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1.
Nutrients ; 13(3)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803758

RESUMO

We investigated the association between dietary patterns and serum hepatic enzyme levels in adults with dyslipidemia and impaired fasting glucose in Taiwan. A total of 15,005 subjects (5452 men and 9553 women) aged 35-69 years were selected. Two major dietary patterns were identified by principal component analysis: Western dietary pattern and Mediterranean dietary pattern. Subjects in the highest quartile (Q4) of the Western dietary pattern showed an increased risk of elevated serum alanine aminotransferase (ALT) levels (OR: 1.24, 95% CI: 1.06-1.45, p-trend = 0.01). Fur-thermore, in the highest quartile of the Western dietary pattern, subjects with high waist circum-ference were observed to have a greater risk for developing abnormal serum ALT levels compared to those in the lowest quartile (Q1) (OR: 1.43, 95% CI: 1.04-1.97, p-trend = 0.01). In the highest quartile of the Western dietary pattern, only women were at an increased risk for having abnormal serum ALT levels (OR: 1.28, 95% CI: 1.04-1.59, p-trend = 0.03). By contrast, in the highest quartile of the Mediterranean dietary pattern, only men were at a reduced risk for having abnormal serum gamma-glutamyl transferase (GGT) levels (OR: 0.72, 95% CI: 0.53-0.97, p-trend = 0.048). We report a positive association between the Western dietary pattern and abnormal serum ALT levels.


Assuntos
Alanina Transaminase/sangue , Dieta Ocidental/efeitos adversos , Dislipidemias/sangue , Estado Pré-Diabético/sangue , gama-Glutamiltransferase/sangue , Adulto , Idoso , Glicemia/metabolismo , Estudos Transversais , Inquéritos sobre Dietas , Dieta Mediterrânea , Dislipidemias/etiologia , Jejum/sangue , Comportamento Alimentar/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estado Pré-Diabético/etiologia , Análise de Componente Principal , Taiwan
2.
Life Sci ; 276: 119403, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785339

RESUMO

AIMS: Many dietary NASH models require a long duration to establish (4-6 months). Chronic intermittent hypoxia (CIH), a cardinal hallmark of obstructive sleep apnea (OSA), may accelerate the progression of pediatric nonalcoholic fatty liver disease (NAFLD). However, diet-induced obese (DIO) mice exposed to CIH have not been perceived as a fast or reliable tool in NASH research. This study was designed to establish a rapid juvenile murine NASH model, and determine whether the combination of CIH and a western-style diet (hypercaloric fatty diet plus high fructose) can fully display key pathologic features of NASH. METHODS: C57BL/6 N mice (3 weeks old) fed a control diet or western diet (WD) were exposed to CIH (9% nadir of inspired oxygen levels) or room air for 6 and 12 weeks. KEY FINDINGS: The Control/CIH group mainly exhibited hyperinsulinemia and insulin resistance (IR). In contrast, mice fed a WD developed weight gain after 3 weeks, microvesicular steatosis in 6 weeks, and indices of metabolic disorders at 12 weeks. Furthermore, CIH exposure accelerated WD- induced macromicrovesicular steatosis (liver triglycerides and de novo lipogenesis), liver injury (ballooned hepatocytes and liver enzymes), lobular/portal inflammation (inflammatory cytokines and macrophage recruitment), and fibrogenesis (hydroxyproline content and TGF-ß protein). Notably, only the WD/CIH group exhibited elevated hepatic MDA content, protein levels of NOX4, α-SMA and collagen I, as well as reduced Nrf2 and HO-1 protein expression. SIGNIFICANCE: WD/CIH treatment rapidly mimics the histological characteristics of pediatric NASH with metabolic dysfunction and fibrosis, representing an appropriate experimental model for NASH research.


Assuntos
Dieta Ocidental/efeitos adversos , Hipóxia/fisiopatologia , Inflamação/patologia , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Animais , Animais Recém-Nascidos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo
3.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33670975

RESUMO

Excessive intake of fructose results in metabolic syndrome (MS) and kidney damage, partly mediated by its metabolism by fructokinase-C or ketohexokinase-C (KHK-C). Osthol has antioxidant properties, is capable of regulating adipogenesis, and inhibits KHK-C activity. Here, we examined the potential protective role of osthol in the development of kidney disease induced by a Western (high-fat/high-sugar) diet. Control rats fed with a high-fat/high-sugar diet were compared with two groups that also received two different doses of osthol (30 mg/kg/d or 40 mg/kg/d body weight BW). A fourth group served as a normal control and received regular chow. At the end of the follow-up, kidney function, metabolic markers, oxidative stress, and lipogenic enzymes were evaluated. The Western diet induced MS (hypertension, hyperglycemia, hypertriglyceridemia, obesity, hyperuricemia), a fall in the glomerular filtration rate, renal tubular damage, and increased oxidative stress in the kidney cortex, with increased expression of lipogenic enzymes and increased kidney KHK expression. Osthol treatment prevented the development of MS and ameliorated kidney damage by inhibiting KHK activity, preventing oxidative stress via nuclear factor erythroid 2-related factor (Nrf2) activation, and reducing renal lipotoxicity. These data suggest that the nutraceutical osthol might be an ancillary therapy to slow the progression of MS and kidney damage induced by a Western diet.


Assuntos
Cumarínicos/farmacologia , Dieta Ocidental/efeitos adversos , Frutoquinases/antagonistas & inibidores , Nefropatias/prevenção & controle , Síndrome Metabólica/prevenção & controle , Animais , Cumarínicos/uso terapêutico , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Frutoquinases/metabolismo , Frutose/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Wistar
4.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673073

RESUMO

Western diets contribute to metabolic diseases. However, the effects of various diets and epigenetic mechanisms are mostly unknown. Here, six week-old C57BL/6J male and female mice were fed with a low-fat diet (LFD), high-fat diet (HFD), and high-fat high-fructose diet (HFD-HF) for 20 weeks. We determined that HFD-HF or HFD mice experienced significant metabolic dysregulation compared to the LFD. HFD-HF and HFD-fed male mice showed significantly increased body weight, liver size, and fasting glucose levels with downregulated PPARγ, SCD1, and FAS protein expression. In contrast, female mice were less affected by HFD and HFD-HF. As miR-27b contains a seed sequence in PPARγ, it was discovered that these changes are accompanied by male-specific upregulation of miR-27b-5p, which is even more pronounced in the HFD-HF group (p < 0.01 vs. LFD) compared to the HFD group (p < 0.05 vs. LFD). Other miR-27 subtypes were increased but not significantly. HFD-HF showed insignificant changes in fibrosis markers when compared to LFD. Interestingly, fat ballooning in hepatocytes was increased in HFD-fed mice compared to HFD-HF fed mice, however, the HFD-HF liver showed an increase in the number of small cells. Here, we concluded that chronic Western diet-composition administered for 20 weeks may surpass the non-alcoholic fatty liver (NAFL) stage but may be at an intermediate stage between fatty liver and fibrosis via miR-27b-5p-induced PPARγ downregulation.


Assuntos
Dieta Ocidental/efeitos adversos , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR gama/metabolismo , Transdução de Sinais , Animais , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia
5.
Physiol Behav ; 234: 113389, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33741375

RESUMO

Exercise behavior is under partial genetic control, but it is also affected by numerous environmental factors, potentially including early-life experiences whose effects persist into adulthood. We studied genetic and early-life environmental effects on wheel-running behavior in a mouse model that includes four replicate high runner (HR) lines selectively bred for increased voluntary wheel running as young adults and four non-selected control (C) lines. In a full factorial design, mice from each line were granted wheel access or not and administered either standard or Western diet (WD) from weaning (3 weeks old) to 6 weeks of age (sexual maturity). In addition to acute effects, after a washout period of 8 weeks (∼6 human years) in which all mice had standard diet and no wheel access, we found both beneficial and detrimental effects of these early-life exposures. During the first week of treatments, WD increased distance run by 29% in C mice and 48% in HR mice (significant Diet × Linetype interaction), but diet effects disappeared by the third week. Across the three weeks of juvenile treatment, WD significantly increased fat mass (with lean mass as a covariate). Tested as adults, early-life exercise increased wheel running of C mice but not HR mice in the first week. Early-life exercise also reduced adult anxiety-like behavior and increased adult fasted blood glucose levels, triceps surae mass, subdermal fat pad mass, and brain mass, but decreased heart ventricle mass. Using fat mass as a covariate, early-life exercise treatment increased adult leptin concentration. In contrast, early-life WD increased adult wheel running of HR mice but not C mice. Early-life WD also increased adult lean mass and adult preference for Western diet in all groups. Surprisingly, early-life treatment had no significant effect on adult body fat or maximal aerobic capacity (VO2max). No previous study has tested for combined or interactive effects of early-life WD and exercise. Our results demonstrate that both factors can have long-lasting effects on adult voluntary exercise and related phenotypes, and that these effects are modulated by genetic background. Overall, the long-lasting effects of early-life exercise were more pervasive than those of WD, suggesting critical opportunities for health intervention in childhood habits, as well as possible threats from modern challenges. These results may be relevant for understanding potential effects of activity reductions and dietary changes associated with the obesity epidemic and COVID-19 pandemic.


Assuntos
Dieta Ocidental , Atividade Motora , Adiposidade , Animais , Dieta Ocidental/efeitos adversos , Camundongos , Camundongos Endogâmicos , Fenótipo
6.
Metabolism ; 117: 154724, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33548253

RESUMO

AIMS: Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity. METHODS: SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry. RESULTS: SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes. CONCLUSIONS: SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Obesidade/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Calorimetria Indireta/métodos , Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Obesidade/metabolismo
7.
Nutrients ; 13(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477671

RESUMO

Access to renal transplantation guarantees a substantial improvement in the clinical condition and quality of life (QoL) for end-stage renal disease (ESRD) patients. In recent years, a greater number of older patients starting renal replacement therapies (RRT) have shown the long-term impact of conservative therapies for advanced CKD and the consequences of the uremic milieu, with a frail clinical condition that impacts not only their survival but also limits their access to transplantation. This process, referred to as "inflammaging," might be reversible with a tailored approach, such as RRT accompanied by specific nutritional support. In this review, we summarize the evidence demonstrating the presence of several proinflammatory substances in the Western diet (WD) and the positive effect of unprocessed food consumption and increased fruit and vegetable intake, suggesting a new approach to reduce inflammaging with the improvement of ESRD clinical status. We conclude that the Mediterranean diet (MD), because of its modulative effects on microbiota and its anti-inflammaging properties, may be a cornerstone in a more precise nutritional support for patients on the waiting list for kidney transplantation.


Assuntos
Inflamação/etiologia , Inflamação/terapia , Transplante de Rim , Terapia Nutricional/métodos , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal/efeitos adversos , Adulto , Idoso , Dieta Mediterrânea , Dieta Ocidental/efeitos adversos , Feminino , Frutas , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/prevenção & controle , Falência Renal Crônica/terapia , Masculino , Qualidade de Vida , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/microbiologia , Verduras
8.
PLoS One ; 16(1): e0244763, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33395434

RESUMO

BACKGROUND & AIM: Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease. METHODS: The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome. RESULTS: There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales. CONCLUSIONS: We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.


Assuntos
Disbiose/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Bactérias , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Disbiose/complicações , Fezes/microbiologia , Fibrose/complicações , Fibrose/microbiologia , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Variação Genética/genética , Humanos , Inflamação/complicações , Cirrose Hepática/patologia , Neoplasias Hepáticas/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/microbiologia
9.
PLoS One ; 15(12): e0242543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33326419

RESUMO

Clinical studies using a range of omega-3 supplements have yielded conflicting results on their efficacy to control inflammation. Omega-3 fatty acids are substrate for the formation of potent immune-protective mediators, termed as specialized pro-resolving mediators (SPM). Herein, we investigated whether observed differences in the potencies of distinct omega-3 supplements were linked with their ability to upregulate SPM formation. Using lipid mediator profiling we found that four commercially available supplements conferred a unique SPM signature profile to human macrophages, with the overall increases in SPM concentrations being different between the four supplements. These increases in SPM concentrations were linked with an upregulation of macrophage phagocytosis and a decreased uptake of oxidized low-density lipoproteins. Pharmacological inhibition of two key SPM biosynthetic enzymes 5-Lipoxygenase or 15-Lipoxygenase reversed the macrophage-directed actions of each of the omega-3 supplements. Furthermore, administration of the two supplements that most potently upregulated macrophage SPM formation and reprogrammed their responses in vitro, to APOE-/- mice fed a western diet, increased plasma SPM concentrations and reduced vascular inflammation. Together these findings support the utility of SPM as potential prognostic markers in determining the utility of a given supplement to regulate macrophage responses and inflammation.


Assuntos
Aterosclerose/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Leucotrienos/biossíntese , Lipoxinas/biossíntese , Macrófagos/efeitos dos fármacos , Prostaglandinas/biossíntese , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/imunologia , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/imunologia , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/imunologia , Aterosclerose/etiologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Dieta Ocidental/efeitos adversos , Ácidos Graxos Ômega-3/metabolismo , Feminino , Expressão Gênica , Humanos , Leucotrienos/imunologia , Lipoproteínas LDL/antagonistas & inibidores , Lipoproteínas LDL/farmacologia , Lipoxinas/imunologia , Inibidores de Lipoxigenase/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Fagocitose/efeitos dos fármacos , Cultura Primária de Células , Análise de Componente Principal , Prostaglandinas/imunologia
10.
PLoS One ; 15(12): e0244007, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33320898

RESUMO

PURPOSE: We examined the association between meat intake and mortality due to all-cause and major causes of death using a population-based cohort study in Japan. METHODS: 87,507 Japanese aged between 45 and 74 years old at 5-year follow-up study were followed for 14.0 years on average. Associations between meat intake and mortality risk were assessed using a Cox proportional hazards model. RESULTS: A heavy intake of total meat was associated with a higher risk of all-cause mortality relative to the lowest quartile intake in men (Q4: HR,1.18; 95%CIs, 1.06-1.31). A higher intake of total meat was associated with a lower risk of stroke mortality in women (Q2: HR, 0.70; 95%CIs, 0.51-0.94, Q3: HR, 0.68; 95%CIs, 0.50-0.95, Q4: HR, 0.66; 95%CIs, 0.44-0.99). A heavy intake of red meat was also associated with all-cause mortality (Q4: HR, 1.13; 95%CIs, 1.02-1.26) and heart disease mortality (Q4: HR, 1.51; 95%CIs, 1.11-2.06) in men but not in women. Heavy intake of chicken was inversely associated with cancer mortality in men. CONCLUSIONS: Heavy intakes of total and red meat were associated with an increase in all-cause and heart disease mortality in men, while total meat intake was associated with a lower risk of stroke mortality in women.


Assuntos
Dieta Ocidental/estatística & dados numéricos , Cardiopatias/mortalidade , Produtos da Carne/estatística & dados numéricos , Neoplasias/mortalidade , Acidente Vascular Cerebral/mortalidade , Idoso , Dieta Ocidental/efeitos adversos , Feminino , Humanos , Japão , Masculino , Produtos da Carne/efeitos adversos , Pessoa de Meia-Idade , Mortalidade/tendências , Fatores Sexuais
11.
Nat Commun ; 11(1): 3612, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681035

RESUMO

Bile acid synthesis plays a key role in regulating whole body cholesterol homeostasis. Transcriptional factor EB (TFEB) is a nutrient and stress-sensing transcriptional factor that promotes lysosomal biogenesis. Here we report a role of TFEB in regulating hepatic bile acid synthesis. We show that TFEB induces cholesterol 7α-hydroxylase (CYP7A1) in human hepatocytes and mouse livers and prevents hepatic cholesterol accumulation and hypercholesterolemia in Western diet-fed mice. Furthermore, we find that cholesterol-induced lysosomal stress feed-forward activates TFEB via promoting TFEB nuclear translocation, while bile acid-induced fibroblast growth factor 19 (FGF19), acting via mTOR/ERK signaling and TFEB phosphorylation, feedback inhibits TFEB nuclear translocation in hepatocytes. Consistently, blocking intestinal bile acid uptake by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic TFEB nuclear localization and improves cholesterol homeostasis in Western diet-fed mice. This study has identified a TFEB-mediated gut-liver signaling axis that regulates hepatic cholesterol and bile acid homeostasis.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/antagonistas & inibidores , Linhagem Celular , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Células Hep G2 , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/prevenção & controle , Íleo/efeitos dos fármacos , Íleo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores
12.
Medicine (Baltimore) ; 99(29): e20186, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702808

RESUMO

It has been well established that dietary patterns play important roles in the pathogenesis and development of hypertension. Our aim was to investigate the association between pregnancy dietary patterns and the risk of hypertension among nulliparous pregnant Chinese women.A cross-sectional, case-control study.Three hospitals in Haikou, the capital of Hainan Province, South China.A total of 2580 participants who reported dietary intake using a validated food frequency questionnaire (FFQ).Four primary dietary patterns were identified by principal component factor analysis and labeled as traditional Chinese, animal food, Western food, and salty snacks patterns. Women with high scores on pattern characterized by salty snacks were at increased risk.This study suggests that dietary pattern characterized by salty snack increases the risk of hypertension during pregnancy.


Assuntos
Dieta Ocidental/efeitos adversos , Dieta/efeitos adversos , Hipertensão Induzida pela Gravidez/epidemiologia , Sais/efeitos adversos , Adulto , Estudos de Casos e Controles , China/epidemiologia , Estudos Transversais , Dieta/tendências , Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Feminino , Humanos , Hipertensão Induzida pela Gravidez/etiologia , Incidência , Paridade/fisiologia , Gravidez , Inquéritos e Questionários
13.
Am J Clin Nutr ; 112(2): 268-283, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32520313

RESUMO

BACKGROUND: The Western dietary pattern (WD) is positively associated with risk of coronary artery disease (CAD) and cancer, whereas the Prudent dietary pattern (PD) may be protective. Foods may influence metabolite concentrations as well as oxidative stress and lipid dysregulation, biological mechanisms associated with CAD and cancer. OBJECTIVE: The aim was to assess the association of 2 derived dietary pattern scores with serum metabolites and identify metabolic pathways associated with the metabolites. METHODS: We evaluated the cross-sectional association between each dietary pattern (WD, PD) and metabolites in 2199 Women's Health Initiative (WHI) participants. With FFQ and factor analysis, we determined 2 dietary patterns consistent with WD and PD. Metabolites were measured with LC-tandem MS. Metabolite discovery among 904 WHI Observational Study (WHI-OS) participants was replicated among 1295 WHI Hormone Therapy Trial (WHI-HT) participants. We analyzed each of 495 metabolites with each dietary score (WD, PD) in linear regression models. RESULTS: The PD included higher vegetables and fruit intake compared with the WD with higher saturated fat and meat intake. Independent of energy intake, BMI, physical activity, and other confounding variables, 45 overlapping metabolites were identified (WHI-OS) and replicated (WHI-HT) with an opposite direction of associations for the WD compared with the PD [false discovery rate (FDR) P < 0.05]. In metabolite set enrichment analyses, phosphatidylethanolamine (PE) plasmalogens were positively enriched for association with WD [normalized enrichment score (NES) = 2.01, P = 0.001, FDR P = 0.005], and cholesteryl esters (NES = -1.77, P = 0.005, FDR P = 0.02), and phosphatidylcholines (NES = -1.72, P = 0.01, P = 0.03) were negatively enriched for WD. PE plasmalogens were positively correlated with saturated fat and red meat. Phosphatidylcholines and cholesteryl esters were positively correlated with fatty fish. CONCLUSIONS: Distinct metabolite signatures associated with Western and Prudent dietary patterns highlight the positive association of mitochondrial oxidative stress and lipid dysregulation with a WD and the inverse association with a PD.


Assuntos
Doença das Coronárias/metabolismo , Dieta Saudável , Dieta Ocidental/efeitos adversos , Neoplasias/metabolismo , Idoso , Estudos Transversais , Gorduras/metabolismo , Comportamento Alimentar , Feminino , Humanos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Estresse Oxidativo , Verduras/metabolismo
14.
Nat Commun ; 11(1): 2397, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409697

RESUMO

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.


Assuntos
Diaminas/administração & dosagem , Resistência à Insulina , Mitocôndrias/efeitos dos fármacos , Obesidade/tratamento farmacológico , Oxidiazóis/administração & dosagem , Pirazinas/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Administração Oral , Animais , Glicemia/análise , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diaminas/efeitos adversos , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnica Clamp de Glucose , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Oxidiazóis/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Pirazinas/efeitos adversos
15.
PLoS One ; 15(5): e0233183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413078

RESUMO

Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.


Assuntos
Dieta Ocidental/efeitos adversos , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Lúpus Eritematoso Sistêmico/dietoterapia , Dióxido de Silício/toxicidade , Animais , Linfócitos B/imunologia , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Feminino , Glomerulonefrite/dietoterapia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Inflamação/imunologia , Interferon gama/metabolismo , Rim/metabolismo , Rim/patologia , Pulmão/metabolismo , Pulmão/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Camundongos , Linfócitos T/imunologia
16.
PLoS One ; 15(5): e0227527, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374776

RESUMO

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.


Assuntos
Diabetes Mellitus Tipo 2/genética , Degeneração do Disco Intervertebral/genética , Leptina/genética , Obesidade/genética , Receptores para Leptina/genética , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Obesidade/metabolismo , Obesidade/patologia , Receptores para Leptina/deficiência , Caracteres Sexuais , Transdução de Sinais/genética , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia
17.
Am J Physiol Renal Physiol ; 318(5): F1220-F1228, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32281419

RESUMO

Consumption of a Western diet (WD) induces central aortic stiffening that contributes to the transmittance of pulsatile blood flow to end organs, including the kidney. Our recent work supports that endothelial epithelial Na+ channel (EnNaC) expression and activation enhances aortic endothelial cell stiffening through reductions in endothelial nitric oxide (NO) synthase (eNOS) and bioavailable NO that result in inflammatory and oxidant responses and perivascular fibrosis. However, the role that EnNaC activation has on endothelial responses in the renal circulation remains unknown. We hypothesized that cell-specific deletion of the α-subunit of EnNaC would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Twenty-eight-week-old female αEnNaC knockout and wild-type mice were fed either mouse chow or WD containing excess fat (46%), sucrose, and fructose (17.5% each). WD feeding increased fat mass, indexes of vascular stiffening in the aorta and renal artery (in vivo pulse wave velocity and ultrasound), and renal endothelial cell stiffening (ex vivo atomic force microscopy). WD further impaired aortic endothelium-dependent relaxation and renal artery compliance (pressure myography) without changes in blood pressure. WD-induced renal arterial stiffening occurred in parallel to attenuated eNOS activation, increased oxidative stress, and aortic and renal perivascular fibrosis. αEnNaC deletion prevented these abnormalities and support a novel mechanism by which WD contributes to renal arterial stiffening that is endothelium and Na+ channel dependent. These results demonstrate that cell-specific EnNaC is important in propagating pulsatility into the renal circulation, generating oxidant stress, reduced bioavailable NO, and renal vessel wall fibrosis and stiffening.


Assuntos
Aorta/metabolismo , Dieta Ocidental/efeitos adversos , Canais Epiteliais de Sódio/metabolismo , Artéria Renal/fisiopatologia , Doenças Vasculares/metabolismo , Rigidez Vascular , Animais , Aorta/patologia , Aorta/fisiopatologia , Elasticidade , Canais Epiteliais de Sódio/deficiência , Canais Epiteliais de Sódio/genética , Feminino , Fibrose , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Artéria Renal/patologia , Transdução de Sinais , Doenças Vasculares/genética , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia , Remodelação Vascular
18.
Metabolism ; 109: 154223, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32275972

RESUMO

OBJECTIVE: Obesity is associated with myocardial fibrosis and impaired diastolic relaxation, abnormalities that are especially prevalent in women. Normal coronary vascular endothelial function is integral in mediating diastolic relaxation, and recent work suggests increased activation of the endothelial cell (EC) mineralocorticoid receptor (ECMR) is associated with impaired diastolic relaxation. As the endothelial Na+ channel (EnNaC) is a downstream target of the ECMR, we sought to determine whether EC-specific deletion of the critical alpha subunit, αEnNaC, would prevent diet induced-impairment of diastolic relaxation in female mice. METHODS AND MATERIALS: Female αEnNaC KO mice and littermate controls were fed a Western diet (WD) high in fat (46%), fructose corn syrup (17.5%) and sucrose (17.5%) for 12-16 weeks. Measurements were conducted for in vivo cardiac function, in vitro cardiomyocyte stiffness and EnNaC activity in primary cultured ECs. Additional biochemical studies examined indicators of oxidative stress, including aspects of antioxidant Nrf2 signaling, in cardiac tissue. RESULTS: Deletion of αEnNaC in female mice fed a WD significantly attenuated WD mediated impairment in diastolic relaxation. Improved cardiac relaxation was accompanied by decreased EnNaC-mediated Na+ currents in ECs and reduced myocardial oxidative stress. Further, deletion of αEnNaC prevented WD-mediated increases in isolated cardiomyocyte stiffness. CONCLUSION: Collectively, these findings support the notion that WD feeding in female mice promotes activation of EnNaC in the vasculature leading to increased cardiomyocyte stiffness and diastolic dysfunction.


Assuntos
Diástole/efeitos dos fármacos , Dieta Ocidental/efeitos adversos , Células Endoteliais/química , Coração/fisiopatologia , Canais de Sódio/metabolismo , Rigidez Vascular/efeitos dos fármacos , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Estresse Oxidativo , Canais de Sódio/deficiência
19.
PLoS Pathog ; 16(3): e1008391, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163524

RESUMO

Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 µg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals.


Assuntos
Acanthocheilonema/imunologia , Acantoqueilonemíase/imunologia , Dieta Ocidental/efeitos adversos , Proteínas de Helminto/imunologia , Longevidade/imunologia , Modelos Imunológicos , Animais , Feminino , Masculino , Camundongos
20.
Sci Rep ; 10(1): 4701, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170127

RESUMO

Humans and rodents with Comparative Gene Identification-58 (CGI-58) mutations manifest nonalcoholic fatty liver disease (NAFLD). Here we show that liver CGI-58 knockout (LivKO) mice fed a Western diet rapidly develop advanced NAFLD, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. After 14 weeks of diet challenge, starting at 6 weeks of age, LivKO mice showed increased inflammatory cell infiltration and proinflammatory gene expression in the liver, which was associated with elevated plasma levels of aminotransferases. Hepatic ductular reactions, pericellular fibrosis, and bridging fibrosis were observed only in the LivKO mice. Consistently, the KO mice had a significant increase in hepatic mRNAs for fibrogenic genes. In addition, LivKO mice displayed massive accumulation of lipid droplets (LDs) in hepatocytes. LDs were also observed in the cholangiocytes of the LivKO mice, but not the floxed controls. Four of the five LD coat proteins, including perilipins 2, 3, 4, and 5, were increased in the CGI-58 KO liver. CRISPR/Cas9-mediated knockout of CGI-58 in Huh7 human hepatoma cells induced LD deposition and perilipin expression, suggesting a cell autonomous effect. Our findings establish the Western diet-fed LivKO mice as an animal model of NASH and hepatic fibrosis. These animals may facilitate preclinical screening of therapeutic agents that counter against NAFLD progression.


Assuntos
1-Acilglicerol-3-Fosfato O-Aciltransferase/deficiência , Dieta Ocidental/efeitos adversos , Suscetibilidade a Doenças , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Peso Corporal , Modelos Animais de Doenças , Progressão da Doença , Predisposição Genética para Doença , Glucose/metabolismo , Hepatomegalia , Humanos , Cirrose Hepática/patologia , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença
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