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1.
Chemosphere ; 241: 125092, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683443

RESUMO

Environmental pollution is increasingly considered an important factor involved in the obesity incidence. Endocrine disruptors (EDs) are important actors in the concept of DOHaD (Developmental Origins of Health and Disease), where epigenetic mechanisms play crucial roles. Bisphenol A (BPA), a monomer used in the manufacture of plastics and resins is one of the most studied obesogenic endocrine disruptor. Bisphenol S (BPS), a BPA substitute, has the same obesogenic properties, acting at low doses with a sex-specific effect following perinatal exposure. Since the liver is a major organ in regulating body lipid homeostasis, we investigated gene expression and DNA methylation under low-dose BPS exposure. The BPS obesogenic effect was associated with an increase of hepatic triglyceride content. These physiological disturbances were accompanied by genome-wide changes in gene expression (1366 genes significantly modified more than 1.5-fold). Gene ontology analysis revealed alteration of gene cascades involved in protein translation and complement regulation. It was associated with hepatic DNA hypomethylation in autosomes and hypermethylation in sex chromosomes. Although no systematic correlation has been found between gene repression and hypermethylation, several genes related to liver metabolism were either hypermethylated (Acsl4, Gpr40, Cel, Pparδ, Abca6, Ces3a, Sgms2) or hypomethylated (Soga1, Gpihbp1, Nr1d2, Mlxipl, Rps6kb2, Esrrb, Thra, Cidec). In specific cases (Hapln4, ApoA4, Cidec, genes involved in lipid metabolism and liver fibrosis) mRNA upregulation was associated with hypomethylation. In conclusion, we show for the first time wide disruptive physiological effects of low-dose of BPS, which raises the question of its harmlessness as an industrial substitute for BPA.


Assuntos
Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/induzido quimicamente , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Disruptores Endócrinos/toxicidade , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Fenóis/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/genética , Sulfonas/administração & dosagem , Testes de Toxicidade
2.
J Ethnopharmacol ; 246: 112225, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509781

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Our previous research found that Sangguayin (SGY) deccoction made by four dietary and medicinal plant components (Leaf of Morus alba L., Root of Pueraria lobata (Willd.) Ohwi., Root of Dioscorea opposita Thunb. and Fruit of Momordica charantia L.) showed significant anti-diabetic effects on db/db mice and high fat diet induced obese mice. Nevertheless, it remained unclear what the role of gut microbiota in the hypoglycaemia effects of SGY. AIMS OF THE STUDY: This study aimed to examine the beneficial effects of Sangguayin Deccoction against metabolic syndrome and and its regulating role in gut microbiota and hepatic metabolome. MATERIALS AND METHODS: C57BL/6J mice were divided to a normal chow diet (NCD), high-fat diet (HFD), and high-fat diet with Sangguayin Decoction (HFD-SGY, oral dose of 250 mg/kg/d) for 16 weeks. Next generation sequencing was applied for analyzing the gut microbial community of colonic contents. Further, untargeted metabolomic analysis based on LC-MS was used for determining the changes of hepatic metabolites. Hepatic genes expression were measured by quantitative PCR. RESULTS: SGY supplement decreased blood glucose level and glucose intolerance. Illumina MiSeq sequencing revealed that SGY increased Verrucomicrobia phylum, resulting in a bloom of Akkermansia, and eventually upregulated the contents of Lachoclostridium and Roseburia. Additionally, dietary SGY decreased bacteria including Faecalibaculum, and Blautia. Moreover, the hepatic lipid metabolism was notably altered by SGY treatment. The oxidation of glutamione metabolism idecreasees, production of poly-unsaturated fatty acid (PUFA) got significant increase in liver tissue. The reversion of PUFA metabolism by SGY may act through PPARα mediated Fads1 and Fads2 gene expression. The altered metabolites in liver showed intimate correlatship with modified genera. CONCLUSION: Data indicated that SGY reshaped gut microbial structure and improved PUFA metabolism. These functions of SGY may alter hepatic lipid metabolism, conferring preventative effects against high-fat diet induced metabolic syndrome.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fitoterapia , Extratos Vegetais/química
3.
Environ Int ; 133(Pt B): 105191, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31639604

RESUMO

BACKGROUND: Perchlorate, nitrate, and thiocyanate are well-known thyroid disrupters and may contribute to changes in body weight. However, the associations between environmental exposure to these chemicals and obesity-related outcomes remain unclear. OBJECTIVES: We aim to examine the urinary levels of perchlorate, nitrate, and thiocyanate and their associations with obesity and abdominal obesity in the U.S. METHODS: Here, we investigated the data of 16,265 adults aged 20-85 years from the National Health and Nutritional Examination Survey (NHANES) in 2001-2014. Urinary levels of perchlorate, nitrate, and thiocyanate were measured by ion chromatography combined with electrospray tandem mass spectrometry. Obesity and abdominal obesity were defined by the body mass index and waist circumference, respectively. Logistic regression models were used to estimate the associations. RESULTS: Overall, 5794 (35.6%) cases of obesity and 9090 cases (55.9%) of abdominal obesity were observed among the participants. In multivariable-adjusted logistic regression models, urinary nitrate was inversely associated with obesity (p = 0.0022 for trend), while urinary thiocyanate was positively related to obesity (p < 0.001 for trend). Compared with the lowest quartile, the odds ratios with 95% confidence intervals (CIs) across increasing quartiles were 0.95 (95% CI, 0.83-1.08), 0.88 (0.75-1.03), and 0.74 (0.60-0.90) for urinary nitrate and 1.31 (1.16-1.48), 1.53 (1.36-1.73), and 1.73 (1.47-2.03) for urinary thiocyanate. Urinary perchlorate was not correlated with obesity. Similar associations were also found between exposure to these chemicals and abdominal obesity. CONCLUSIONS: A higher exposure to urinary nitrate was associated with a lower risk of obesity, while a positive association was observed for urinary thiocyanate. These findings emphasize the need to longitudinally evaluate environmental exposure to perchlorate, nitrate, and thiocyanate with respect to their effect on obesity in humans.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Nitratos/toxicidade , Obesidade/induzido quimicamente , Percloratos/toxicidade , Tiocianatos/toxicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Peso Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Circunferência da Cintura , Adulto Jovem
4.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500194

RESUMO

Bisphenol A (BPA) is the most well-known compound from the bisphenol family. As BPA has recently come under pressure, it is being replaced by compounds very similar in structure, but data on the occurrence of these BPA analogues in food and human matrices are limited. The main objective of this work was to investigate human exposure to BPA and analogues and the associated health effects. We performed a literature review of the available research made in humans, in in vivo and in vitro tests. The findings support the idea that exposure to BPA analogues may have an impact on human health, especially in terms of obesity and other adverse health effects in children.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Compostos Benzidrílicos/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Contaminação de Alimentos , Obesidade/induzido quimicamente , Fenóis/efeitos adversos , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Compostos Benzidrílicos/análise , Disruptores Endócrinos/análise , Humanos , Obesidade/metabolismo , Obesidade/fisiopatologia , Fenóis/análise , Medição de Risco , Fatores de Risco
5.
Nutrients ; 11(9)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438590

RESUMO

Male C57BL/6J mice were used to determine the possible therapeutic effects of our previously described tart cherry extract in a chronic obesity mouse model on metabolic parameters, glucose tolerance, inflammatory mediators, and antioxidant capacity. The control group received standard mouse chow, and the high fat control group was switched to a high fat diet and tap water supplemented with 5% sucrose. The high fat + anthocyanin group received the high fat and sucrose diet, but received the anthocyanin-rich tart cherry extract dissolved in their drinking water. After six weeks, an oral glucose tolerance test was performed, and the water-soluble antioxidant capacity (ACW), superoxide dismutase (SOD) activity, and the plasma levels of insulin, C-peptide, leptin, IL-6, MCP-1, adiponectin and resistin were measured. The high fat diet increased body weight, reduced glucose tolerance, and caused an elevation in leptin, IL-6, MCP-1, and resistin levels. Furthermore, antioxidant capacity was decreased with a significant elevation of SOD activity. Anthocyanin treatment failed to reverse the effects of the high fat diet on body weight and glucose tolerance, but significantly reduced the leptin and IL-6 levels. The tart cherry extract also made a significant enhancement in antioxidant capacity and SOD activity. Our results show that chronic anthocyanin intake has a potential to enhance redox status and alleviate inflammation associated with obesity.


Assuntos
Antocianinas/química , Dieta Hiperlipídica/efeitos adversos , Inflamação/metabolismo , Obesidade/induzido quimicamente , Extratos Vegetais/farmacologia , Prunus avium/química , Adipocinas , Adiponectina , Animais , Antioxidantes , Diabetes Mellitus Tipo 2/induzido quimicamente , Teste de Tolerância a Glucose , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Resistina , Superóxido Dismutase
6.
J Neuroinflammation ; 16(1): 169, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426806

RESUMO

BACKGROUND: Environmental factors are critical in the development of age-related cognitive decline and dementia. A western diet (WD) can cause nutrient deficiency and inflammation that could impact cognition directly. It is increasingly recognized that innate immune responses by brain myeloid cells, such as resident microglia, and infiltrating peripheral monocytes/macrophages may represent an essential link between a WD, cognitive decline, and dementia. Our previous data demonstrated that chronic consumption of a WD induced inflammation through brain myeloid cells in aging mice and a mouse model of Alzheimer's disease (AD). However, the subtypes of myeloid cells that contribute to the WD-induced inflammation remain unclear. METHODS: C57BL/6J (B6), myeloid cell reporter mice (B6.Ccr2RFP/+Cx3cr1GFP/+), and Ccr2-deficient mice (B6.Ccr2RFP/RFP) were fed a WD or a control chow diet (CD) from 2 to 6 or 12 months of age. CD11b+CD45lo and CD11b+CD45hi cells from WD- and CD-fed B6 or Ccr2-deficient mice were characterized using flow cytometry, RNA-sequencing, and immunofluorescence. RESULTS: Ccr2::RFP expressing myeloid cells were significantly increased in brains of WD- compared to CD-fed mice, but were not elevated in Ccr2-deficient WD-fed mice. The percent of CD11b+CD45hi cells was significantly increased in WD- compared to CD-fed mice. Comparison of RNA-sequencing data with immune cell data in ImmGen supports that CD11b+CD45hi cells from WD-fed mice are enriched for peripheral monocytes and neutrophils. Ingenuity pathway analysis predicted these cells elicit proinflammatory responses that may be damaging to the brain. Using stringent criteria for gene expression levels between CD11b+CD45hi and CD11b+CD45lo cells, we identified approximately 70 genes that we predict are uniquely expressed in infiltrating cells, including Itgal, Trem1, and Spp1 (osteopontin, OPN). Finally, we show a significantly greater number of OPN+IBA1- cells in WD- compared to CD-fed mice that we propose are activated neutrophils based on ImmGen data. OPN+IBA1- cells are not significantly increased in Ccr2-deficient WD-fed mice. CONCLUSIONS: These data further support the model that peripheral myeloid cells enter the brain in response to diet-induced obesity. Elucidating their contribution to age-related cognitive decline and age-related neurodegenerative diseases should offer new avenues for therapeutic intervention in Alzheimer's disease and related dementias, where diet/obesity are major risk factors.


Assuntos
Antígeno CD11a/metabolismo , Dieta Ocidental/efeitos adversos , Perfilação da Expressão Gênica/métodos , Obesidade/metabolismo , Osteopontina/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/metabolismo , Obesidade/induzido quimicamente , Obesidade/genética , Osteopontina/genética , Receptor Gatilho 1 Expresso em Células Mieloides/genética
7.
Medicine (Baltimore) ; 98(33): e16811, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415396

RESUMO

Glucocorticoids used to treat acute lymphoblastic leukemia (ALL) are associated with cytotoxicity and obesity. The aim of the study was to investigate the effects of high-proportion medium chain triglyceride (MCT) on body fat distribution and levels of leptin and adiponectin during chemotherapy of children with ALL.New-onset ALL children treated at the Guangzhou Women and Children's Medical Center between March 2016 and March 2017 were enrolled. Children were divided into the MCT and control groups. For the MCT group, high-proportion MCT nutrition preparation was added to the diet, while no MCT was added for the control group. The MCT group was further divided into subgroups A and B based on the amount of supplement. Waist circumference, hip circumference, waist-to-hip ratio, bone marrow concentrations of leptin and adiponectin, and leptin-to-adiponectin ratio were measured before and on days 19 and 46 of chemotherapy. Body weight and body mass index (BMI) were measured on admission and discharge.Waist circumference in the control group increased by day 46 (P = .047), but did not change in the MCT group. The BMI of the children in the control group was higher than those in the MCT group on admission (P = .003), but not different at discharge. No significant differences in hip circumference, leptin levels, adiponectin levels, and body weight were observed between the 2 groups.This preliminary study suggests that short-term supplementation of high-proportion MCT nutrition preparation may help reduce the centripetal distribution of adipose induced by the application of glucocorticoids in children with ALL. This will have to be confirmed in future studies.


Assuntos
Adiponectina/sangue , Adiposidade/efeitos dos fármacos , Suplementos Nutricionais , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Triglicerídeos/farmacologia , Distribuição da Gordura Corporal , Índice de Massa Corporal , Peso Corporal , Criança , Pré-Escolar , Feminino , Glucocorticoides/efeitos adversos , Humanos , Leptina/sangue , Masculino , Obesidade/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Circunferência da Cintura
8.
Endocrinology ; 160(10): 2485-2494, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31386147

RESUMO

27-Hydroxycholesterol (27HC) is an abundant cholesterol metabolite and has detrimental effects on the cardiovascular system, whereas its impact on adiposity is not well known. In this study, we found that elevations in 27HC cause increased body weight gain in mice fed a high-fat/high-cholesterol diet in an estrogen receptor α-dependent manner. Regardless of diet type, body fat mass was increased by 27HC without changes in food intake or fat absorption. 27HC did not alter energy expenditure in mice fed a normal chow diet and increased visceral white adipose mass by inducing hyperplasia but not hypertrophy. Although 27HC did not augment adipocyte terminal differentiation, it increased the adipose cell population that differentiates to mature adipocytes. RNA sequencing analysis revealed that 27HC treatment of mice fed a normal chow diet induces inflammatory gene sets similar to those seen after high-fat/high-cholesterol diet feeding, whereas there was no overlap in inflammatory gene expression among any other 27HC administration/diet change combination. Histological analysis showed that 27HC treatment increased the number of total and M1-type macrophages in white adipose tissues. Thus, 27HC promotes adiposity by directly affecting white adipose tissues and by increasing adipose inflammatory responses. Lowering serum 27HC levels may lead to an approach targeting cholesterol to prevent diet-induced obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Hidroxicolesteróis , Obesidade/induzido quimicamente , Animais , Família 7 do Citocromo P450/genética , Família 7 do Citocromo P450/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
9.
Part Fibre Toxicol ; 16(1): 27, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266526

RESUMO

BACKGROUND: Obesity is an uncontrolled global epidemic and one of the leading global public health challenges. Maternal exposure to ambient fine particulate matter (PM2.5) may adversely program offspring's adiposity, suggesting a specialized role of PM2.5 pollution in the global obesity epidemic. However, the vulnerable window for this adverse programming and how it is cross-generationally transmitted have not been determined. Therefore, in the present study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during different periods, and the development and adulthood adiposity of their four-generational offspring were assessed. RESULTS: Our data show that the pre-conceptional but not gestational exposure to CAP was sufficient to cause male but not female offspring's low birth weight, accelerated postnatal weight gain, and increased adulthood adiposity. These adverse developmental traits were transmitted into the F2 offspring born by the female but not male F1 offspring of CAP-exposed dams. In contrast, no adverse development was noted in the F3 offspring. CONCLUSIONS: The present study identified a pre-conceptional window for the adverse programming of adiposity by maternal exposure to PM2.5, and showed that it was maternally transmitted into the third generation. These data not only call special attention to the protection of women from exposure to PM2.5, but also may facilitate the development of intervention to prevent this adverse programming.


Assuntos
Adiposidade/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Exposição Materna/efeitos adversos , Obesidade/induzido quimicamente , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adiposidade/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Predisposição Genética para Doença , Recém-Nascido de Baixo Peso , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Tamanho da Partícula , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores Sexuais , Ganho de Peso
10.
Ecotoxicol Environ Saf ; 182: 109406, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31288122

RESUMO

Obesity, a risk factor for the development of type-2 diabetes, hypertension, cardiovascular disease, hepatic steatosis and some cancers, has been ranked in the top 10 health risk in the world by the World Health Organization. Despite the growing body of literature evidencing an association between the obesity epidemic and specific chemical exposure across a wide range of animal taxa, very few studies assessed the effects of chemical mixtures and environmental samples on lipid homeostasis. Additionally, the mode of action of several chemicals reported to alter lipid homeostasis is still poorly understood. Aiming to fill some of these gaps, we combined an in vivo assay with the model species zebrafish (Danio rerio) to screen lipid accumulation and evaluate expression changes of key genes involved in lipid homeostasis, alongside with an in vitro transactivation assay using human and zebrafish nuclear receptors, retinoid X receptor α and peroxisome proliferator-activated receptor γ. Zebrafish larvae were exposed from 4 th day post-fertilization until the end of the experiment (day 18), to six different treatments: experimental control, solvent control, tributyltin at 100 ng/L Sn and 200 ng/L Sn (positive control), and wastewater treatment plant influent at 1.25% and 2.5%. Exposure to tributyltin and to 2.5% influent led to a significant accumulation of lipids, with white adipose tissue deposits concentrating in the perivisceral area. The highest in vitro tested influent concentration (10%) was able to significantly transactivate the human heterodimer PPARγ/RXRα, thus suggesting the presence in the influent of HsPPARγ/RXRα agonists. Our results demonstrate, for the first time, the ability of complex environmental samples from a municipal waste water treatment plant influent to induce lipid accumulation in zebrafish larvae.


Assuntos
Larva/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/induzido quimicamente , Compostos de Trialquitina/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Relação Dose-Resposta a Droga , Homeostase , Humanos , Larva/metabolismo , Obesidade/metabolismo , Águas Residuárias/química , Purificação da Água
11.
Int J Mol Sci ; 20(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319467

RESUMO

Meibomian gland dysfunction (MGD) is the leading cause of dry eye disease and loss of ocular surface homeostasis. Increasingly, several observational clinical studies suggest that dyslipidemia (elevated blood cholesterol, triglyceride or lipoprotein levels) can initiate the development of MGD. However, conclusive evidence is lacking, and an experimental approach using a suitable model is necessary to interrogate the relationship between dyslipidemia and MGD. This systematic review discusses current knowledge on the associations between dyslipidemia and MGD. We briefly introduce a diet-induced obesity model where mice develop dyslipidemia, which can serve as a potential tool for investigating the effects of dyslipidemia on the meibomian gland. Finally, the utility of lipidomics to examine the link between dyslipidemia and MGD is considered.


Assuntos
Dieta/efeitos adversos , Dislipidemias , Obesidade , Animais , Modelos Animais de Doenças , Dislipidemias/induzido quimicamente , Dislipidemias/metabolismo , Dislipidemias/patologia , Humanos , /metabolismo , Camundongos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/patologia
12.
Biol Sex Differ ; 10(1): 36, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315689

RESUMO

BACKGROUND: Angiotensin-(1-7) is a beneficial hormone of the renin-angiotensin system known to play a positive role in regulation of blood pressure and glucose homeostasis. Previous studies have shown that in high-fat diet (HFD)-induced obese male mice, circulating angiotensin-(1-7) levels are reduced and chronic restoration of this hormone reverses diet-induced insulin resistance; however, this has yet to be examined in female mice. We hypothesized angiotensin-(1-7) would improve insulin sensitivity and glucose tolerance in obese female mice, to a similar extent as previously observed in male mice. METHODS: Five-week-old male and female C57BL/6J mice (8-12/group) were placed on control diet or HFD (16% or 59% kcal from fat, respectively) for 11 weeks. After 8 weeks of diet, mice were implanted with an osmotic pump for 3-week subcutaneous delivery of angiotensin-(1-7) (400 ng/kg/min) or saline vehicle. During the last week of treatment, body mass and composition were measured and intraperitoneal insulin and glucose tolerance tests were performed to assess insulin sensitivity and glucose tolerance, respectively. Mice were euthanized at the end of the study for blood and tissue collection. RESULTS: HFD increased body mass and adiposity in both sexes. Chronic angiotensin-(1-7) infusion significantly decreased body mass and adiposity and increased lean mass in obese mice of both sexes. While both sexes tended to develop mild hyperglycemia in response to HFD, female mice developed less marked hyperinsulinemia. There was no effect of angiotensin-(1-7) on fasting glucose or insulin levels among diet and sex groups. Male and female mice similarly developed insulin resistance and glucose intolerance in response to HFD feeding. Angiotensin-(1-7) improved insulin sensitivity in both sexes but corrected glucose intolerance only in obese female mice. There were no effects of sex or angiotensin-(1-7) treatment on any of the study outcomes in control diet-fed mice. CONCLUSIONS: This study provides new evidence for sex differences in the impact of chronic angiotensin-(1-7) in obese mice, with females having greater changes in glucose tolerance with treatment. These findings improve understanding of sex differences in renin-angiotensin mechanisms in obesity and illustrate the potential for targeting angiotensin-(1-7) for treatment of this condition.


Assuntos
Angiotensina I/farmacologia , Obesidade/induzido quimicamente , Fragmentos de Peptídeos/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Feminino , Intolerância à Glucose , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Caracteres Sexuais
13.
Nutrients ; 11(7)2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31330894

RESUMO

Paramylon (PM), a type of ß-glucan, functions like dietary fiber, which has been suggested to exert a protective effect against obesity. We evaluated the potential beneficial effects of PM powder on obesity in mice. Male C57BL/6J mice were fed a high-fat diet supplemented with either 2.5 or 5% PM powder, extracted from Euglena gracilis, for 74 days. Growth parameters, abdominal fat content, serum biochemical markers, hepatic lipid accumulation and hepatic mRNA expression were measured. Dietary supplementation with PM resulted in decreased food efficiency ratios and abdominal fat accumulation. Dose-dependent decreases were observed in postprandial glucose levels, serum low-density lipoprotein (LDL)-cholesterol, and serum secretary immunoglobulin A (sIgA) concentrations. PM supplementation increased peroxisome proliferator-activated receptor α (PPARα) mRNA expression in the liver which is suggested to induce ß-oxidation through activation of acyl-coenzyme A oxidase (ACOX), carnitine palmitoyltransferase (CPT) and fatty acid transport protein 2 (FATP2) mRNA expression. Changes in fatty acid metabolism may improve lipid and glucose metabolism. In conclusion, a preventive effect against obesity was observed in mice given a PM-enriched diet. The mechanism is suggested to involve a reduction in both serum LDL-cholesterol levels and the accumulation of abdominal fat, in addition to an improvement in postprandial glucose concentration.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Euglena gracilis/química , Glucanos/farmacologia , Obesidade/induzido quimicamente , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/efeitos dos fármacos , Animais , Ceco/anatomia & histologia , Ceco/efeitos dos fármacos , Ácidos Graxos Voláteis/química , Fezes/química , Conteúdo Gastrointestinal , Regulação da Expressão Gênica/efeitos dos fármacos , Glucanos/administração & dosagem , Glucose/metabolismo , Teste de Tolerância a Glucose , Imunoglobulina A Secretora , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
14.
N Engl J Med ; 381(9): 816-826, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31339676

RESUMO

BACKGROUND: An efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings. METHODS: We conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of low-dose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points. RESULTS: A total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], -1.6 to 12.7; P<0.001 for noninferiority). Among those with a baseline viral load of at least 100,000 copies per milliliter, a viral load of less than 50 copies per milliliter was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the EFV400 group, with a difference of 4.7 percentage points (95% CI, -4.6 to 14.0). Virologic failure (a viral load of >1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%). CONCLUSIONS: In HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression. (Funded by Unitaid and the French National Agency for AIDS Research; NAMSAL ANRS 12313 ClinicalTrials.gov number, NCT02777229.).


Assuntos
Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Adulto , Benzoxazinas/efeitos adversos , Quimioterapia Combinada , Feminino , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lamivudina/administração & dosagem , Masculino , Obesidade/induzido quimicamente , Gravidez , RNA Viral/sangue , Tenofovir/administração & dosagem , Carga Viral/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
15.
Mol Cell ; 75(4): 823-834.e5, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31302001

RESUMO

Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.


Assuntos
Cisteína Endopeptidases/metabolismo , Mitocôndrias/metabolismo , Mutação , Obesidade/metabolismo , Transdução de Sinais , Sirtuína 3/metabolismo , Sumoilação , Acetilação , Animais , Cisteína Endopeptidases/genética , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Mutantes , Mitocôndrias/genética , Mitocôndrias/patologia , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/patologia , Sirtuína 3/genética
16.
Vopr Pitan ; 88(3): 44-52, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31265774

RESUMO

Changes in plasma levels of the main groups of cytokines and adipokines may correlate with the severity of metabolic disorders in hyperlipidemia and obesity. The aim of the study was to assess the significance of ghrelin, leptin, their ratio (L/Gh), and the cytokine profile as biomarkers at dietary-induced hyperlipidemia. Material and methods. We used 48 female Wistar rats with an initial body weight of 123±1 g, which were divided into 6 groups. Group 1 (control) received a balanced semi-synthetic diet according to AIN93; group 2 - diet with excess fat (30% by weight); group 3 - a diet with the addition of 20% fructose solution instead of drinking water, group 4 - a diet with excess fat and fructose, group 5 - a diet with added cholesterol (0.5%), group 6 - a diet with cholesterol and fructose. On the 64th day of the experiment, the mass of internal organs was determined; the levels of cytokines and adipokines in blood plasma were measured by multiplex immunoassay. Results and discussion. A decrease in the level of leptin was found in group 5 compared with the control and with groups 2, 4 and 6 groups (p<0.05). The lowest level of ghrelin was found in group 2 (p<0.05) against the background of high concentrations of leptin. Significant correlations were found between L/Gh and the total mass of animals (r=0.321; р=0.034), the relative mass of adipose tissue (r=0.439; р=0.003) and with the relative mass of the spleen (r=-0.460; р=0.003). In group 2, at the maximum L/Gh ratio, a significantly higher weight of adipose tissue was found, whereas in groups 3 and 5, at the lowest L/Gh ratio, the relative amount of total fat was the lowest. L/Gh ratio correlated with the level of monocyte chemotactic protein-1 (MCP-1), RANTES, IL-18 and macrophage colony-stimulating factor (M-CSF). The concentrations of IL-17, IL-18, IL-4, IL-5, MIP-3a, IFN-γ, M-CSF and RANTES in the experimental groups were reduced compared with the control, with the most pronounced effect in group 5 together with the lowest L/Gh ratio. Conclusion. The presence of a significant correlation between L/Gh ratio and changes in the weight of rats' body, spleen, adipose tissue, as well as levels of cytokines involved in inflammation regulation, confirms the importance of L/Gh ratio as a biomarker in an in vivo model of dyslipidemia.


Assuntos
Adipocinas/sangue , Tecido Adiposo/metabolismo , Citocinas/sangue , Alimentos Formulados/efeitos adversos , Hiperlipidemias , Obesidade , Animais , Biomarcadores/sangue , Feminino , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Obesidade/sangue , Obesidade/induzido quimicamente , Ratos , Ratos Wistar
17.
Vopr Pitan ; 88(3): 63-68, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31265776

RESUMO

The results of experimental studies indicate that the preventive and therapeutic effects of polyphenols in obesity are accompanied by a significant decrease in the severity of dysbiosis caused by the predominance of fats and simple carbohydrates in the diet, especially fructose, and the restoration of the functional state of the microbiota. The aim of the work was to study the effect of quercetin and resveratrol - polyphenols, widely represented in the daily human diet, on the activity of bacterial glycosidases in rats receiving diets high in fructose or fat and fructose. Material and methods. Using spectrophotometric analysis, the activity of ß-galactosidase (Gal), ß-glucosidase (Glu) and ß-glucuronidase (Gluс) was studied in the content of the cecum of Wistar rats receiving a semi-synthetic diet and a 20% solution of fructose instead of drinking water (hfr diet) or a semi-synthetic diet with a high (30%) fat content and a 20% solution of fructose instead of drinking water (hf/hfr diet). Results and discussion. Feeding rats with the hfr diet for 20 weeks led to the suppression of Gal activity by 35, Glu by 46 and Gluс by 31%. With the inclusion of quercetin in the hfr diet at a dose of 34 mg/kg b.w. enzyme activity was restored to the control values and exceeded the level of activity in rats fed hfr ration without quercetin by 60, 100 and 47%, respectively, for Gal, Glu, and Gluс. Feeding rats with the hf/hfr diet for 10 weeks did not have a significant impact on the activity of bacterial enzymes. The inclusion of resveratrol in the hf/hfr diet at a dose of 10 mg/kg b.w. resulted in a decrease in Glu activity by 58 and Gluс by 28%, and an increase in resveratrol dose to 100 mg/kg b.w. caused further suppression of Gal activity by 30, Glu by 76 and Gluc by 64% comparative to the activity in rats on the hf/hfr diet without resveratrol. Conclusion. The obtained data suggest that quercetin restores reduced by hfr diet activity of glycosyl hydrolases of the cecum microflora of rats, most likely due to an increase in the representation of the types of enzyme activity carriers. The suppressive effect of resveratrol on the activity of glycosyl hydrolases of the cecum microflora of rats fed a hf/hfr diet may be the result of its direct action on enzymes and is not associated with the effect on the composition of the intestinal microbiota.


Assuntos
Proteínas de Bactérias/metabolismo , Ceco , Carboidratos da Dieta/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Glicosídeo Hidrolases/metabolismo , Obesidade , Polifenóis/farmacologia , Animais , Ceco/enzimologia , Ceco/microbiologia , Carboidratos da Dieta/farmacologia , Frutose/efeitos adversos , Frutose/farmacologia , Masculino , Obesidade/induzido quimicamente , Obesidade/enzimologia , Obesidade/microbiologia , Quercetina/farmacologia , Ratos , Ratos Wistar , Resveratrol/farmacologia
18.
Nutrients ; 11(7)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311133

RESUMO

Obesity, caused by a high-fat diet (HFD), leads to insulin resistance, which is a precursor of diabetes and a risk factor for impaired cognitive function, dementia, and brain diseases, such as Alzheimer's disease. Physical exercise has positive effects on obesity and brain functions. We investigated whether the decline in cognitive function caused by a HFD could be improved through exercise by examining insulin signaling pathways and neuroplasticity in the hippocampus. Four-week-old C57BL/6 male mice were fed a HFD or a regular diet for 20 weeks, followed by 12 weeks of treadmill exercise. To ascertain the effects of treadmill exercise on impaired cognitive function caused by obesity, the present study implemented behavioral testing (Morris water maze, step-down). Moreover, insulin-signaling and neuroplasticity were measured in the hippocampus and dentate gyrus. Our results demonstrated that HFD-fed obesity-induced insulin resistance was improved by exercise. In addition, the HFD group showed a decrease in insulin signaling and neuroplasticity in the hippocampus and the dentate gyrus and increased cognitive function impairment, which were reversed by physical exercise. Overall, our findings indicate that physical exercise may act as a non-pharmacologic method that protects against cognitive dysfunction caused by obesity by improving hippocampal insulin signaling and neuroplasticity.


Assuntos
Cognição , Dieta Hiperlipídica/efeitos adversos , Hipocampo/fisiologia , Insulina/metabolismo , Obesidade/induzido quimicamente , Condicionamento Físico Animal , Ração Animal , Animais , Dieta/veterinária , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
19.
PLoS One ; 14(6): e0217287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166980

RESUMO

IMPACT, a highly conserved protein, is an inhibitor of the eIF2α kinase GCN2. In mammals, it is preferentially expressed in neurons. Knock-down of IMPACT expression in neuronal cells increases basal GCN2 activation and eIF2α phosphorylation and decreases translation initiation. In the mouse brain, IMPACT is particularly abundant in the hypothalamus. Here we describe that the lack of IMPACT in mice affects hypothalamic functions. Impact-/- mice (Imp-KO) are viable and have no apparent major phenotypic defect. The hypothalamus in these animals shows increased levels of eIF2α phosphorylation, as expected from the described role of IMPACT in inhibiting GCN2 and from its abundance in this brain region. When fed a normal chow, animals lacking IMPACT weight slightly less than wild-type mice. When fed a high-fat diet, Imp-KO animals gain substantially less weight due to lower food intake when compared to wild-type mice. STAT3 signaling was depressed in Imp-KO animals even though leptin levels were identical to the wild-type mice. This finding supports the observation that Imp-KO mice have defective thermoregulation upon fasting. This phenotype was partially dependent on GCN2, whereas the lean phenotype was independent of GCN2. Taken together, our results indicate that IMPACT contributes to GCN2-dependent and -independent mechanisms involved in the regulation of autonomic functions in response to energy availability.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Obesidade/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Regulação da Temperatura Corporal/genética , Gorduras na Dieta/farmacologia , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Hipotálamo/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/patologia , Proteínas Serina-Treonina Quinases/genética
20.
Eur J Pharmacol ; 857: 172457, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202804

RESUMO

Short-chain fatty acids (SCFAs) are produced by the fermentation of dietary fiber by the gut microbiota and are beneficial to the health of the body. Insufficient SCFAs productions are associated with type 2 diabetes (T2D). We used a long-term high-fat diet to simulate the pathogenesis of T2D and studied the effects of baicalin on gut microbiota and metabolites in mice as well as its mechanism, providing a theoretical basis for the treatment of T2D. Baicalin groups were given 200 mg/kg/day, and control groups were given an equal volume of 0.5% sodium carboxymethyl cellulose solution for 15 weeks. 16S rRNA amplicon pyrosequences was performed to evaluate the gut microbiota composition, and gas chromatography was used to detect SCFAs in stool samples in the different experimental groups. The abundance of gut microbiota in the high-fat model group was altered, and was associated with a decreased production of SCFAs. The microbiota abundance of the baicalin group was closer to that of the control group, increasing the population of SCFA-producing bacteria spp and improving metabolic syndrome, including abnormal glucose and lipid metabolism caused by a high-fat diet. Baicalin may improve abnormalities in glycolipid metabolism by affecting the production of SCFAs.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Flavonoides/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Fezes/química , Flavonoides/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Ácido Glucárico/metabolismo , Glucose/metabolismo , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/microbiologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/microbiologia
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