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1.
Toxicol Lett ; 332: 42-55, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32629074

RESUMO

Obesity is associated with several female reproductive complications, such as polycystic ovary syndrome (PCOS). The exact mechanism of this relationship remains unclear. Few previous studies using diet containing refined carbohydrate (HCD) leading to obesity have been performed and it is unclear if HCD is linked with reproductive dysfunctions. In this investigation, we assessed whether subchronic HCD exposure results in reproductive and other irregularities. Female rats were fed with HCD for 15 days and metabolic outcomes and reproductive tract morphophysiology were assessed. We further assessed reproductive tract inflammation, oxidative stress (OS) and fibrosis. HCD rats displayed metabolic impairments, such as an increase in body weight/adiposity, adipocyte hypertrophic, abnormal lipid profile, glucose tolerance and insulin resistance (IR) and hyperleptinemia. Improper functioning of the HCD reproductive tract was observed. Specifically, irregular estrous cyclicity, high LH levels and abnormal ovarian morphology coupled with reduction in primordial and primary follicle numbers was observed, suggesting ovarian reserve depletion. Improper follicular development and a reduction in antral follicles, corpora lutea and granulosa layer area together with an increase in cystic follicles were apparent. Uterine atrophy and reduction in endometrial gland (GE) number was observed in HCD rats. Reproductive tract inflammation, OS and fibrosis were seen in HCD rats. Further, strong positive correlations were observed between body weight/adiposity and IR with estrous cycle length, cystic follicles, ovarian reserve, GE and other abnormalities. Thus, these data suggest that the subchronic HCD exposure led to PCOS-like features, impaired ovarian reserve, GE number, and other reproductive abnormalities in female rats.


Assuntos
Carboidratos da Dieta/toxicidade , Reserva Ovariana/efeitos dos fármacos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal , Dieta , Ciclo Estral/efeitos dos fármacos , Feminino , Fibrose , Intolerância à Glucose/sangue , Intolerância à Glucose/induzido quimicamente , Resistência à Insulina , Leptina/sangue , Metabolismo dos Lipídeos , Folículo Ovariano/efeitos dos fármacos , Ovário/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar
2.
Life Sci ; 256: 118012, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32593710

RESUMO

AIMS: Bisphenol (BP)-A exposure can impair glucose and lipid metabolism. However, it is unclear whether this endocrine disruptor (ED) modulates these processes in postmenopause, a period with organic changes that increase the risk for metabolic diseases. Herein, we evaluated the effects of BPA exposure on adiposity, glucose homeostasis and hepatic steatosis in ovariectomized (OVX) mice fed on a high-fat diet (HFD). MAIN METHODS: Adult Swiss female mice were OVX and submitted to a normolipidic diet or HFD and drinking water without [control (OVX CTL) and OVX HFD groups, respectively] or with 1 µg/mL BPA (OVX CBPA and OVX HBPA groups, respectively), for 3 months. KEY FINDINGS: OVX HFD females displayed increased adiposity, glucose intolerance, insulin resistance and moderate hepatic steatosis. This effect was associated with a high hepatic expression of genes involved in lipogenesis (Srebf1 and Scd1), ß-oxidation (Cpt1a) and endoplasmic reticulum (ER) stress (Hspa5 and Hyou1). BPA did not alter adiposity or glucose homeostasis disruptions induced by HFD. However, this ED triggered severe steatosis, exacerbating hepatic fat and collagen depositions in OVX HBPA, in association with a reduction in Mttp mRNA, and up-regulation of genes involved in ß-oxidation (Acox1 and Acadvl), mitochondrial uncoupling (Ucp2), ER stress (Hyou1 and Atf6) and chronic liver injury (Tgfb1and Casp8). Furthermore, BPA caused mild steatosis in OVX CBPA females, increasing the hepatic total lipids and mRNAs for Srebf1, Scd1, Hspa5, Hyou1 and Atf6. SIGNIFICANCE: BPA aggravated hepatic steatosis in OVX mice. Especially when combined with a HFD, BPA caused NAFLD progression, which was partly mediated by chronic ER stress and the TGF-ß1 pathway.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Fenóis/toxicidade , Adiposidade/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Glucose/metabolismo , Resistência à Insulina , Lipogênese/efeitos dos fármacos , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Ovariectomia
3.
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
4.
Chemosphere ; 255: 127000, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32417515

RESUMO

BACKGROUND: Bisphenol-A (BPA) exposure is widespread and early life exposure is associated with metabolic syndrome. While visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are implicated in the development of metabolic syndrome, the adipose depot-specific effects of prenatal BPA treatment are poorly understood. OBJECTIVE: To determine the impact of prenatal BPA exposure on genome-wide gene expression of VAT and SAT depots. METHODS: RNA sequencing was performed on SAT and VAT from 21-month old control and prenatal BPA-treated female sheep. Gene expression and pathway differences between SAT and VAT depots with or without prenatal BPA-treatment and the effect of prenatal BPA treatment on each depot were tested. RESULTS: There were 179 differentially expressed genes (padjusted < 0.05, log2-fold change >2.5) between SAT and VAT. Development and immune response pathways were upregulated in SAT, while metabolic pathways were upregulated in VAT. These adipose depot-specific genes and pathways were consistent with prenatal BPA-treatment. In SAT, BPA-treatment resulted in differential expression of 108 genes (78% upregulated with BPA) and altered pathways (immune response downregulated, RNA processing upregulated). In contrast in VAT, BPA-treatment differentially expressed 4 genes and upregulated chromatin and RNA processing pathways. CONCLUSION: Prenatal BPA-treatment induces adult depot-specific alterations in RNA expression in inflammation, RNA processing, and chromatin pathways, reflecting the diverse roles of SAT and VAT in regulating lipid storage and insulin sensitivity. These adipose tissue transcriptional dysregulations may contribute to the metabolic disorders observed in prenatal BPA-treated female sheep.


Assuntos
Adiposidade/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Gordura Subcutânea/efeitos dos fármacos , Adiposidade/genética , Animais , Compostos Benzidrílicos/sangue , Regulação para Baixo , Disruptores Endócrinos/sangue , Feminino , Perfilação da Expressão Gênica , Inflamação , Gordura Intra-Abdominal/crescimento & desenvolvimento , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Fenóis/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , RNA/genética , RNA/metabolismo , Ovinos , Gordura Subcutânea/crescimento & desenvolvimento , Gordura Subcutânea/metabolismo
5.
Clin Sci (Lond) ; 134(7): 827-851, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32271386

RESUMO

Major shifts in human lifestyle and dietary habits toward sedentary behavior and refined food intake triggered steep increase in the incidence of metabolic disorders including obesity and Type 2 diabetes. Patients with metabolic disease are at a high risk of cardiovascular complications ranging from microvascular dysfunction to cardiometabolic syndromes including heart failure. Despite significant advances in the standards of care for obese and diabetic patients, current therapeutic approaches are not always successful in averting the accompanying cardiovascular deterioration. There is a strong relationship between adipose inflammation seen in metabolic disorders and detrimental changes in cardiovascular structure and function. The particular importance of epicardial and perivascular adipose pools emerged as main modulators of the physiology or pathology of heart and blood vessels. Here, we review the peculiarities of these two fat depots in terms of their origin, function, and pathological changes during metabolic deterioration. We highlight the rationale for pharmacological targeting of the perivascular and epicardial adipose tissue or associated signaling pathways as potential disease modifying approaches in cardiometabolic syndromes.


Assuntos
Adipocinas/antagonistas & inibidores , Tecido Adiposo/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Vasos Sanguíneos/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Inflamação/tratamento farmacológico , Pericárdio/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Metabolismo Energético/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Pericárdio/metabolismo , Pericárdio/patologia , Pericárdio/fisiopatologia , Transdução de Sinais
6.
Nutr Metab Cardiovasc Dis ; 30(5): 843-846, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278610

RESUMO

BACKGROUND AND AIMS: Prospective epidemiological studies highlighted recently the link between artificial sweeteners (AS) consumption and the risk of developing cardiometabolic diseases. However, underlying mechanisms remain unknown. Thus, the aim of this preliminary study was to characterize, in a healthy rat population, the effect of chronic AS consumption on body composition and vascular function, an early marker for cardiovascular disease. METHODS AND RESULTS: Healthy Wistar rats followed a 10-week standard diet including the consumption of water sweetened or not with a sucralose/acesulfame potassium solution at different concentrations: for moderate consumption at 1 and 2 mg.kg-1.day-1, respectively or high intake at 15 and 15 mg.kg-1.day-1 for both molecules (acceptable daily intake). Body fat composition has been evaluated and ex vivo aortic vasomotor function has been investigated with a pharmacological approach. CONCLUSION: Both groups of AS-treated rats showed a significant increase in subcutaneous and perirenal adipose tissue mass storage, without changes in total body mass. However, rats that have consumed AS at Acceptable Daily Intake (ADI) concentration revealed a significant vascular endothelial dysfunction compared to other groups. These results are interesting because they will help to better explain the observed increase in cardiometabolic risk.


Assuntos
Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Sacarose/análogos & derivados , Edulcorantes/toxicidade , Tiazinas/toxicidade , Vasodilatação/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Animais , Aorta/fisiopatologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiopatologia , Dados Preliminares , Ratos Wistar , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/fisiopatologia , Sacarose/administração & dosagem , Sacarose/toxicidade , Edulcorantes/administração & dosagem , Tiazinas/administração & dosagem
7.
Nutr Metab Cardiovasc Dis ; 30(4): 616-624, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32127340

RESUMO

BACKGROUND AND AIMS: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes. METHODS AND RESULTS: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911). CONCLUSION: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss. TRIAL REGISTRY NUMBER: NCT01761318.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Liraglutida/uso terapêutico , Perda de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Idoso , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
8.
Obesity (Silver Spring) ; 28(5): 932-941, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32196994

RESUMO

OBJECTIVE: Arsenic is an endocrine-disrupting chemical associated with diabetes risk. Increased adiposity is a significant risk factor for diabetes and its comorbidities. Here, the impact of chronic arsenic exposure on adiposity and metabolic health was assessed in mice. METHODS: Male C57BL/6J mice were provided ad libitum access to a normal or high-fat diet and water +/- 50 mg/L of sodium arsenite. Changes in body weight, body composition, insulin sensitivity, energy expenditure, and locomotor activity were measured. Measures of adiposity were compared with accumulated arsenic in the liver. RESULTS: Despite uniform arsenic exposure, internal arsenic levels varied significantly among arsenic-exposed mice. Hepatic arsenic levels in exposed mice negatively correlated with overall weight gain, individual adipose depot masses, and hepatic triglyceride accumulation. No effects were observed in mice on a normal diet. For mice on a high-fat diet, arsenic exposure reduced fasting insulin levels, homeostatic model assessment of insulin resistance and ß-cell function, and systemic insulin resistance. Arsenic exposure did not alter energy expenditure or activity. CONCLUSIONS: Collectively, these data indicate that arsenic is antiobesogenic and that concentration at the source poorly predicts arsenic accumulation and phenotypic outcomes. In future studies, investigators should consider internal accumulation of arsenic rather than source concentration when assessing the outcomes of arsenic exposure.


Assuntos
Adiposidade/efeitos dos fármacos , Arsênico/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Obesidade/tratamento farmacológico , Animais , Arsênico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
9.
PLoS One ; 15(2): e0228400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027667

RESUMO

Obesity is a multifactorial disease caused by complex interactions between genes and dietary factors. Salt-rich diet is related to the development and progression of several chronic diseases including obesity. However, the molecular basis of how salt sensitivity genes (SSG) contribute to adiposity in obesity patients remains unexplored. In this study, we used the microarray expression data of visceral adipose tissue samples and constructed a complex protein-interaction network of salt sensitivity genes and their co-expressed genes to trace the molecular pathways connected to obesity. The Salt Sensitivity Protein Interaction Network (SSPIN) of 2691 differentially expressed genes and their 15474 interactions has shown that adipose tissues are enriched with the expression of 23 SSGs, 16 hubs and 84 bottlenecks (p = 2.52 x 10-16) involved in diverse molecular pathways connected to adiposity. Fifteen of these 23 SSGs along with 8 other SSGs showed a co-expression with enriched obesity-related genes (r ≥ 0.8). These SSGs and their co-expression partners are involved in diverse metabolic pathways including adipogenesis, adipocytokine signaling pathway, renin-angiotensin system, etc. This study concludes that SSGs could act as molecular signatures for tracing the basis of adipogenesis among obese patients. Integrated network centered methods may accelerate the identification of new molecular targets from the complex obesity genomics data.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Obesidade Pediátrica/genética , Estresse Salino/genética , Cloreto de Sódio na Dieta/farmacologia , Adiposidade/efeitos dos fármacos , Adiposidade/genética , Adolescente , Estudos de Casos e Controles , Epistasia Genética/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Análise em Microsséries/métodos , Obesidade Pediátrica/metabolismo , Obesidade Pediátrica/patologia , Estresse Salino/efeitos dos fármacos , Integração de Sistemas , Adulto Jovem
10.
Mol Med Rep ; 21(3): 1059-1070, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016448

RESUMO

Obesity has been increasing globally for over three decades. According to previous studies, dietary obesity is usually associated with endoplasmic reticulum stress (ERS) and STAT3 signaling, which result in interference with the homeostatic control of energy and lipid metabolism. Ginsenosides (GS) administered to mice will modulate adiposity and food intake; however, the mechanism of food inhibition is unknown. The aim of the present study was to investigate whether GS may inhibit ERS and regulate STAT3 phosphorylation in GT1­7 cells (a mouse hypothalamus gonadotropin­releasing hormone neuron cell line) and the hypothalamus in order to reduce the body weight and ameliorate hepatic steatosis in high fat diet (HFD)­induced obese mice. In the present study, GS inhibited the appetite, reduced the body weight, visceral fat, body fat content and blood glucose, and ameliorated the glucose tolerance of the obese mice compared with HFD mice. In addition, the levels of aspartate aminotransferase and alanine aminotransferase, triglyceride (TG), leptin and insulin in the serum were reduced compared with HFD mice. There was less TG in the liver, but more in the feces compared with HFD mice. Using hematoxylin and eosin staining of HepG2 cells and liver tissues, GS were demonstrated to improve the non­alcoholic fatty liver of the HFD­induced obese mice and reduce the diameter of the fat cells compared with HFD mice. GS also increased oxygen consumption and carbon dioxide emissions in the metabolic cage data compared with HFD mice. In the GT1­7 cells, GS alleviated the ERS induced by tunicamycin and enhanced the activation of the STAT3 phosphorylation pathway. Furthermore the ERS of the liver was relieved to achieve the aforementioned pharmacological effects. GS were used in the homeostatic control of the energy and lipid metabolism of a diet­induced obesity model. In conclusion, present studies suggest that GS exert these effects by increasing STAT3 phosphorylation expression and reducing the ERS. Thus, GS reduce body weight and ameliorate hepatic steatosis in HFD­induced obese mice.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Ginsenosídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Insulina/metabolismo , Leptina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos
11.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G428-G438, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928222

RESUMO

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Superóxido Dismutase-1/administração & dosagem , Adiposidade/efeitos dos fármacos , Animais , Catalase/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Fígado Gorduroso Alcoólico/enzimologia , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Regulação da Expressão Gênica , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/patologia , Lipólise/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Nanomedicina , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Perilipina-1/genética , Perilipina-1/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/química
12.
J Cardiovasc Comput Tomogr ; 14(4): 343-348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31983575

RESUMO

BACKGROUND AND AIMS: The association between inflammation and atherosclerosis has been well described in the literature. There is now mounting evidence in support of adipose tissue as a reservoir for inflammatory markers. Epicardial adipose tissue (EAT) has been shown to associate with coronary atherosclerosis and found to be a predictor of future adverse cardiovascular events. This study, VIA-EAT, assesses the change in epicardial fat volume (EFV) after treatment with an investigational anti-inflammatory agent (VIA-2291) in a cohort of post-acute coronary syndrome (ACS) patients. METHODS: This study is derived from a post-hoc analysis of a previously conducted randomized clinical trial (NCT00358826). Patients were recruited for a prospective, double-blind, multi-center randomized trial of a 5-lipooxygenase inhibitor or placebo in a 3:1 randomization, including doses of placebo, and 25 mg, 50 mg and 100 mg of active treatment. Cardiac computed tomography was performed at baseline and at 24 weeks after treatment with VIA-2291. EAT and pericardial adipose tissue (PAT) were measured using previously published methodology. A Pearson correlation test was used to determine the relationship between change in epicardial fat and change in plaque composition. RESULTS: We analyzed 54 pre- and post-treatment scans. There were no major differences between traditional cardiovascular risk factors among the 4 randomized study arms. There was a significant decrease in EAT and PAT in patients in the treatment arms vs. placebo, -3.0 ± 8.2mm3 and -3.9 ± 10.9mm3 vs. 1.7 ± 7.5mm3 and 1.4 ± 10.7mm3 (p = 0.001), respectively. The changes in EAT and PAT were more pronounced in patients taking 100 mg of the drug vs. placebo: 4.2 ± 9.6mm3, -7.6 ± 8.5mm3, p = 0.0001, respectively. In a subgroup analysis, reduction in epicardial fat volume correlated with reduction in total atherosclerotic plaque volume across all VIA treatment groups, r = 0.52 (p = 0.004). CONCLUSIONS: After adjustment for traditional cardiovascular risk factors including age, gender, body mass index, dyslipidemia and smoking, VIA-2291 decreases EAT and PAT in individuals with recent ACS. Treatment with the drug also appears to alter plaque volume and composition.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Hidroxiureia/análogos & derivados , Inibidores de Lipoxigenase/uso terapêutico , Pericárdio/efeitos dos fármacos , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/fisiopatologia , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/fisiopatologia , Anti-Inflamatórios/efeitos adversos , Canadá , Angiografia por Tomografia Computadorizada , Método Duplo-Cego , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Inibidores de Lipoxigenase/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pericárdio/diagnóstico por imagem , Pericárdio/fisiopatologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
13.
Sci Transl Med ; 12(528)2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996464

RESUMO

Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERß, with the contribution of the G protein-coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1-treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptores Acoplados a Proteínas-G/agonistas , Tecido Adiposo/patologia , Adiposidade/efeitos dos fármacos , Animais , Respiração Celular , Modelos Animais de Doenças , Metabolismo Energético , Estrogênios/deficiência , Feminino , Genes Mitocondriais , Glucose/metabolismo , Homeostase , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Obesidade/complicações , Ovariectomia , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Resultado do Tratamento , Regulação para Cima , Ganho de Peso
14.
Food Funct ; 10(12): 7667-7677, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31793969

RESUMO

Adipocyte-macrophage interaction in obesity can cause adipose tissue inflammation and contribute to insulin resistance. Here, we investigated the effect of SlimTrym®-a formulated product containing citrus polymethoxyflavones (PMFs), green tea extract, and lychee polyphenols-on 3T3-L1 adipocyte differentiation and obesity-induced inflammation. SlimTrym® inhibited mitotic clonal expansion (MCE) of 3T3-L1 adipocytes by inducing G1 cell cycle arrest via upregulation of p21 and p53. SlimTrym® attenuated adipogenic differentiation by downregulating adipogenic factors, such as CCAAT-enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), and upregulating AMP-activated protein kinase (AMPK). Pretreatment with compound C significantly reduced SlimTrym®-mediated suppression of lipid accumulation. SlimTrym® reduced the expression of pro-inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1ß and IL-6, in co-cultured 3T3-L1 adipocytes and RAW264.7 macrophages. C57BL/6 mice administered with SlimTrym® for 16 weeks showed markedly reduced high-fat diet (HFD)-induced infiltration of monocytes/macrophages in adipose tissue; however, the level of M2 macrophage markers (CD163 and IL-10) was increased. Taken together, these findings indicate that SlimTrym® exerts both anti-adipogenic and anti-inflammatory effects, and can potentially treat obesity and adipose tissue inflammation.


Assuntos
Camellia sinensis/química , Citrus/química , Flavonas/administração & dosagem , Litchi/química , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/imunologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/imunologia , Frutas/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , Obesidade/fisiopatologia , PPAR gama/genética , PPAR gama/imunologia
15.
PLoS One ; 14(12): e0225736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31830056

RESUMO

The objective of this study was to evaluate the biological effects of roasted Cashew nuts consumption on biochemical and murinometric parameters in dyslipidemic rats receiving lipid supplementation. Young male rats were randomly assigned to three experimental groups (n = 10). The Control group (CONT) was treated with water, the Dyslipidemic group (DL) received a high fat content emulsion throughout the experiment, and the Dyslipidemic Cashew Nuts group (DLCN) received the same high fat content emulsion throughout the experiment, yet was treated with Cashew nuts. Body parameters, biochemical, hepatic and fecal fatty acid profiles were all evaluated. The levels of total cholesterol and triglycerides were higher in the DL and DLCN groups as compared to the control group. DLCN and CONT presented no difference in HDL levels. DLCN presented higher glycemia levels than the other groups. There was reduction of body fat in DLCN as compared to other groups, but with higher accumulations of liver fat. DLCN presented a reduction in saturated hepatic fatty acids of 20.8%, and an increase of 177% in relation to CONT; there was also a 21% in increase DL for ω9 fatty acids in comparison to CONT. As for fecal fatty acids, there was a lower concentration of polysaturates in DLCN as compared to the other groups. The data showed that the consumption of Cashew nuts by the dyslipidemic animals treated with a hyperlipidic diet induced greater accumulations of liver fat and worsened glycemic levels, despite having reduced visceral fats and increased fecal fat excretion.


Assuntos
Anacardium/química , Glicemia/metabolismo , Dislipidemias/sangue , Gordura Intra-Abdominal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Área Sob a Curva , Peso Corporal , Ingestão de Energia , Ácidos Graxos/metabolismo , Fezes/química , Comportamento Alimentar , Teste de Tolerância a Glucose , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Fenóis/análise , Ratos Wistar
16.
J Renin Angiotensin Aldosterone Syst ; 20(4): 1470320319895933, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856649

RESUMO

OBJECTIVE: Increased circulating level of plasminogen activator inhibitor-1 (PAI-1) is associated with menopausal oestrogen deficiency. We therefore hypothesised that the combined oral contraceptive (COC) with spironolactone (SPL) improves insulin resistance (IR) in ovariectomised (OVX) rats by reducing circulating PAI-1. METHODS: Twelve-week-old female Wistar rats were divided into sham-operated (SHM), OVX, OVX+SPL (0.25 mg/kg), COC (1.0 µg ethinylestradiol and 5.0 µg levonorgestrel) and OVX+COC+SPL rats treated with COC and SPL daily for eight weeks. IR was assessed by homeostatic model assessment of IR (HOMA-IR). RESULTS: Data showed that OVX rats had a higher HOMA-IR value that is associated with increased visceral adiposity, triglycerides (TG), total cholesterol/high-density lipoprotein cholesterol (HDL-C), TG/HDL-C, plasma insulin, GSK-3, corticosterone and decreased 17ß-oestradiol. However, these effects were attenuated in OVX+COC, OVX+SPL and OVX+COC+SPL rats compared to OVX rats. OVX rats had lower PAI-1 than SHM rats, whereas the beneficial effect on IR and other parameters by COC or SPL was accompanied with increased PAI-1. Improvement of IR and other parameters with combined COC and SPL in OVX rats was accompanied with reduced PAI-1. CONCLUSION: Taken together, COC or SPL improves IR independent of PAI-1, whereas a combination of COC and SPL in OVX rats ameliorates IR in a PAI-1-dependent manner.


Assuntos
Etinilestradiol/farmacologia , Resistência à Insulina , Levanogestrel/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Espironolactona/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Corticosterona/sangue , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/prevenção & controle , Estradiol/sangue , Feminino , Quinase 3 da Glicogênio Sintase/sangue , Ovariectomia , Ratos Wistar
17.
Nutrients ; 11(12)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842363

RESUMO

Since arginase has been shown to compete with nitric oxide (NO) synthase, emerging evidence has reported that arginase inhibition improves obesity by increasing NO production. Semen cuscutae (SC), which is a well-known Chinese medicine, has multiple biological functions such as anti-oxidant function and immune regulation. In this study, we investigated whether the SC as a natural arginase inhibitor influences hepatic lipid abnormalities and whole-body adiposity in high-fat diet (HFD)-induced obese mice. The lipid accumulation was significantly reduced by SC treatment in oleic acid-induced hepatic steatosis in vitro. Additionally, SC supplementation substantially lowered HFD-induced increases in arginase activity and weights of liver and visceral fat tissue, while increasing hepatic NO. Furthermore, elevated mRNA expressions of sterol regulatory element-binding transcription factor 1 (SREBP-1c), fatty-acid synthase (FAS), peroxisome proliferator-activated receptor-gamma (PPAR-γ)1, and PPAR-γ2 in HFD-fed mice were significantly attenuated by SC supplementation. Taken together, SC, as a novel natural arginase inhibitor, showed anti-obesity properties by modulating hepatic arginase and NO production and metabolic pathways related to hepatic triglyceride (TG) metabolism.


Assuntos
Adiposidade/efeitos dos fármacos , Cuscuta , Suplementos Nutricionais , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Animais , Arginase/antagonistas & inibidores , Técnicas de Cultura de Células , Dieta Hiperlipídica , Ácido Graxo Sintase Tipo I/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Óxido Nítrico/biossíntese , Obesidade/terapia , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
18.
Biomed Res Int ; 2019: 6508094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737672

RESUMO

In cartilage tissue engineering, the target cells' functional performance depends on the biomaterials. However, it is difficult to develop an appropriate scaffold to differentiate mouse adipose-derived stem cells (mADSCs) into chondrocyte despite an increasing number of studies on biological scaffold materials. The purpose of this study was to create a novel scaffold for mADSC culture and chondrogenic differentiation with a new series of microgels based on polyethyleneimine (PEI), polyethylene glycol (PEG), and poly (L-lactic acid) (PLLA) and able to resist swelling with changes in temperature, pH, and polymer concentration. The biocompatibility and ability of the nonswelling microgels were then examined and served as scaffolds for cell culture and for cartilage differentiation. The results show that the new microgels are a novel biomaterial that both retains its nonswelling properties under various conditions and facilitates important scaffold functions such as cell adhesion, proliferation, and cartilage induction.


Assuntos
Adiposidade/efeitos dos fármacos , Cartilagem/efeitos dos fármacos , Microgéis/administração & dosagem , Células-Tronco/efeitos dos fármacos , Animais , Materiais Biocompatíveis/química , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Camundongos , Microgéis/química , Poliésteres/química , Polietilenoglicóis/química , Polietilenoimina/química , Engenharia Tecidual/métodos , Tecidos Suporte/química
19.
Nutrients ; 11(11)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717265

RESUMO

Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood-brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood-brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.


Assuntos
Adiposidade , Encéfalo/metabolismo , Comportamento Alimentar , Leptina/metabolismo , Obesidade/metabolismo , Ganho de Peso , Adiposidade/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Permeabilidade Capilar , Comportamento Alimentar/efeitos dos fármacos , Humanos , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Obesidade/psicologia , Transdução de Sinais , Ganho de Peso/efeitos dos fármacos
20.
Int J Mol Sci ; 20(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31627416

RESUMO

Obesity is associated with disrupted energy homeostasis and intestinal dysbiosis. Caulis Spatholobi, traditional Chinese medicine for herbal therapy, contains a wide range of bioactive compounds and has a specific pharmacological function. However, its effects on obesity and related metabolic disorder have remained largely unexplored. In this study, we showed that the water extract of Caulis Spatholobi (WECS) has a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, reducing insulin resistance and improving hepatic steatosis in diet-introduced obesity (DIO) mice. Besides, the administration of WECS significantly increased the expression levels of genes involved in the brown adipose tissue (BAT) activation and thermogenesis in DIO mice. Also, the activation of BAT treated with WECS was also confirmed in BAT primary cells. Mechanisms, the improvement of glucose homeostasis and insulin resistance may be related to the upregulated MAPK and AMPK pathways in white adipose tissue (WAT) and BAT. Notably, WECS also improved the obesity-induced gut microbiota dysbiosis, which induced an increase of anti-obesity and anti-diabetes related bacteria genus. In conclusion, Caulis Spatholobi can ameliorate obesity through activating brown adipose tissue and modulating the composition of gut microbiota. Our findings provide a novel perspective on Chinese medicine applications and provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.


Assuntos
Adiposidade/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Obesidade/tratamento farmacológico , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Metabolismo Energético , Microbioma Gastrointestinal/efeitos dos fármacos , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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