogenesis in 3T3-L1 cells. The cellular oil droplet content was decreased to 68.14%, 56.75%, and 48.39% and triglyceride accumulation decreased to 74.53%, 61.54%, and 47.86% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin, respectively, when compared with DMSO group. Furthermore, pelargonidin treatment led to decrease in glucose consumption. Western blot assay illustrated that the expression of PPAR-γ was suppressed to 63.25%, 47.52%, and 21.23% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin when compared with DMSO group. Then, we measured the expression of some target proteins of PPAR-γ, and found that pelargonidin decreased the expressions of HMGCR, LPL, Glut4, and A-FABP. Besides, the result of Luciferase Reporter Assay indicated that pelargonidin inhibited PPAR-γ transcription activity. These results indicated that pelargonidin exerts anti-adipogenic activity in 3T3-L1 cells through inhibition of PPAR-γ signaling pathway, and pelargonidin could be used as a potential anti-obesity agent.


Assuntos
Adipogenia/efeitos dos fármacos , Antocianinas/farmacologia , Fármacos Antiobesidade/farmacologia , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Antocianinas/metabolismo , Fármacos Antiobesidade/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos , Triglicerídeos/genética , Triglicerídeos/metabolismo
9.
Chem Biol Interact ; 324: 109093, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298659

RESUMO

Polycystic Ovary Syndrome (PCOS), as a common endocrine disorder is accompanied by hyperandrogenism, insulin resistance, ovulation problems, and infertility. Various types of off-label drugs like metformin have been used for the management of targeted problems caused by PCOS such as insulin resistance and hyperandrogenism. Nicotinamide (NAM) acts as a substrate of visfatin and Nicotinamide N-Methyltransferase (NNMT) leading to the generation of Nicotinamide Adenine Dinucleotide (NAD) and N1-Methylnicotinamide (MNAM), respectively. MNAM is known as an anti-inflammatory, anti-thrombosis, and anti-diabetic agent. In this study, the effects of NAM and MNAM on metabolic and endocrine abnormalities were evaluated in the adipose and ovarian tissues of a letrozole-induced rat model of PCOS. Our results showed that MNAM and NAM reversed abnormal estrous cycle and reduced the serum testosterone levels and CYP17A1 gene expression. Furthermore, all therapeutic factors improved HOMA-IR after treatment and NAM significantly increased the expression of GLUT4 and decreased the gene expression of visfatin. Also, MNAM diminished the gene expression of visfatin and resistin. It is noteworthy that all the therapeutic factors successfully activated the AMPK. In summary, this study is the first study reported beneficial effects of NAM and MNAM on the treatment of PCOS. Additionally, the alleviative effects of our therapeutic factors may be partially mediated by the AMPK-dependent manner due to the contribution of the AMPK in the expression of CYP17A1, visfatin, resistin, and GLUT4. Although more studies are required to unravel the exact mode of actions of MNAM and NAM in the PCOS, the findings of the current study shed light on an urgent need for discovering novel therapeutic pharmaceuticals regarding the treatment of PCOS.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/tratamento farmacológico , Hormônio Luteinizante/metabolismo , Metformina/uso terapêutico , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Ratos Wistar , Resistina/genética , Resistina/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/metabolismo
10.
Phytomedicine ; 68: 153178, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32126492

RESUMO

BACKGROUND: Lowering blood glucose levels by increasing glucose uptake in insulin target tissues, such as skeletal muscle and adipose tissue, is one strategy to discover and develop antidiabetic drugs from natural products used as traditional medicines. PURPOSE: Our goal was to reveal the mechanism and activity of acacetin (5,7-dihydroxy-4'-methoxyflavone), one of the major compounds in Agastache rugose, in stimulating glucose uptake in muscle cells. METHODS: To determine whether acacetin promotes GLUT4-dependent glucose uptake in cultured L6 skeletal muscle cells, we performed a [14C] 2-deoxy-D-glucose (2-DG) uptake assay after treating differentiated L6-GLUT4myc cells with acacetin. RESULTS: Acacetin dose-dependently increased 2-DG uptake by enhancing GLUT4 translocation to the plasma membrane. Our results revealed that acacetin activated the CaMKII-AMPK pathway by increasing intracellular calcium concentrations. We also found that aPKCλ/ζ phosphorylation and intracellular reactive oxygen species (ROS) production were involved in acacetin-induced GLUT4 translocation. Moreover, acacetin-activated AMPK inhibited intracellular lipid accumulation and increased 2-DG uptake in HepG2 cells. CONCLUSION: Taken together, these results suggest that acacetin might be useful as an antidiabetic functional ingredient. Subsequent experiments using disease model animals are needed to verify our results.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Flavonas/farmacologia , Glucose/metabolismo , Insulina/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Desoxiglucose/farmacocinética , Relação Dose-Resposta a Droga , Glucose/farmacocinética , Transportador de Glucose Tipo 4/metabolismo , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Fosforilação , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-32126286

RESUMO

Alterations in fatty acid metabolism are associated with impaired glucose uptake in skeletal muscle. Long-chain acyl-CoA synthetase (Acsl) 6 is the one of the Acsl isoforms expressed in skeletal muscle although its role in muscle energy metabolism has not been studied. Thus, the aims of this study were to investigate the role of Acsl6 in fatty acid partitioning and glucose uptake in differentiated skeletal myotubes using a siRNA-mediated knockdown approach. Compared with cells transfected with control siRNA, cells transfected with Acsl6 siRNA exhibited reduced intracellular triacylglycerol (TAG) accumulation. The initial rate of [1­14C]­oleic acid uptake was not altered while the incorporation of [1­14C]­acetic acids into total cellular lipids decreased under Acsl6 knockdown (p < 0.05). In a metabolic labeling study, Acsl6 suppression decreased the incorporation of [1­14C]­oleic acids and [1­14C]­acetic acids into TAG and diacylglycerol (DAG) (p < 0.05). During the chase period of a pulse-chase experiment, Acsl6 suppression increased the intracellular free fatty acids and decreased the fatty acid channeling toward the reacylation of TAG (p < 0.05). The incorporation of the labeled fatty acids into acid-soluble metabolites, ß-oxidation product, was not changed under Acsl6 knockdown. Acsl6 siRNA decreased the insulin-induced uptake of [1­14C]­2­deoxyglucose (p < 0.05) but did not change the glucose uptake in the presence of acipimox, inhibitor of lipolysis. Suppression of Acsl6 deteriorated Akt phosphorylation and Glut4 mRNA expression in response to insulin. These results suggest that Acsl6 activates and channels fatty acids toward anabolic pathways and has a role in glucose and fatty acid cycling through the re-esterification of fatty acids in skeletal muscle.


Assuntos
Coenzima A Ligases/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animais , Linhagem Celular , Coenzima A Ligases/genética , Diglicerídeos/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triglicerídeos/metabolismo
12.
Oxid Med Cell Longev ; 2020: 8609213, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215179

RESUMO

Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder characterized by chronic hyperglycemia and an inadequate response to circulatory insulin by peripheral tissues resulting in insulin resistance. Insulin resistance has a complex pathophysiology, and it is contributed to by multiple factors including oxidative stress. Oxidative stress refers to an imbalance between free radical production and the antioxidant system leading to a reduction of peripheral insulin sensitivity and contributing to the development of T2DM via several molecular mechanisms. In this review, we present the molecular mechanisms by which the oxidative milieu contributes to the pathophysiology of insulin resistance and diabetes mellitus.


Assuntos
Diabetes Mellitus/metabolismo , Resistência à Insulina , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Diabetes Mellitus/classificação , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
13.
Life Sci ; 248: 117474, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112869

RESUMO

BACKGROUND/OBJECTIVES: Nicotinamide N-methyltransferase (NNMT) is a novel regulator of energy homeostasis in adipocytes. NNMT expression in adipose tissue is increased in obesity and diabetes. Knockdown of NNMT prevents mice from developing diet-induced obesity, which is closely linked to insulin resistance. An early sign of systemic insulin resistance is reduced expression of glucose transporter 4 (GLUT4) selectively in adipose tissue. Adipose tissue-specific knockout and overexpression of GLUT4 cause reciprocal changes in NNMT expression. The aim of the current study was to elucidate the mechanism that regulates NNMT expression in adipocytes. METHODS: 3T3-L1 adipocytes were cultured in media with varying glucose concentrations or activators and inhibitors of intracellular pathways. NNMT mRNA and protein levels were measured with quantitative polymerase chain reaction and Western blotting. RESULTS: Glucose deprivation of 3T3-L1 adipocytes induced a 2-fold increase in NNMT mRNA and protein expression. This effect was mimicked by inhibition of glucose transport with phloretin, and by inhibition of glycolysis with the phosphoglucose isomerase inhibitor 2-deoxyglucose. Conversely, inhibition of the pentose phosphate pathway did not affect NNMT expression. Pharmacological activation of the cellular energy sensor AMP-activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin (mTOR) pathway caused an increase in NNMT levels that was similar to the effect of glucose deprivation. Activation of mTOR with MHY1485 prevented the effect of glucose deprivation on NNMT expression. Furthermore, upregulation of NNMT levels depended on functional autophagy and protein translation. CONCLUSION: Glucose availability regulates NNMT expression via an mTOR-dependent mechanism.


Assuntos
Adipócitos/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Glucose/farmacologia , Nicotinamida N-Metiltransferase/genética , Serina-Treonina Quinases TOR/genética , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Transporte Biológico/efeitos dos fármacos , Diferenciação Celular , Desoxiglucose/farmacologia , Metabolismo Energético/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Transportador de Glucose Tipo 4/antagonistas & inibidores , Transportador de Glucose Tipo 4/metabolismo , Glucose-6-Fosfato Isomerase/antagonistas & inibidores , Glucose-6-Fosfato Isomerase/genética , Glucose-6-Fosfato Isomerase/metabolismo , Homeostase/genética , Camundongos , Morfolinas/farmacologia , Nicotinamida N-Metiltransferase/antagonistas & inibidores , Nicotinamida N-Metiltransferase/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , Via de Pentose Fosfato/genética , Floretina/farmacologia , Biossíntese de Proteínas , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia
14.
BMC Complement Med Ther ; 20(1): 22, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32020870

RESUMO

BACKGROUND: Alisol A-24-acetate (AA-24-a) is one of the main active triterpenes isolated from the well-known medicinal plant Alisma orientale (Sam.) Juz., which possesses multiple biological activities, including a hypoglycemic effect. Whether AA-24-a is a hypoglycemic-active compound of A. orientale (Sam.) Juz. is unclear. The present study aimed to clarify the effect and potential mechanism of action of AA-24-a on glucose uptake in C2C12 myotubes. METHOD: Effects of AA-24-a on glucose uptake and GLUT4 translocation to the plasma membrane were evaluated. Glucose uptake was determined using a 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG) uptake assay. Cell membrane proteins were isolated and glucose transporter 4 (GLUT4) protein was detected by western blotting to examine the translocation of GLUT4 to the plasma membrane. To determine the underlying mechanism, the phosphorylation levels of proteins involved in the insulin and 5'-adenosine monophosphate-activated protein kinase (AMPK) pathways were examined using western blotting. Furthermore, specific inhibitors of key enzymes in AMPK signaling pathway were used to examine the role of these kinases in the AA-24-a-induced glucose uptake and GLUT4 translocation. RESULTS: We found that AA-24-a significantly promoted glucose uptake and GLUT4 translocation in C2C12 myotubes. AA-24-a increased the phosphorylation of AMPK, but had no effect on the insulin-dependent pathway involving insulin receptor substrate 1 (IRS1) and protein kinase B (PKB/AKT). In addition, the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the AKT substrate of 160 kDa (AS160), two proteins that act downstream of AMPK, was upregulated. Compound C, an AMPK inhibitor, blocked AA-24-a-induced AMPK pathway activation and reversed AA-24-a-induced glucose uptake and GLUT4 translocation to the plasma membrane, indicating that AA-24-a promotes glucose metabolism via the AMPK pathway in vitro. STO-609, a calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß) inhibitor, also attenuated AA-24-a-induced glucose uptake and GLUT4 translocation. Moreover, STO-609 weakened AA-24-a-induced phosphorylation of AMPK, p38 MAPK and AS160. CONCLUSIONS: These results indicate that AA-24-a isolated from A. orientale (Sam.) Juz. significantly enhances glucose uptake via the CaMKKß-AMPK-p38 MAPK/AS160 pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Colestenonas/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Alisma/química , Animais , Western Blotting , Linhagem Celular , Camundongos , Fibras Musculares Esqueléticas/enzimologia , Projetos Piloto , Plantas Medicinais/química
15.
Biomed Pharmacother ; 125: 109952, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32036216

RESUMO

Trelagliptin inhibits the enzyme dipeptidyl-4 (DPP-4) to treat type 2 diabetes and it may possess the potential to improve insulin resistance. However, the molecular mechanism is not known. In this study, the effect of trelagliptin succinate in improving insulin resistance was investigated. The differentiation system of 3T3-L1 mouse preadipocytes was used to determine the content of adipokines and the content of GLUT4 in the outer membrane. The expression of AKT, P-AKT, IRS-1 and P-IRS-1 in differentiated 3T3-L1 adipocytes was determined by western blotting. Our results demonstrated that trelagliptin succinate increased the expression of AKT, P-AKT, IRS-1 and P-IRS-1 in the PI-3K/AKT insulin signaling pathway. These events promote the trans-membrane function of GLUT4 and concomitant glucose intake in adipocytes. In addition, the secretion of free fatty acids and resistin were decreased. In conclusion, our study suggested that trelagliptin succinate improved insulin resistance in adipocytes via regulation of PI-3K/AKT/GLUT4 insulin signaling pathway.


Assuntos
Adipócitos/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Resistência à Insulina , Uracila/análogos & derivados , Células 3T3-L1 , Adipocinas/genética , Adipocinas/metabolismo , Animais , Ácidos Graxos não Esterificados , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/genética , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Resistina/genética , Resistina/metabolismo , Transdução de Sinais , Uracila/farmacologia
16.
Mol Med Rep ; 21(3): 1461-1470, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016479

RESUMO

The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high­dose BGC (BGC­H) and low­dose BGC (BGC­L) group. Serum levels of follicle­stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α (TNF­α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF­κB, IKKß and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL­6 and TNF­α, and the expression of IKKß, NF­κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low­grade chronic inflammation in the hypothalamus.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hiperandrogenismo/tratamento farmacológico , Resistência à Insulina , Fitoterapia , Preparações de Plantas/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Citocinas/sangue , Endométrio/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/metabolismo , Hipotálamo/metabolismo , Insulina/sangue , Leptina/sangue , Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/metabolismo , Ratos , Testosterona/sangue , Útero/metabolismo
17.
Sci Rep ; 10(1): 1908, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024865

RESUMO

Perturbations in skeletal muscle metabolism have been reported for a variety of neuromuscular diseases. However, the role of metabolism after constriction injury to a nerve and the associated muscle atrophy is unclear. We have analyzed rat tibialis anterior (TA) four weeks after unilateral constriction injury to the sciatic nerve (DMG) and in the contralateral control leg (CTRL) (n = 7) to investigate changes of the metabolome, immunohistochemistry and protein levels. Untargeted metabolomics identified 79 polar metabolites, 27 of which were significantly altered in DMG compared to CTRL. Glucose concentrations were increased 2.6-fold in DMG, while glucose 6-phosphate (G6-P) was unchanged. Intermediates of the polyol pathway were increased in DMG, particularly fructose (1.7-fold). GLUT4 localization was scattered as opposed to clearly at the sarcolemma. Despite the altered localization, we found GLUT4 protein levels to be increased 7.8-fold while GLUT1 was decreased 1.7-fold in nerve damaged TA. PFK1 and GS levels were both decreased 2.1-fold, indicating an inability of glycolysis and glycogen synthesis to process glucose at sufficient rates. In conclusion, chronic nerve constriction causes increased GLUT4 levels in conjunction with decreased glycolytic activity and glycogen storage in skeletal muscle, resulting in accumulation of intramuscular glucose and polyol pathway intermediates.


Assuntos
Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Traumatismos dos Nervos Periféricos/complicações , Polímeros/metabolismo , Animais , Modelos Animais de Doenças , Transportador de Glucose Tipo 1/metabolismo , Glicogênio/biossíntese , Glicólise , Humanos , Masculino , Metabolômica , Músculo Esquelético/inervação , Atrofia Muscular/etiologia , Traumatismos dos Nervos Periféricos/patologia , Ratos , Nervo Isquiático/lesões
18.
Gene ; 735: 144404, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32018013

RESUMO

Glucose uptake in adipocytes is crucial for regulating systemic metabolism. Long noncoding RNAs (lncRNAs), defined as being transcripts with lengths exceeding 200 nucleotides that are not translated, are recently identified regulators of cellular functions. Previously, we have shown that an lncRNA, "down-regulated expression by hepatitis B virus X" (dreh), is involved in glucose transport in skeletal muscle cells. Here, we aimed to examine the involvement of dreh in glucose transport in 3T3-L1 adipocytes. Expression analysis showed that dreh was expressed in 3T3-L1 fibroblasts and adipocytes. Knockdown of dreh expression using its specific siRNAs lowered the glucose concentration of the medium and facilitated [3H]-2-deoxyglucose transport in adipocytes. Additionally, dreh silencing enhanced the protein expression of glucose transporter (GLUT4) in the plasma membrane of adipocytes. Treatment with siRNA against vimentin attenuated the glucose-lowering effect of dreh depletion. These results suggest that the repression of dreh facilitates glucose transport via increased GLUT4 expression in the plasma membrane through the involvement of vimentin in 3T3-L1 adipocytes. In conclusion, dreh is the first observed lncRNA that regulates glucose transport in adipocytes and could serve as a novel therapeutic target for diabetes by modulating adipocyte function. Considering the new function of dreh, we propose that dreh be renamed "down-regulated expression-related hexose/glucose transport enhancer."


Assuntos
Adipócitos/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , RNA Longo não Codificante/genética , Vimentina/metabolismo , Animais , Linhagem Celular , Fibroblastos/metabolismo , Camundongos , RNA Longo não Codificante/metabolismo
19.
Nutrients ; 12(1)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952248

RESUMO

This study evaluated the effects and the underlying mechanisms of casein glycomacropeptide hydrolysate (GHP) on high-fat diet-fed and streptozotocin-induced type 2 diabetes (T2D) in C57BL/6J mice. Results showed that 8-week GHP supplementation significantly decreased fasting blood glucose levels, restored insulin production, improved glucose tolerance and insulin tolerance, and alleviated dyslipidemia in T2D mice. In addition, GHP supplementation reduced the concentration of lipopolysaccharides (LPSs) and pro-inflammatory cytokines in serum, which led to reduced systematic inflammation. Furthermore, GHP supplementation increased muscle glycogen content in diabetic mice, which was probably due to the regulation of glycogen synthase kinase 3 beta and glycogen synthase. GHP regulated the insulin receptor substrate-1/phosphatidylinositol 3-kinase/protein kinase B pathway in skeletal muscle, which promoted glucose transporter 4 (GLUT4) translocation. Moreover, GHP modulated the overall structure and diversity of gut microbiota in T2D mice. GHP increased the Bacteroidetes/Firmicutes ratio and the abundance of S24-7, Ruminiclostridium, Blautia and Allobaculum, which might contribute to its antidiabetic effect. Taken together, our findings demonstrate that the antidiabetic effect of GHP may be associated with the recovery of skeletal muscle insulin sensitivity and the regulation of gut microbiota.


Assuntos
Caseínas/farmacologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Fragmentos de Peptídeos/farmacologia , Animais , Caseínas/administração & dosagem , Diabetes Mellitus Experimental , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Masculino , Camundongos , Fragmentos de Peptídeos/administração & dosagem
20.
Nat Commun ; 11(1): 575, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996678

RESUMO

mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Adipócitos Marrons/metabolismo , Lipogênese/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetato-CoA Ligase/metabolismo , Animais , Proteínas de Transporte , Epigênese Genética , Ácido Graxo Sintases , Edição de Genes , Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Células HEK293 , Histonas/metabolismo , Humanos , Lipogênese/genética , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/metabolismo , Fosforilação , Proteômica , Elementos de Resposta
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