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1.
J Endocrinol ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505462

RESUMO

Adenosine 2A receptor (A2AR) exerts a protective role in obesity-related non-alcoholic fatty liver disease. Here, we examined whether A2AR protects against non-alcoholic steatohepatitis (NASH). In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregation of macrophages in the liver compared with mice fed a chow diet. MCD feeding also significantly increased the numbers of A2AR-positive macrophages/Kupffer cells in liver sections although decreasing A2AR amount in liver lysates compared with chow diet feeding. Next, MCD-induced NASH phenotype was examined in A2AR-disrupted mice and control mice. Upon MCD feeding, A2AR-disruptd mice and control mice displayed comparable decreases in body weight and fat mass. However, MCD-fed A2AR-disrupted mice revealed greater liver weight and increased severity of hepatic steatosis compared with MCD-fed control mice. Moreover, A2AR-disupted mice displayed increased severity of MCD-induced liver inflammation, indicated by massive aggregation of macrophages and increased phosphorylation states of Jun-N terminal kinase (JNK) p46 and nuclear factor kappa B (NFκB) p65 and mRNA levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. In vitro, incubation with MCD-mimicking media increased lipopolysaccharide (LPS)-induced phosphorylation states of JNK p46 and/or NFκB p65 and cytokine mRNAs in control macrophages and RAW264.7 cells, but not primary hepatocytes. Additionally, MCD-mimicking media significantly increased lipopolysaccharide-induced phosphorylation states of p38 and NFκB p65 in A2AR-deficient macrophages, but insignificantly decreased lipopolysaccharide-induced phosphorylation states of JNK p46 and NFκB p65 in A2AR-deficient hepatocytes. Collectively, these results suggest that A2AR disruption exacerbates MCD-induced NASH, which is attributable to, in large part, increased inflammatory responses in macrophages.

2.
Acta Pharmacol Sin ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213670

RESUMO

Type 2 diabetes (T2D) and Alzheimer's disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, is a specific and reversible inhibitor of acetylcholinesterase, which is clinically used for the treatment of AD. In this study, we investigated whether Hup A improved the metabolic and cognitive functions in the high fat-induced (HFD) obese mice and genetic ob/ob mice. HFD and ob/ob mice were treated with Hup A (0.1, 0.3 mg · kg-1 · d-1, ig) for 3 months. Body weight was monitored and glucose tolerance tests were performed. Novel object recognition test and Morris water maze assay were conducted to evaluate the cognitive functions. We found that the Hup A treatment had no significant effect on peripheral metabolism of obese mice, whereas Hup A (0.1, mg · kg-1 · d-1) improved both the abilities of object recognition and spatial memory in HFD-fed mice, but not in ob/ob mice. Furthermore, Hup A treatment significantly upregulated the insulin and phosphorylated Akt levels in the cortex of HFD-fed mice, but not ob/ob mice. In addition, Hup A (0.3, mg · kg-1 · d-1) significantly decreased cortical ß-secretase (BACE1) expression. In conclusion, these results demonstrate that treatment with Hup A (0.1, mg · kg-1 · d-1) can effectively improve the cognitive functions, at least in diet-induced obese mice.

3.
Cell Physiol Biochem ; 52(5): 1103-1116, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977991

RESUMO

BACKGROUND/AIMS: Gestational diabetes mellitus (GDM) is closely associated with early perinatal complications and long-term health problems, such as cardiovascular disease, in offspring. AMP-activated protein kinase (AMPK) is cardioprotective, particularly in the treatment of ischemia/reperfusion (I/R). However, whether GDM programs offspring susceptibility to cardiac I/R and the involvement of AMPK remain unclear. METHODS: Streptozotocin was administered to rats during mid pregnancy; the postpartum maternal metabolome was assessed by chromatography-mass spectrometry (GC-MS). Male offspring were subjected to body composition scanning followed by ex vivo global I/R. Cardiac signaling was determined by Western blotting. RESULTS: The body weights (BWs) of the GDM male offspring were significantly heavier than those of the control group from the age of 8 weeks; the heart weights (HWs) and HW/BW were also increased in the GDM group compared to the control group. The ex vivo post-I/R cardiac contractile function recovery was significantly compromised in the GDM male offspring. The phosphorylation of AMPK and ACC was elevated by ex vivo I/R in both groups, but to a significantly lesser extent in the GDM group. CONCLUSION: GDM male offspring rats have higher risks of overgrowth and intolerance to cardiac I/R, which may be due to a compromised AMPK signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Gestacional/enzimologia , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/enzimologia , Transdução de Sinais , Animais , Diabetes Gestacional/induzido quimicamente , Diabetes Gestacional/patologia , Feminino , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Tamanho do Órgão , Gravidez , Ratos
4.
J Diabetes Res ; 2019: 3256060, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993115

RESUMO

Exosome-like vesicles (ELVs), the smallest class of extracellular vesicles released from cells, function in cellular crosstalk and therefore profoundly affect physiologic responses and pathologic progression. A growing body of evidence supports a novel role for ELVs as important mediators and therapeutic targets due to their effects on regulation of both insulin signaling and ß-cell mass. Pathologic conditions associated with type 2 diabetes (such as high blood glucose, inflammation, hypoxia, and fatty acids) can alter the quantity and components of ELVs secreted from the pancreas or peripheral insulin-targeting tissues. These released ELVs can either enter the blood circulation or be taken up by neighboring cells or macrophages, which can lead to insulin resistance or ß-cell apoptosis. This review focuses on the roles of ELVs in insulin resistance and ß-cell failure and also highlights the potential use of ELVs and exosome-based delivery systems in therapeutic interventions aimed at treating type 2 diabetes mellitus as well as the challenges associated with exosome-targeting therapeutics.

5.
Life Sci ; 218: 265-273, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605650

RESUMO

AIMS: We sought to reveal the key molecular signature in subcutaneous adipose tissue (scAT) following Roux-en-Y gastric bypass (RYGB), through bioinformatics analysis and further verification in vivo. MAIN METHODS: We obtained a transcriptome data of scAT from RYGB and sham-operated rats from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were screened and the DEGs-related Gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed. Also, the protein-protein interaction (PPI) network was constructed among the DEGs. Furthermore, we established an experimental rat model to verify the bioinformatics findings. KEY FINDINGS: Using the method of bioinformatics, a total of 602 genes were found to be differentially expressed in scAT between the RYGB group and the sham-operated group. GO analysis showed that DEGs were significantly enriched in extracellular matrix(ECM) -associated functions or processes. KEGG pathway analysis revealed that the protein digestion and absorption pathway and ECM-receptor interaction pathway were the most significantly enriched pathways. The genes encoding ECM components and ECM remodeling-related proteins interact substantially in the PPI network. Then the results of rat experimental verified that the gene expression levels of ECM components(Collagen I and III) and ECM cross-linking related proteins(lysyl oxidase and lysyl oxidase-like 1) decreased and ECM dagradation-related proteins increased in scAT following RYGB. These beneficial results were positively associated with improved insulin resistance (IR). SIGNIFICANCE: Appropriate ECM remodeling, primarily the reduction of ECM deposition and cross-linking and the increase of ECM dagradation, may be the key molecular signature in scAT following RYGB.


Assuntos
Biomarcadores/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Derivação Gástrica , Gordura Subcutânea/metabolismo , Transcriptoma , Animais , Biologia Computacional , Proteínas da Matriz Extracelular/genética , Masculino , Mapas de Interação de Proteínas , Ratos , Ratos Sprague-Dawley , Gordura Subcutânea/cirurgia
6.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 147-160, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30404040

RESUMO

OBJECTIVE: Diabetes exerts adverse effects on the initiation or progression of diabetes and metabolic syndrome in the next generation. In past studies, limited attention has been given to the fathers' role in shaping the metabolic landscape of offspring. Our study was designed to investigate how paternal hyperglycemia exerts an intergenerational effect in mammals as well as the underlying mechanisms. METHODS: Hyperglycemia was introduced in male rats by intraperitoneally injected streptozotocin and these males were bred with healthy females to generate offspring. The metabolic profiles of the progeny were assessed; DNA methylation profiles and gene expression were investigated. Mutagenesis constructs of the Ppara promoter region, and a luciferase reporter assay were used to determine transcription factor binding sites (TFBSs) and the effects of hypermethylation on Ppara transcription. RESULTS: Paternal hyperglycemia induced increased liver weight, and plasma TC, TG, LDL, accumulation of triglycerides in the liver. We discovered that CpG 13 in the amplified promoter region (-852 to -601) of Ppara was hypermethylated in adult offspring liver and expression of Ppara, Acox1, Cpt-1α, and Cd36 was down regulated. Hypermethylation of CpG site 13 in the Ppara promoter inhibited the gene transcription, probably through abrogation of SP1 binding. The same epigenetic alteration was discovered in the fetus (E16.5) liver of hyperglycemic father's progeny. CONCLUSIONS: Paternal hyperglycemia may induce epigenetic modification of Ppara in offspring's liver, probably through interaction with SP1 binding, causing impaired lipid metabolism. Our investigation may have implications for the understanding of father-offspring interactions with the potential to account for metabolic syndromes.


Assuntos
Metilação de DNA , Fígado Gorduroso/metabolismo , Hiperglicemia/metabolismo , PPAR alfa/genética , Herança Paterna , Regiões Promotoras Genéticas/genética , Animais , Sítios de Ligação , Filho de Pais Incapacitados , Diabetes Mellitus/metabolismo , Pai , Fígado Gorduroso/sangue , Feminino , Hepatócitos/metabolismo , Hepatócitos/patologia , Hiperglicemia/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/metabolismo , Mutagênese , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição
7.
Genes Dis ; 5(3): 290-299, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30320193

RESUMO

Traditional thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) potent agonists that can be used to treat type 2 diabetes but carry unwanted effects, including increased risk for fracture. The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008, a novel TZDs-like PPARγ partial agonist, with those of rosiglitazone. A TR-FRET PPARγ competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone. Mice were administered vehicle, CMHX008 or rosiglitazone for 16 weeks. Mesenchymal stem cells (MSCs) were used to examine differences in differentiation into osteoblasts after compounds treatment. TR-FRET showed lower affinity to PPARγ by CMHX008 compared with rosiglitazone. Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone, which was related to the significant inhibition of PPARγ Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues. Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone, as evidenced by consistent changes in BV/TV, Tb.N, Tb.Th, Tb.Sp, and the mineral apposition rate. MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test. Thus, CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss, suggesting that PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

8.
Gastroenterology ; 155(6): 1971-1984.e4, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213555

RESUMO

BACKGROUND & AIMS: Transmembrane protein 173 (TMEM173 or STING) signaling by macrophage activates the type I interferon-mediated innate immune response. The innate immune response contributes to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). We investigated whether STING regulates diet-induced in hepatic steatosis, inflammation, and liver fibrosis in mice. METHODS: Mice with disruption of Tmem173 (STINGgt) on a C57BL/6J background, mice without disruption of this gene (controls), and mice with disruption of Tmem173 only in myeloid cells were fed a standard chow diet, a high-fat diet (HFD; 60% fat calories), or a methionine- and choline-deficient diet (MCD). Liver tissues were collected and analyzed by histology and immunohistochemistry. Bone marrow cells were isolated from mice, differentiated into macrophages, and incubated with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; an activator of STING) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Macrophages or their media were applied to mouse hepatocytes or human hepatic stellate cells (LX2) cells, which were analyzed for cytokine expression, protein phosphorylation, and fat deposition (by oil red O staining after incubation with palmitate). We obtained liver tissues from patients with and without NAFLD and analyzed these by immunohistochemistry. RESULTS: Non-parenchymal cells of liver tissues from patients with NAFLD had higher levels of STING than cells of liver tissues from patients without NAFLD. STINGgt mice and mice with disruption only in myeloid cells developed less severe hepatic steatosis, inflammation, and/or fibrosis after the HFD or MCD than control mice. Levels of phosphorylated c-Jun N-terminal kinase and p65 and mRNAs encoding tumor necrosis factor and interleukins 1B and 6 (markers of inflammation) were significantly lower in liver tissues from STINGgt mice vs control mice after the HFD or MCD. Transplantation of bone marrow cells from control mice to STINGgt mice restored the severity of steatosis and inflammation after the HFD. Macrophages from control, but not STINGgt, mice increased markers of inflammation in response to lipopolysaccharide and cGAMP. Hepatocytes and stellate cells cocultured with STINGgt macrophages in the presence of DMXAA or incubated with the medium collected from these macrophages had decreased fat deposition and markers of inflammation compared with hepatocytes or stellate cells incubated with control macrophages. CONCLUSIONS: Levels of STING were increased in liver tissues from patients with NAFLD and mice with HFD-induced steatosis. In mice, loss of STING from macrophages decreased the severity of liver fibrosis and the inflammatory response. STING might be a therapeutic target for NAFLD.

9.
Neuropharmacology ; 138: 160-169, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29885817

RESUMO

Acute intracerebral hemorrhage (ICH) complicated by hyperglycemia is associated with aggravation of post-stroke inflammation, leading to exacerbation of brain edema and predicting poor neurological outcomes and higher mortality of patients. Osteopontin (OPN) is a neuroprotective glycoprotein, which is able to attenuate brain injury induced by hemorrhagic stroke. In the current study we investigated whether OPN will decrease the inflammatory post-ICH response as well as attenuate brain edema and neurological deficits in hyperglycemic rats. We employed a collagenase model of ICH on male Sprague-Dawley rats (n = 148) rats and 50% of Dextrose was injected intraperitoneally (i.p) 3 h after ICH (ICH + HG). Intranasal administration of recombinant OPN (rOPN) was performed 1 h after ICH. The development of brain injury was evaluated by brain water content (BWC) and neurological deficits, western blot and immunohistochemistry study. Small interfering ribonucleic acid (siRNA) for integrin-ß1 receptor and a JAK2 agonist, Coumermycin A1 (C-A1), were used for detailed investigation of the molecular pathway. The administration of OPN (3 µg) significantly improved neurobehavior and increased expression of OPN and integrin-ß1 receptor in the brain followed with decrease of neutrophil infiltration, JAK2, STAT1, TNF-a, IL-1b, MMP-9 and brain edema in the ICH + HG + OPN rats compared with ICH + HG rats. The effects of OPN were reversed by the intervention of intergrin-ß1 siRNA and C-A1. In conclusion, rOPN attenuated ICH-induced brain inflammation in hyperglycemic rats, leading to attenuation of brain edema and improving neurological functions. Effects of rOPN were mediated at least partly by integrin-ß1 induced inhibition of JAK2/STAT1 pathway.

10.
Hepatology ; 68(1): 48-61, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29315766

RESUMO

Adenosine 2A receptor (A2A R) exerts protective roles in endotoxin- and/or ischemia-induced tissue damage. However, the role for A2A R in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. We sought to examine the effects of global and/or myeloid cell-specific A2A R disruption on the aspects of obesity-associated NAFLD and to elucidate the underlying mechanisms. Global and/or myeloid cell-specific A2A R-disrupted mice and control mice were fed a high-fat diet (HFD) to induce NAFLD. In addition, bone marrow-derived macrophages and primary mouse hepatocytes were examined for inflammatory and metabolic responses. Upon feeding an HFD, both global A2A R-disrupted mice and myeloid cell-specific A2A R-defcient mice revealed increased severity of HFD-induced hepatic steatosis and inflammation compared with their respective control mice. In in vitro experiments, A2A R-deficient macrophages exhibited increased proinflammatory responses, and enhanced fat deposition of wild-type primary hepatocytes in macrophage-hepatocyte cocultures. In primary hepatocytes, A2A R deficiency increased the proinflammatory responses and enhanced the effect of palmitate on stimulating fat deposition. Moreover, A2A R deficiency significantly increased the abundance of sterol regulatory element-binding protein 1c (SREBP1c) in livers of fasted mice and in hepatocytes upon nutrient deprivation. In the absence of A2A R, SREBP1c transcription activity was significantly increased in mouse hepatocytes. CONCLUSION: Taken together, our results demonstrate that disruption of A2A R in both macrophage and hepatocytes accounts for increased severity of NAFLD, likely through increasing inflammation and through elevating lipogenic events due to stimulation of SREBP1c expression and transcription activity. (Hepatology 2018;68:48-61).

11.
FASEB J ; 32(2): 1007-1016, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29042453

RESUMO

The prevalence of hyperuricemia has increased rapidly over the past decades. Bisphenol A (BPA) is an environmental endocrine disruptor. We investigated the effects of BPA on uric acid metabolism and its potential mechanisms. Experiments were performed in different animal models, cell cultures, and humans. In 3 different animal models, BPA exposure increased serum and hepatic uric acid with enhanced activity of xanthine oxidase (XO) in liver, whereas the excretion of uric acid was unchanged. Both in vivo and in vitro, BPA-induced uric acid production was decreased after treatment with allopurinol, which is a XO inhibitor. XO led to the accumulation of uric acid after xanthine was added, with the enzyme-catalyzed reaction, which was enhanced by BPA. Altered secondary structures of XO were found by circular dichroism analysis in the conditions of different BPA concentrations. Molecular docking portrayed Asp360 and Lys422 of XO to be the preferred binding sites for BPA. Mutation of both sites significantly blocked the effect of BPA on XO activity. In humans, patients with hyperuricemia exhibited higher levels of serum BPA than subjects without hyperuricemia. These findings demonstrate BPA promotes hyperuricemia by increasing hepatic uric acid synthesis via the activation of XO, probably through direct binding.-Ma, L., Hu, J., Li, J., Yang, Y., Zhang, L., Zou, L., Gao, R., Peng, C., Wang, Y., Luo, T., Xiang, X., Qing, H., Xiao, X., Wu, C., Wang, Z., He, J. C., Li, Q., Yang, S. Bisphenol A promotes hyperuricemia via activating xanthine oxidase.


Assuntos
Compostos Benzidrílicos/toxicidade , Hiperuricemia , Fígado/enzimologia , Simulação de Acoplamento Molecular , Fenóis/toxicidade , Xantina Oxidase , Animais , Sítios de Ligação , Indução Enzimática/efeitos dos fármacos , Hiperuricemia/induzido quimicamente , Hiperuricemia/enzimologia , Masculino , Camundongos , Xantina Oxidase/biossíntese , Xantina Oxidase/química
13.
Exp Ther Med ; 14(3): 2536-2542, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28947917

RESUMO

The present study aimed to explore the effect of Roux-en-Y gastric bypass (RYGB) surgery on protein tyrosine phosphatase 1B (PTP1B) expression levels and leptin activity in hypothalami of obese rats. Obese rats induced by a high-fat diet (HFD) that underwent RYGB (n=11) or sham operation (SO, n=9), as well as an obese control cohort (Obese, n=10) and an additional normal-diet group (ND, n=10) were used. Food efficiency was measured at 8 weeks post-operation. Plasma leptin levels were evaluated and hypothalamic protein tyrosine phosphatase 1B (PTP1B) levels and leptin signaling activity were examined at the genetic and protein levels. The results indicated that food efficiency was typically lower in RYGB rats compared with that in the Obese and SO rats. In the RYGB group, leptin receptor expression and proopiomelanocortin was significantly higher, while Neuropeptide Y levels were lower than those in the Obese and SO groups. Furthermore, the gene and protein expression levels of PTP1B in the RYGB group were lower, while levels of phosphorylated signal transducer and activator of transcription 3 protein were much higher compared with those in the Obese and SO groups. In conclusion, RYGB surgery significantly suppressed hypothalamic PTP1B protein expression. PTP1B regulation may partially alleviate leptin resistance.

14.
Sci Rep ; 7(1): 6355, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28743914

RESUMO

Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses. In obese mice, treatment with cGAMP significantly decreases diet-induced proinflammatory responses in liver and adipose tissues and ameliorates metabolic dysregulation. Strikingly, cGAMP exerts cell-type-specific anti-inflammatory effects on macrophages, hepatocytes, and adipocytes, which is distinct from the effect of STING activation by DMXAA on enhancing proinflammatory responses. While enhancing insulin-stimulated Akt phosphorylation in hepatocytes and adipocytes, cGAMP weakens the effects of glucagon on stimulating hepatocyte gluconeogenic enzyme expression and glucose output and blunts palmitate-induced hepatocyte fat deposition in an Akt-dependent manner. Taken together, these results suggest an essential role for cGAMP in linking innate immunity and metabolic homeostasis, indicating potential applications of cGAMP in treating obesity-associated inflammatory and metabolic diseases.

15.
Obes Facts ; 10(3): 191-206, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28564652

RESUMO

OBJECTIVE: This study was initiated to investigate the effects of Roux-en-Y gastric bypass (RYGB) surgery on hepatic glucose metabolism and hepatic expression of protein tyrosine phosphatase 1B (PTP1B) in obese rats. METHODS: Body weight, glucose, intraperitoneal glucose, insulin, and pyruvate tolerance tests were performed pre- and postoperatively, and plasma lipid, insulin and glucagon-like peptide 1 (GLP-1) were measured. The mRNA levels of G6Pase, Pepck, Gsk-3ß and Gys-2, and the expression levels of PTP1B mRNA, protein, and other components of the insulin signaling pathway were measured by using RT-PCR and western blotting. The intracellular localization of PTP1B and hepatic glycogen deposition was also observed. RESULTS: RYGB surgery-treated rats showed persistent weight loss, significantly improved glucose tolerance, pyruvate tolerance, and dyslipidemia, as well as increased insulin sensitivity, hepatic glycogen deposition and increased plasma GLP-1 in obese rats. RT-PCR analyses showed Pepck, G6Pase, and Gsk-3ß mRNA to be significantly decreased, and Gys-2 mRNA to be significantly increased in liver tissue in the RYGB group (p < 0.05 vs. high-fat diet (HFD) or HFD + sham group); in addition, the expression of PTP1B were significantly decreased and insulin signaling were improved in the RYGB group (p < 0.05 vs. HFD or HFD + sham group). CONCLUSION: RYGB can improve hepatic glucose metabolism and down-regulate PTP1B in obese rats. An increased circulating GLP-1 concentration may be correlated with the effects following RYGB in obese rats.


Assuntos
Derivação Gástrica , Glucose/metabolismo , Fígado/metabolismo , Obesidade/enzimologia , Obesidade/cirurgia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Regulação para Baixo , Peptídeo 1 Semelhante ao Glucagon/sangue , Insulina/sangue , Resistência à Insulina , Fígado/enzimologia , Masculino , Obesidade/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/análise , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley
16.
Med Sci Monit ; 23: 2151-2158, 2017 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-28477035

RESUMO

BACKGROUND Over the past few decades, bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), has become widely considered the most effective treatment for morbid obesity. In most cases, it results in enhanced glucose management in patients with obesity and type 2 diabetes (T2D), which is observed before significant weight loss. However, what accounts for this effect remains controversial. To gain insight into the benefits of RYGB in T2D, we investigated changes in the ß-cell mass of obese rats following RYGB. MATERIAL AND METHODS RYGB or a sham operation was performed on obese rats that had been fed a high-fat diet (HFD) for 16 weeks. Then, the HFD was continued for 8 weeks in both groups. Additional normal chow diet (NCD) and obese groups were used as controls. RESULTS In the present study, RYGB induced improved glycemic control and enhanced ß-cell function, which was reflected in a better glucose tolerance and a rapidly increased secretion of insulin and C-peptide after glucose administration. Consistently, rats in the RYGB group displayed increased ß-cell mass and islet numbers, which were attributed in part to increased glucagon-like peptide 1 levels following RYGB. CONCLUSIONS Our data indicate that RYGB can improve b-cell function via increasing ß-cell mass, which plays a key role in improved glycemic control after RYGB.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Animais , Cirurgia Bariátrica/métodos , Glicemia/metabolismo , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Masculino , Obesidade/metabolismo , Obesidade Mórbida/cirurgia , Ratos , Ratos Sprague-Dawley , Perda de Peso
17.
J Endocrinol ; 234(2): 175-186, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28533422

RESUMO

Parental history with obesity or diabetes will increase the risk for developing metabolic diseases in offspring. However, literatures as to transgenerational inheritance of metabolic dysfunctions through male lineage are relatively scarce. In the current study, we aimed to evaluate influences of paternal hyperglycemia on metabolic phenotypes in offspring. Male SD rats were i.p. injected with streptozotocin (STZ) or citrate buffer (CB, as control). STZ-injected rats with glucose levels higher than 16.7 mM were selected to breed with normal female rats. Offspring from STZ or CB treated fathers (STZ-O and CB-O) were maintained in the identical condition. We monitored body weight and food intake, and tests of glucose and insulin tolerance (GTTs and ITTs), fasting-refeeding and cold exposure were performed. Expression of factors involved in hypothalamic feeding and brown adipose tissue (BAT) thermogenic activity was performed by real-time PCR and Western blot. Adult STZ-O were heavier than CB-O. Impairment of GTTs was observed in STZ-O compared with CB-O at 22 and 32 weeks of age; ITTs results showed decreased insulin sensitivity in STZ-O. Daily food intake and accumulated food intake during 12-h refeeding after fasting were significantly higher in STZ-O. UCP1 levels were downregulated in BAT from STZ-O at room temperature and cold exposure. Finally, STZ-O rats showed suppressed leptin signaling in the hypothalamus as evidenced by upregulated SOCS3, reduced phosphorylation of STAT3, impaired processing POMC and decreased α-MSH production. Our study revealed that paternal hyperglycemia predisposes offspring to developing obesity, which is possibly associated with impaired hypothalamic leptin signaling.


Assuntos
Regulação da Expressão Gênica/fisiologia , Hiperglicemia/complicações , Obesidade/etiologia , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Branco/fisiologia , Animais , Diabetes Mellitus Experimental , Epididimo , Feminino , Hiperfagia , Hipotálamo/fisiologia , Leptina/sangue , Leptina/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , alfa-MSH/sangue , alfa-MSH/metabolismo
18.
J Endocrinol ; 234(2): 143-154, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28500084

RESUMO

Bisphenol A (BPA), one of the most common environmental endocrine disruptors, is considered to promote hepatic lipid deposition. However, the mechanism has not been fully elucidated. The polarization of Kupffer cells (KCs) plays an important role in hepatic inflammation by promoting pro-inflammatory M1 phenotype (M1KCs), which contributes to dysregulated lipid metabolism. The purpose of this study is to investigate the role of KC polarization in BPA-induced hepatosteatosis in male mice. In this study, we examined hepatic lipid contents and quantified M1KC in BPA-treated CD1 mice, and further explored the interaction between KCs and hepatocytes using conditional HepG2 cell culture. BPA treatment significantly increased hepatic fat contents in CD1 mice, accompanied by increased number of pro-inflammatory M1KCs and enhanced secretion of inflammatory cytokines. Increased lipid contents were also observed in HepG2 cells treated with BPA. Interestingly, higher TG contents were observed in HepaG2 cells treated with conditional media from BPA-treated KCs, compared with those treated with BPA directly. Incubation of KCs with BPA promoted the polarization of KCs to pro-inflammatory M1 dominant subtypes, which was blocked by estrogen antagonist ICI182780. Taken together, our results revealed that M1KCs polarization is involved in BPA-induced hepatic fat deposition, which is possibly associated with the estrogen receptor signaling pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Estrogênios não Esteroides/toxicidade , Macrófagos do Fígado/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fenóis/toxicidade , Animais , Transporte Biológico/fisiologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/fisiologia , Macrófagos do Fígado/classificação , Masculino , Camundongos , Receptores Estrogênicos/metabolismo , Transdução de Sinais
19.
Nutrients ; 9(4)2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28368295

RESUMO

Elevated circulating homocysteine (Hcy) has been proposed to be associated with non-alcoholic fatty liver disease (NAFLD). It is also reported that Hcy causes protein misfolding in the endoplasmic reticulum (ER). In this study, we used a high methionine diet (HMD)-fed mouse model and cultured primary hepatocytes to investigate the effects of Hcy on hepatic lipids metabolism. C57BL/6J mice received either standard chow diet (CT, n = 10) or diet supplemented with 2% methionine (MET, n = 10) for 16 weeks. In in vitro experiments, cultured mouse primary hepatocytes were treated with Hcy, or Hcy combined with 4-phenylbutyric acid (4-PBA), or tunicamycin (TM), respectively. HMD-fed mice exhibited a mild increase in plasma Hcy level. There was no significant difference of body weight gain between the two groups. Nevertheless, HMD feeding increased epididymal fat/body weight ratio, elevated plasma triglyceride (TG) level, and decreased high-density lipoprotein cholesterol (HDL) level. Similarly, mice on HMD displayed higher liver/body weight ratio, plasma aspartate aminotransferase (AST) and its ratio to alanine aminotransferase (ALT), which was supported by the morphological observations of hepatic triglyceride accumulation in liver tissue as well as primary hepatocytes. Activation of the sterol response element-binding protein 1c (SREBP1c) in Hcy-treated hepatocytes with increased expression of genes involved in hepatic de novo lipogenesis was partially reduced by pretreatment of 4-PBA. Hcy-induced ER stress was also ameliorated by 4-PBA pretreatment, thus demonstrating an important role of Hcy-induced ER stress response in hepatic steatosis. These findings suggest that elevated Hcy was a critical factor in the pathogenesis of NAFLD. Activation of the ER stress response may be involved in Hcy-induced hepatic steatosis.


Assuntos
Estresse do Retículo Endoplasmático , Hiper-Homocisteinemia/fisiopatologia , Fígado/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Homocisteína/efeitos adversos , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Metionina/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Fenilbutiratos/farmacologia , Distribuição Aleatória , Tunicamicina/farmacologia
20.
Endocrinology ; 158(9): 2799-2812, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323964

RESUMO

Accumulating evidence suggests that bisphenol A (BPA) exposure is associated with nonalcoholic fatty liver disease. Disruption of autophagy causes lipid accumulation in hepatocytes. Whether and how BPA regulates autophagy remains to be explored. We investigated the effect of BPA on autophagy in hepatocytes and examined the influence of BPA-regulated autophagy on hepatic lipid accumulation. Male CD1 mice were treated with BPA for 8 weeks, followed by histological and biochemical evaluation of liver lipids and autophagy. Also, the effects of BPA on autophagy and hepatic lipid accumulation were examined in primary hepatocytes and HepG2 cells. Lipid content in HepG2 cells and/or primary hepatocytes was increased obviously after BPA exposure. In addition, BPA exposure caused accumulation of autophagosomes in HepG2 cells and enhanced colocalization of Bodipy 493/503 with microtubule associated protein light-chain 3. These changes were accompanied with increased expression levels of p-mammalian target of rapamycin, p-p70S6 kinase, p-ULK1 and decreased expression levels of Atg5. BPA exposure also downregulated the expression of cathepsin L and decreased cytoplasmic retention of acridine orange in HepG2 cells. The impaired autophagic degradation was further evidenced by increased levels of p62 in BPA-treated HepG2 cells. At the whole animal level, BPA treatment induced lipid accumulation in livers of male CD1 mice, which was accompanied with changes in hepatic autophagy-related proteins. Moreover, induction of autophagy by Torin1 protected against BPA-induced lipid accumulation whereas suppression of autophagy by chloroquine exacerbated BPA-induced lipid accumulation in HepG2 cells. BPA dysregulates autophagy in hepatocytes, which is linked to BPA-induced hepatic lipid accumulation.


Assuntos
Autofagia/fisiologia , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Células Hep G2 , Hepatócitos/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
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