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1.
Immunol Lett ; 226: 38-45, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659267

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of deadly Coronavirus disease-19 (COVID-19) pandemic, which emerged as a major threat to public health across the world. Although there is no clear gender or socioeconomic discrimination in the incidence of COVID-19, individuals who are older adults and/or with comorbidities and compromised immunity have a relatively higher risk of contracting this disease. Since no specific drug has yet been discovered, strengthening immunity along with maintaining a healthy living is the best way to survive this disease. As a healthy practice, calorie restriction in the form of intermittent fasting (IF) in several clinical settings has been reported to promote several health benefits, including priming of the immune response. This dietary restriction also activates autophagy, a cell surveillance system that boosts up immunity. With these prevailing significance in priming host defense, IF could be a potential strategy amid this outbreak to fighting off SARS-CoV-2 infection. Currently, no review so far available proposing IF as an encouraging strategy in the prevention of COVID-19. A comprehensive review has therefore been planned to highlight the beneficial role of fasting in immunity and autophagy, that underlie the possible defense against SARS-CoV-2 infection. The COVID-19 pathogenesis and its impact on host immune response have also been briefly outlined. This review aimed at revisiting the immunomodulatory potential of IF that may constitute a promising preventive approach against COVID-19.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/metabolismo , Suscetibilidade a Doenças , Jejum , Interações Hospedeiro-Patógeno , Pneumonia Viral/etiologia , Pneumonia Viral/metabolismo , Autofagia , Restrição Calórica , Resistência à Doença/imunologia , Suscetibilidade a Doenças/imunologia , Jejum/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune , Imunidade , Pandemias
2.
PLoS One ; 15(7): e0234916, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614882

RESUMO

A great deal of attention has been focused on nanoparticles for cancer therapy, with the promise of tumor-selective delivery. However, despite intense work in the field over many years, the biggest obstacle to this vision remains extremely low delivery efficiency of nanoparticles into tumors. Due to the cost, time, and impact on the animals for in vivo studies, the nanoparticle field predominantly uses cellular uptake assays as a proxy to predict in vivo outcomes. Extensive research has focused on decreasing macrophage uptake in vitro as a proxy to delay nanoparticle accumulation in the mononuclear phagocytic system (MPS), mainly the liver and spleen, and thereby increase tumor accumulation. We have recently reported novel synthetic methods employing small molecule crosslinkers for the controlled assembly of small nanoparticles into larger aggregates and found that these nanoaggregates had remarkably high surface coverage and low cell uptake, even in macrophages. We further found that this extremely low cellular uptake could be recapitulated on solid gold nanoparticles by densely coating their surface with small molecules. Here we report our studies on the biodistribution and clearance of these materials in comparison to more conventional PEGylated gold nanoparticles. It was expected that the remarkably low macrophage uptake in vitro would translate to extended blood circulation time in vivo, but instead we found no correlation between either surface coverage or in vitro macrophage cell uptake and in vivo blood circulation. Gold nanoaggregates accumulate more rapidly and to a higher level in the liver compared to control gold nanoparticles. The lack of correlation between in vitro macrophage uptake and in vivo blood circulation suggests that the field must find other in vitro assays to use as a primary proxy for in vivo outcomes or use direct in vivo experimentation as a primary assay.


Assuntos
Materiais Revestidos Biocompatíveis/farmacocinética , Ouro/farmacocinética , Nanopartículas Metálicas , Polietilenoglicóis , Animais , Endocitose , Jejum/metabolismo , Feminino , Ouro/administração & dosagem , Ouro/sangue , Meia-Vida , Rim/metabolismo , Fígado/metabolismo , Macrófagos/fisiologia , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/classificação , Camundongos , Especificidade de Órgãos , Projetos Piloto , Células RAW 264.7 , Organismos Livres de Patógenos Específicos , Baço/metabolismo , Distribuição Tecidual
3.
Nat Commun ; 11(1): 2080, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350271

RESUMO

Excessive insulin signaling through the insulin receptor (IR) may play a role in the pathogenesis of diet-induced metabolic disease, including obesity and type 2 diabetes. Here we investigate whether heterozygous impairment of insulin receptor (IR) expression limited to peripheral, i.e. non-CNS, tissues of adult mice impacts the development of high-fat diet-induced metabolic deterioration. While exhibiting some features of insulin resistance, PerIRKO+/- mice display a hepatic energy deficit accompanied by induction of energy-sensing AMPK, mitochondrial biogenesis, PPARα, unexpectedly leading to protection from, and reversal of hepatic lipid accumulation (steatosis hepatis, NAFLD). Consistently, and unlike in control mice, the PPARα activator fenofibrate fails to further affect hepatic lipid accumulation in PerIRKO+/- mice. Taken together, and opposing previously established diabetogenic features of insulin resistance, incomplete impairment of insulin signaling may mimic central aspects of calorie restriction to limit hepatic lipid accumulation during conditions of metabolic stress.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Jejum/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Receptor de Insulina/metabolismo , Animais , Composição Corporal , Metabolismo Energético , Comportamento Alimentar , Glucose/metabolismo , Homeostase , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
4.
Diabet Med ; 37(7): 1094-1102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333691

RESUMO

The month of Ramadan forms one of the five pillars of the Muslim faith. Adult Muslims are obligated to keep daily fasts from dawn to sunset, with exceptions. This year Ramadan is due to begin on 23 April 2020 and the longest fast in the UK will be approximately 18 hours in length. In addition, due to the often high-calorie meals eaten to break the fast, Ramadan should be seen as a cycle of fasting and feasting. Ramadan fasting can impact those with diabetes, increasing the risk of hypoglycaemia, hyperglycaemia and dehydration. This year, Ramadan will occur during the global COVID-19 pandemic. Reports show that diabetes appears to be a risk factor for more severe disease with COVID-19. In addition, the UK experience has shown diabetes and COVID-19 is associated with dehydration, starvation ketosis, diabetic ketoacidosis and hyperosmolar hyperglycaemic state. This makes fasting in Ramadan particularly challenging for those Muslims with diabetes. Here, we discuss the implications of fasting in Ramadan during the COVID-19 pandemic and make recommendations for those with diabetes who wish to fast.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Jejum/metabolismo , Férias e Feriados , Islamismo , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Desidratação/epidemiologia , Desidratação/metabolismo , Desidratação/prevenção & controle , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Cetoacidose Diabética/epidemiologia , Dietoterapia , Gerenciamento Clínico , Jejum/efeitos adversos , Hidratação , Humanos , Hiperglicemia/epidemiologia , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Coma Hiperglicêmico Hiperosmolar não Cetótico/epidemiologia , Coma Hiperglicêmico Hiperosmolar não Cetótico/metabolismo , Hipoglicemia/epidemiologia , Hipoglicemia/metabolismo , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Cetose/epidemiologia , Cetose/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Medição de Risco , Reino Unido
5.
Am J Med ; 133(8): 901-907, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32330491

RESUMO

Dietary patterns, such as the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet, have been shown to improve cardiac health. Intermittent fasting is another type of popular dietary pattern that is based on timed periods of fasting. Two different regimens are alternative day fasting and time-restricted eating. Although there are no large, randomized control trials examining the relationship between intermittent fasting and cardiovascular outcomes, current human studies that suggest this diet could reduce the risk for cardiovascular disease with improvement in weight control, hypertension, dyslipidemia, and diabetes. Intermittent fasting may exert its effects through multiple pathways, including reducing oxidative stress, optimization of circadian rhythms, and ketogenesis. This review evaluates current literature regarding the potential cardiovascular benefits of intermittent fasting and proposes directions for future research.


Assuntos
Doenças Cardiovasculares/metabolismo , Ritmo Circadiano/fisiologia , Diabetes Mellitus/metabolismo , Dislipidemias/metabolismo , Jejum/metabolismo , Hipertensão/metabolismo , Obesidade/metabolismo , Diabetes Mellitus/dietoterapia , Dieta Cetogênica , Dislipidemias/dietoterapia , Jejum/fisiologia , Humanos , Hipertensão/fisiopatologia , Corpos Cetônicos/metabolismo , Obesidade/dietoterapia , Estresse Oxidativo/fisiologia , Fatores de Risco , Comportamento de Redução do Risco
6.
Artigo em Inglês | MEDLINE | ID: mdl-32292065

RESUMO

In rats, overnight fasting reduces the ability of systemic cholecystokinin-8 (CCK) to suppress food intake and to activate cFos in the caudal nucleus of the solitary tract (cNTS), specifically within glucagon-like peptide-1 (GLP-1) and noradrenergic (NA) neurons of the A2 cell group. Systemic CCK increases vagal sensory signaling to the cNTS, an effect that is amplified by leptin and reduced by ghrelin. Since fasting reduces plasma leptin and increases plasma ghrelin levels, we hypothesized that peripheral leptin administration and/or antagonism of ghrelin receptors in fasted rats would rescue the ability of CCK to activate GLP-1 neurons and a caudal subset of A2 neurons that coexpress prolactin-releasing peptide (PrRP). To test this, cFos expression was examined in ad libitum-fed and overnight food-deprived (DEP) rats after intraperitoneal CCK, after coadministration of leptin and CCK, or after intraperitoneal injection of a ghrelin receptor antagonist (GRA) before CCK. In fed rats, CCK activated cFos in ~60% of GLP-1 and PrRP neurons. Few or no GLP-1 or PrRP neurons expressed cFos in DEP rats treated with CCK alone, CCK combined with leptin, or GRA alone. However, GRA pretreatment increased the ability of CCK to activate GLP-1 and PrRP neurons and also enhanced the hypophagic effect of CCK in DEP rats. Considered together, these new findings suggest that reduced behavioral sensitivity to CCK in fasted rats is at least partially due to ghrelin-mediated suppression of hindbrain GLP-1 and PrRP neural responsiveness to CCK.


Assuntos
Regulação do Apetite/efeitos dos fármacos , Colecistocinina/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Jejum/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Grelina/sangue , Neurônios/efeitos dos fármacos , Rombencéfalo/efeitos dos fármacos , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Leptina/sangue , Masculino , Neurônios/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Receptores de Grelina/metabolismo , Rombencéfalo/metabolismo , Transdução de Sinais
7.
Nat Commun ; 11(1): 807, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042044

RESUMO

Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPARα to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.


Assuntos
Autofagia/genética , Jejum/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fígado/metabolismo , Animais , Autofagia/efeitos dos fármacos , Epigênese Genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/deficiência , Hepatócitos/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lipólise , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , PPAR alfa/metabolismo , Fosforilação , Ligação Proteica , Transdução de Sinais , Regulação para Cima
8.
Metabolism ; 105: 154185, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32061908

RESUMO

BACKGROUND/AIMS: Uncertainty still exists on the earliest beta-cell defects at the bases of the type 2 diabetes. We assume that this depends on the inaccurate distinction between fasting and post-load glucose homeostasis and aim at providing a description of major beta-cell functions across the full physiologic spectrum of each condition. METHODS: In 1320 non-diabetic individuals we performed an OGTT with insulin secretion modeling and a euglycemic insulin clamp, coupled in subgroups to glucose tracers and IVGTT; 1038 subjects underwent another OGTT after 3.5 years. Post-load glucose homeostasis was defined as mean plasma glucose above fasting levels (δOGTT). The analysis was performed by two-way ANCOVA. RESULTS: Fasting plasma glucose (FPG) and δOGTT were weakly related variables (stß = 0.12) as were their changes over time (r = -0.08). Disruption of FPG control was associated with an isolated and progressive decline (approaching 60%) of the sensitivity of the beta-cell to glucose values within the normal fasting range. Disruption of post-load glucose control was characterized by a progressive decline (approaching 60%) of the slope of the full beta-cell vs glucose dose-response curve and an early minor (30%) decline of potentiation. The acute dynamic beta-cell responses, neither per se nor in relation to the degree of insulin resistance appeared to play a relevant role in disruption of fasting or post-load homeostasis. Follow-up data qualitatively and quantitatively confirmed the results of the cross-sectional analysis. CONCLUSION: In normal subjects fasting and post-load glucose homeostasis are largely independent, and their disruption is sustained by different and specific beta-cell defects.


Assuntos
Doenças Cardiovasculares/epidemiologia , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Adulto , Glicemia/metabolismo , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Europa (Continente)/epidemiologia , Jejum/metabolismo , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
9.
Biochem Soc Trans ; 48(1): 51-59, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32096539

RESUMO

Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-ß-hydroxybutyrate (ßHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate ßHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets. The recent development of an ingestible ßHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The ßHB monoester is a salt-free ßHB precursor that yields only the biologically active d-isoform of the metabolite, the pharmacokinetics of which have been studied, as has safety for human consumption in athletes and healthy volunteers. This review describes fundamental concepts of endogenous and exogenous ketone body metabolism, the differences between the ßHB monoester and other exogenous ketones and summarises the disease-specific biochemical and physiological rationales behind its clinical use in diabetes, neurodegenerative diseases, heart failure, sepsis related muscle atrophy, migraine, and epilepsy. We also address the limitations of using the ßHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.


Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/uso terapêutico , Diabetes Mellitus/dietoterapia , Dieta Cetogênica , Suplementos Nutricionais , Epilepsia/dietoterapia , Jejum/metabolismo , Insuficiência Cardíaca/dietoterapia , Hepatócitos/metabolismo , Humanos , Doenças Neurodegenerativas/dietoterapia , Sepse/dietoterapia
11.
Int J Vitam Nutr Res ; 90(1-2): 95-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30932777

RESUMO

Background: Nonalcoholic fatty liver disease (NAFLD) is a serious global health problem, thus the prevention and management of the disease is necessary. This study aimed to determine the effects of Ramadan Fasting (RF) on liver function, Visceral Adiposity Index (VAI) and Atherogenic Index of Plasma (AIP) in these patients. METHODS: Eighty-three NAFLD patients (57 males and 26 females) were enrolled in the study, 42 patients who practiced RF, between Jun 18 through July 17, 2015 and 41 patients in non-fasting groups. Anthropometric parameters and Ultrasound grading were measured before and after Ramadan. The biochemical parameters including lipid profiles (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), liver enzymes (Aspartate aminotransferase, SGOT and Alanine aminotransferase, SGPT) were evaluated before and after Ramadan. AIP and VAI were calculated based on formula. RESULTS: The mean decreases in anthropometric indices were significantly different between groups. Similarly, the mean decrease in the total cholesterol values in the fasting group was remarkably greater than in the control group (p = 0.02). The values of AIP and VAI decreased at the end of the study in both group and the mean of changes showed no differences between groups (p = 0.79 and p = 0.65 for AIP and VAI, respectively). The changes in the concentrations of liver enzymes, as well as the severity of hepatic steatosis, showed remarkable differences between groups (p = 0.03, p = 0.05, and p = 0.02 for SGOT and SGPT, and Liver steatosis, respectively). CONCLUSION: RF improved liver steatosis in NAFLD patients and might be useful in the management of NAFLD.


Assuntos
HDL-Colesterol/metabolismo , Jejum/metabolismo , Hepatopatia Gordurosa não Alcoólica , Obesidade Abdominal , Triglicerídeos/metabolismo , HDL-Colesterol/química , Feminino , Humanos , Masculino , Triglicerídeos/química
12.
Am J Clin Nutr ; 111(1): 131-140, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557279

RESUMO

BACKGROUND: Crohn's disease (CD) patients suffer postprandial aversive symptoms, which can lead to anorexia and malnutrition. Changes in the regulation of gut hormones and gut dysmotility are believed to play a role. OBJECTIVES: This study aimed to investigate small-bowel motility and gut peptide responses to a standard test meal in CD by using MRI. METHODS: We studied 15 CD patients with active disease (age 36 ± 3 y; BMI 26 ± 1 kg/m 2) and 20 healthy volunteers (HVs; age 31 ± 3 years; BMI 24 ± 1 kg/m 2). They underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling following a 400-g soup meal (204 kcal). Small-bowel motility, other MRI parameters, and glucagon-like peptide-1 (GLP-1), polypeptide YY (PYY), and cholecystokinin peptides were measured. Data are presented as means ± SEMs. RESULTS: HVs had significantly higher fasting motility indexes [106 ± 13 arbitrary units (a.u.)], compared with CD participants (70 ± 8 a.u.; P ≤ 0.05). Postprandial small-bowel water content showed a significant time by group interaction (P < 0.05), with CD participants showing higher levels from 210 min postprandially. Fasting concentrations of GLP-1 and PYY were significantly greater in CD participants, compared with HVs [GLP-1, CD 50 ± 8 µg/mL versus HV 13 ± 3 µg/mL (P ≤ 0.0001); PYY, CD 236 ± 16 pg/mL versus HV 118 ± 12 pg/mL (P ≤ 0.0001)]. The meal challenge induced a significant postprandial increase in aversive symptom scores (fullness, distention, bloating, abdominal pain, and sickness) in CD participants compared with HVs (P ≤ 0.05). CONCLUSIONS: The decrease in fasting small-bowel motility noted in CD participants can be ascribed to the increased fasting gut peptides. A better understanding of the etiology of aversive symptoms in CD will facilitate identification of better therapeutic targets to improve nutritional status. This trial was registered at clinicaltrials.gov as NCT03052465.


Assuntos
Doença de Crohn/metabolismo , Doença de Crohn/fisiopatologia , Hormônios Gastrointestinais/sangue , Intestino Delgado/fisiopatologia , Adulto , Idoso , Colecistocinina/sangue , Doença de Crohn/diagnóstico por imagem , Jejum/metabolismo , Feminino , Motilidade Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Intestino Delgado/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Peptídeo YY/sangue , Período Pós-Prandial , Adulto Jovem
13.
Am J Clin Nutr ; 111(3): 503-514, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31879752

RESUMO

BACKGROUND: Intermittent fasting (IF) and Paleolithic (Paleo) diets produce weight loss in controlled trials, but minimal evidence exists regarding long-term efficacy under free-living conditions without intense dietetic support. OBJECTIVES: This exploratory, observational analysis examined adherence, dietary intake, weight loss, and metabolic outcomes in overweight adults who could choose to follow Mediterranean, IF, or Paleo diets, and standard exercise or high-intensity interval training (HIIT) programs, as part of a 12-mo randomized controlled trial investigating how different monitoring strategies influenced weight loss (control, daily self-weighing, hunger training, diet/exercise app, brief support). METHODS: A total of 250 overweight [BMI (in kg/m2) ≥27] healthy adults attended an individualized dietary education session (30 min) relevant to their self-selected diet. Dietary intake (3-d weighed diet records), weight, body composition, blood pressure, physical activity (0, 6, and 12 mo), and blood indexes (0 and 12 mo) were assessed. Mean (95% CI) changes from baseline were estimated using regression models. No correction was made for multiple tests. RESULTS: Although 54.4% chose IF, 27.2% Mediterranean, and 18.4% Paleo diets originally, only 54% (IF), 57% (Mediterranean), and 35% (Paleo) participants were still following their chosen diet at 12 mo (self-reported). At 12 mo, weight loss was -4.0 kg (95% CI: -5.1, -2.8 kg) in IF, -2.8 kg (-4.4, -1.2 kg) in Mediterranean, and -1.8 kg (-4.0, 0.5 kg) in Paleo participants. Sensitivity analyses showed that, due to substantial dropout, these may be overestimated by ≤1.2 kg, whereas diet adherence increased mean weight loss by 1.1, 1.8, and 0.3 kg, respectively. Reduced systolic blood pressure was observed with IF (-4.9 mm Hg;  -7.2, -2.6 mm Hg) and Mediterranean (-5.9 mm Hg; -9.0, -2.7 mm Hg) diets, and reduced glycated hemoglobin with the Mediterranean diet (-0.8 mmol/mol; -1.2, -0.4 mmol/mol). However, the between-group differences in most outcomes were not significant and these comparisons may be confounded due to the nonrandomized design. CONCLUSIONS: Small differences in metabolic outcomes were apparent in participants following self-selected diets without intensive ongoing dietary support, even though dietary adherence declined rapidly. However, results should be interpreted with caution given the exploratory nature of analyses. This trial was registered with the Australian New Zealand Clinical Trials Registry as ACTRN12615000010594 at https://www.anzctr.org.au.


Assuntos
Dieta Mediterrânea , Dieta Paleolítica , Terapia por Exercício , Sobrepeso/dietoterapia , Adulto , Austrália , Pressão Sanguínea , Exercício Físico , Jejum/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/fisiopatologia , Sobrepeso/terapia , Perda de Peso , Adulto Jovem
14.
BMC Genomics ; 20(1): 919, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791229

RESUMO

BACKGROUND: Compensatory growth refers to the phenomenon in which organisms grow faster after the improvement of an adverse environment and is thought to be an adaptive evolution to cope with the alleviation of the hostile environment. Many fish have the capacity for compensatory growth, but the underlying cellular mechanisms remain unclear. In the present study, microarray and nontargeted metabolomics were performed to characterize the transcriptome and metabolome of zebrafish liver during compensatory growth. RESULTS: Zebrafish could regain the weight they lost during 3 weeks of fasting and reach a final weight similar to that of fish fed ad libitum when refed for 15 days. When refeeding for 3 days, the liver displayed hyperplasia accompanied with decreased triglyceride contents and increased glycogen contents. The microarray results showed that when food was resupplied for 3 days, the liver TCA cycle (Tricarboxylic acid cycle) and oxidative phosphorylation processes were upregulated, while DNA replication and repair, as well as proteasome assembly were also activated. Integration of transcriptome and metabolome data highlighted transcriptionally driven alterations in metabolism during compensatory growth, such as altered glycolysis and lipid metabolism activities. The metabolome data also implied the participation of amino acid metabolism during compensatory growth in zebrafish liver. CONCLUSION: Our study provides a global resource for metabolic adaptations and their transcriptional regulation during refeeding in zebrafish liver. This study represents a first step towards understanding of the impact of metabolism on compensatory growth and will potentially aid in understanding the molecular mechanism associated with compensatory growth.


Assuntos
Jejum/metabolismo , Fígado/metabolismo , Metaboloma , Transcriptoma , Animais , Peso Corporal , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Fígado/anatomia & histologia , Metabolômica , Análise de Sequência com Séries de Oligonucleotídeos , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
15.
J Vis Exp ; (153)2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31840661

RESUMO

Intermittent fasting (IF), a dietary intervention involving periodic energy restriction, has been considered to provide numerous benefits and counteract metabolic abnormalities. So far, different types of IF models with varying durations of fasting and feeding periods have been documented. However, interpreting the outcomes is challenging, as many of these models involve multifactorial contributions from both time- and calorie-restriction strategies. For example, the alternate day fasting model, often used as a rodent IF regimen, can result in underfeeding, suggesting that health benefits from this intervention are likely mediated via both caloric restriction and fasting-refeeding cycles. Recently, it has been successfully demonstrated that 2:1 IF, comprising 1 day of fasting followed by 2 days of feeding, can provide protection against diet-induced obesity and metabolic improvements without a reduction in overall caloric intake. Presented here is a protocol of this isocaloric 2:1 IF intervention in mice. Also described is a pair-feeding (PF) protocol required to examine a mouse model with altered eating behaviors, such as hyperphagia. Using the 2:1 IF regimen, it is demonstrated that isocaloric IF leads to reduced body weight gain, improved glucose homeostasis, and elevated energy expenditure. Thus, this regimen may be useful to investigate the health impacts of IF on various disease conditions.


Assuntos
Restrição Calórica/métodos , Ingestão de Energia/fisiologia , Jejum/metabolismo , Obesidade/dietoterapia , Obesidade/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia
16.
Int J Dev Neurosci ; 79: 76-85, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715265

RESUMO

BACKGROUND: Neonatal anoxia may cause neurological injuries, behavioral alterations and changes in somatic growth. Somatic developmental changes suggest a possible effect of anoxia on energy metabolism and/or feeding behavior. Short-term effects of oxygen deficit on energy homeostasis have been described. In contrast, just a few studies report long-term effects. This study investigated the effects of neonatal anoxia on energy metabolism and somatic development at adulthood of males and females Wistar rats. METHOD: Male (m) and female (f) rats were exposed, on postnatal day 2 (P2), to either 25-min of Anoxia or Control treatment. At P34 part of the subjects of each group was fasted for 18 h, refeed for 1 h and then perfused 30 min later, at P35; the remaining subjects were submitted to these treatments at P94 and perfused at P95. Therefore, there were 8 groups: AmP35, AmP95, AfP35, AfP95, CmP35, CmP95, CfP35 and CfP95. For subjects perfused at P95, body weight and food intake were recorded up to P90. For subjects perfused at P35 and P95, glycemia, leptin and insulin were assessed after fasting and refeed. After perfusion the encephalon and pancreas were collected for Fos immunohistochemistry and Hematoxylin-Eosin stain analyses. RESULTS: Even though neonatal anoxia did not interfere with regular food intake, it reduced body weight gain along growing in both male and female subjects as compared to the corresponding controls. At P35 neonatal anoxia decreased post-prandial glycemia and increased insulin. While at P95 neonatal anoxia altered the pancreatic histomorphology and increased post-fasting weight loss, decreasing leptin, insulin and glycemia secretion, as well Fos immunoreactivity (IR) in ARC. CONCLUSION: Neonatal anoxia impairs long-term energy metabolism and somatic development in Wistar rats, with differences related to sex and age.


Assuntos
Metabolismo Energético/fisiologia , Jejum/metabolismo , Hipóxia/metabolismo , Ganho de Peso/fisiologia , Animais , Animais Recém-Nascidos , Glicemia , Feminino , Insulina/sangue , Leptina/sangue , Masculino , Ratos , Ratos Wistar
17.
Mol Cell ; 76(4): 531-545.e5, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31706703

RESUMO

The glucocorticoid receptor (GR) is a potent metabolic regulator and a major drug target. While GR is known to play integral roles in circadian biology, its rhythmic genomic actions have never been characterized. Here we mapped GR's chromatin occupancy in mouse livers throughout the day and night cycle. We show how GR partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting. Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR. This rhythmic pattern is altered by high-fat diet in a ligand-independent manner. We find that the remodeling of oscillatory gene expression and postprandial GR binding results from a concomitant increase of STAT5 co-occupancy in obese mice. Altogether, our findings highlight GR's fundamental role in the rhythmic orchestration of hepatic metabolism.


Assuntos
Cromatina/metabolismo , Relógios Circadianos , Ritmo Circadiano , Dieta Hiperlipídica , Gorduras na Dieta/metabolismo , Metabolismo Energético , Fígado/metabolismo , Obesidade/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Glicemia/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Modelos Animais de Doenças , Metabolismo Energético/genética , Jejum/metabolismo , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Gluconeogênese , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/sangue , Obesidade/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Período Pós-Prandial , Receptores de Glucocorticoides/deficiência , Receptores de Glucocorticoides/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Via Secretória , Transdução de Sinais , Fatores de Tempo , Transcrição Genética , Triglicerídeos/sangue
18.
Int J Pharm ; 572: 118723, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31628978

RESUMO

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit® L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A γ-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the bloodstream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colo/metabolismo , Sistemas de Liberação de Medicamentos , Mesalamina/administração & dosagem , Administração Oral , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/urina , Estudos Cross-Over , Liberação Controlada de Fármacos , Jejum/metabolismo , Humanos , Masculino , Mesalamina/sangue , Mesalamina/farmacocinética , Mesalamina/urina , Pessoa de Meia-Idade , Cintilografia , Adulto Jovem
19.
Physiol Int ; 106(3): 213-224, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578075

RESUMO

BACKGROUND AND AIMS: In this study, we aimed to investigate the effects of 10 weeks of high-intensity interval training (HIIT) and endurance training (END) on irisin, betatrophin, insulin, fasting blood glucose (FBG) concentrations, and lipid profiles in diabetic rats. METHODS: Twenty-four Wistar rats (weight: 200-250 g) were randomly assigned into four groups as follows: (1) control (Cnt), (2) diabetic (Dibt), (3) diabetic HIIT (Dibt-HIIT), and (4) diabetic END (Dibt-END). For inducing diabetes, after 12 h of food starvation, nicotinamide (120 mg/kg) and streptozotocin (STZ; 65 mg/kg) were intraperitoneally injected. The diabetic training groups received 10 weeks of HIIT or END training following the induction of diabetes. Twenty-four hours following the last training session, blood serum samples were collected for evaluating the concentration of irisin, betatrophin, and insulin hormones through enzyme-linked immunosorbent assay. RESULTS: FBG and lipid profiles were measured by biochemical kits. A significant increase in the serum concentration of irisin (p < 0.05), betatrophin (p < 0.05), and insulin (p < 0.001) and significant decrease in the FBG (P < 0.01) and lipid profiles (p < 0.01) were observed in the Dibt-HIIT group compared to the Dibt-END group. In addition, irisin revealed a significant positive association with betatrophin and insulin values in diabetic training groups (p < 0.01). CONCLUSIONS: It seems that HIIT leads to a more extensive improvement in diabetic conditions compared to the END training. Therefore, HIIT appears to be an important time-efficient approach for the treatment of type 2 diabetes.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fibronectinas/metabolismo , Lipídeos/fisiologia , Animais , Peso Corporal/fisiologia , Treino Aeróbico/métodos , Jejum/metabolismo , Treinamento Intervalado de Alta Intensidade/métodos , Insulina/metabolismo , Masculino , Condicionamento Físico Animal/fisiologia , Ratos , Ratos Wistar
20.
Nat Commun ; 10(1): 4303, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541100

RESUMO

Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. The regulatory factors that are involved in fasting glucagon response are not well understood. Here we report a role of p52, a key activator of the noncanonical nuclear factor-kappaB signaling, in hepatic glucagon response. We show that p52 is activated in livers of HFD-fed and glucagon-challenged mice. Knockdown of p52 lowers glucagon-stimulated hyperglycemia, while p52 overexpression augments glucagon response. Mechanistically, p52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lower blood glucose at least in part by inhibiting p52 activation. Our findings reveal that p52 mediates glucagon-triggered hepatic gluconeogenesis and suggests that pharmacological intervention to prevent p52 processing is a potential therapeutic strategy for diabetes.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Glucagon/metabolismo , Fígado/metabolismo , Subunidade p52 de NF-kappa B/metabolismo , Animais , Glicemia , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Jejum/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Ginsenosídeos , Gluconeogênese , Glucose/metabolismo , Células Hep G2 , Humanos , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p52 de NF-kappa B/antagonistas & inibidores , Subunidade p52 de NF-kappa B/genética , Regiões Promotoras Genéticas , Transdução de Sinais
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