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PURPOSE OF REVIEW: Glucose metabolism is under circadian regulation, with insulin secretion and sensitivity being highest in the morning as compared to the evening. The present review will discuss the existing evidence for the role of meal and macronutrient timing to improve glucose metabolism and reset circadian clocks, with a focus on the evidence in humans. RECENT FINDINGS: Shortening the daily eating window (also known as time-restricted eating), or skewing food intake towards breakfast and away from the evening meal both improve glucose control in people with impaired glucose metabolism. Insulin is recently purported to be a zeitgeber and thus an important reset signal for peripheral circadian clocks in vitro and in mice. Although few studies have tested the impact of macronutrient timing in humans, eating a greater proportion of carbohydrates earlier, rather than later, in the day is associated with better glucose control. SUMMARY: The impact of carbohydrate intake timing on endogenous central and peripheral clocks, and its potential to optimize circadian regulation and improve glycaemic control, are not well understood but are currently under intense exploration.
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Ritmo Circadiano , Ingestão de Alimentos , Animais , Glicemia , Carboidratos , Glucose , Homeostase , Humanos , CamundongosRESUMO
Unbiased and sensitive quantification of low abundance small proteins in human plasma (e.g. hormones, immune factors, metabolic regulators) remains an unmet need. These small protein factors are typically analyzed individually and using antibodies that can lack specificity. Mass spectrometry (MS)-based proteomics has the potential to address these problems, however the analysis of plasma by MS is plagued by the extremely large dynamic range of this body fluid, with protein abundances spanning at least 13 orders of magnitude. Here we describe an enrichment assay (SPEA), that greatly simplifies the plasma dynamic range problem by enriching small-proteins of 2-10 kDa, enabling the rapid, specific and sensitive quantification of >100 small-protein factors in a single untargeted LC-MS/MS acquisition. Applying this method to perform deep-proteome profiling of human plasma we identify C5ORF46 as a previously uncharacterized human plasma protein. We further demonstrate the reproducibility of our workflow for low abundance protein analysis using a stable-isotope labeled protein standard of insulin spiked into human plasma. SPEA provides the ability to study numerous important hormones in a single rapid assay, which we applied to study the intermittent fasting response and observed several unexpected changes including decreased plasma abundance of the iron homeostasis regulator hepcidin.
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Proteínas Sanguíneas/análise , Jejum/sangue , Peptídeos e Proteínas de Sinalização Intercelular/análise , Proteômica/métodos , Restrição Calórica , Cromatografia Líquida/métodos , Ensaio de Imunoadsorção Enzimática , Feminino , Hepcidinas/sangue , Humanos , Insulina/sangue , Marcação por Isótopo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Redução de Peso , Fluxo de TrabalhoRESUMO
Intermittent fasting (IF) increases lifespan and decreases metabolic disease phenotypes and cancer risk in model organisms, but the health benefits of IF in humans are less clear. Human plasma derived from clinical trials is one of the most difficult sample sets to analyze using mass spectrometry-based proteomics due to the extensive sample preparation required and the need to process many samples to achieve statistical significance. Here, we describe an optimized and accessible device (Spin96) to accommodate up to 96 StageTips, a widely used sample preparation medium enabling efficient and consistent processing of samples prior to LC-MS/MS. We have applied this device to the analysis of human plasma from a clinical trial of IF. In this longitudinal study employing 8-weeks IF, we identified significant abundance differences induced by the IF intervention, including increased apolipoprotein A4 (APOA4) and decreased apolipoprotein C2 (APOC2) and C3 (APOC3). These changes correlated with a significant decrease in plasma triglycerides after the IF intervention. Given that these proteins have a role in regulating apolipoprotein particle metabolism, we propose that IF had a positive effect on lipid metabolism through modulation of HDL particle size and function. In addition, we applied a novel human protein variant database to detect common protein variants across the participants. We show that consistent detection of clinically relevant peptides derived from both alleles of many proteins is possible, including some that are associated with human metabolic phenotypes. Together, these findings illustrate the power of accessible workflows for proteomics analysis of clinical samples to yield significant biological insight.
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Apolipoproteína C-III/sangue , Apolipoproteína C-II/sangue , Apolipoproteínas A/sangue , Jejum/sangue , Metabolismo dos Lipídeos/genética , Proteômica/métodos , Adulto , Idoso , Apolipoproteína C-II/genética , Apolipoproteína C-III/genética , Apolipoproteínas A/genética , Cromatografia Líquida , Bases de Dados de Proteínas , Feminino , Expressão Gênica , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/genética , Estudos Longitudinais , Pessoa de Meia-Idade , Tamanho da Partícula , Impressão Tridimensional/instrumentação , Proteômica/instrumentação , Extração em Fase Sólida , Manejo de Espécimes/métodos , Espectrometria de Massas em Tandem , Triglicerídeos/sangueRESUMO
Intraduodenal infusion of lipid or protein potently reduces subsequent energy intake. There is evidence that the underlying mechanisms differ significantly between the two nutrients. While intraduodenal lipid stimulates glucagon-like peptide-1 and CCK much more than protein, the release of insulin and glucagon is substantially greater in response to protein. Ghrelin and PYY are both involved in short-term regulation, while leptin is a long-term regulator, of energy balance; the acute effects of nutrients on leptin release are unclear. We investigated the comparative effects of intraduodenal lipid and protein on plasma ghrelin, PYY, and leptin concentrations. Thirteen lean, young men received 90-min intraduodenal infusions of protein (whey hydrolysate) or lipid (long-chain triglyceride emulsion) at a rate of 3 kcal/min, or saline control, on three separate days. Blood samples were collected at baseline and regularly during infusions. Both lipid and protein potently suppressed plasma ghrelin compared with control (both P < 0.001), with no difference between them. While both lipid and protein stimulated plasma PYY (P < 0.001), the effect of lipid was substantially greater than that of protein (P < 0.001). Neither intraduodenal lipid nor protein affected plasma leptin. In conclusion, intraduodenal lipid and protein have discrepant effects on the release of PYY, but not ghrelin. When considered with our previous findings, it appears that, with the exception of ghrelin, the energy intake-suppressant effects of lipid and protein are mediated by different mechanisms.
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Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Duodeno/efeitos dos fármacos , Grelina/sangue , Leptina/sangue , Proteínas do Leite/administração & dosagem , Peptídeo YY/sangue , Hidrolisados de Proteína/administração & dosagem , Triglicerídeos/administração & dosagem , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Duodeno/metabolismo , Ingestão de Alimentos , Metabolismo Energético , Voluntários Saudáveis , Humanos , Masculino , Período Pós-Prandial , Fatores de Tempo , Proteínas do Soro do Leite , Adulto JovemRESUMO
Protein-rich supplements are used widely for the management of malnutrition in young and older people. Protein is the most satiating of the macronutrients in young. It is not known how the effects of oral protein ingestion on energy intake, appetite, and gastric emptying are modified by age. The aim of the study was to determine the suppression of energy intake by protein compared with control and underlying gastric-emptying and appetite responses of oral whey protein drinks in eight healthy older men (69-80 yr) compared with eight young male controls (18-34 yr). Subjects were studied on three occasions to determine the effects of protein loads of 30 g/120 kcal and 70 g/280 kcal compared with a flavored water control-drink (0 g whey protein) on energy intake (ad libitum buffet-style meal), and gastric emptying (three-dimensional-ultrasonography) and appetite (0-180 min) in a randomized, double-blind, cross-over design. Energy intake was suppressed by the protein compared with control (P = 0.034). Suppression of energy intake by protein was less in older men (1 ± 5%) than in young controls (15 ± 2%; P = 0.008). Cumulative energy intake (meal+drink) on the protein drink days compared with the control day increased more in older (18 ± 6%) men than young (1 ± 3%) controls (P = 0.008). Gastric emptying of all three drinks was slower in older men (50% gastric-emptying time: 68 ± 5 min) than young controls (36 ± 5 min; P = 0.007). Appetite decreased in young, while it increased in older (P < 0.05). In summary, despite having slower gastric emptying, elderly men exhibited blunted protein-induced suppression of energy intake by whey protein compared with young controls, so that in the elderly men, protein ingestion increased overall energy intake more than in the young men.
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Envelhecimento , Ingestão de Energia/efeitos dos fármacos , Proteínas do Soro do Leite/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Método Duplo-Cego , Ingestão de Energia/fisiologia , Esvaziamento Gástrico/efeitos dos fármacos , Humanos , Masculino , Proteínas do Soro do Leite/administração & dosagem , Adulto JovemRESUMO
Growth differentiation factor 15 (GDF15) increases with acute fast in animals, and high GDF15 reduces food intake in rodents. We explored whether GDF15 was altered following intermittent fasting (IF) versus caloric restriction (CR), and associations with energy intake. Females with obesity received all foods at 70% (IF70 and CR70) or 100% of energy requirements for 8 weeks. IF ate 2-9% less than provided on refeeding days, resulting in greater weight losses. GDF15 was increased 5% more in IF70 versus CR70, but not associated with energy intake. This rise in GDF15 is unlikely to explain restriction of energy intake during IF.
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Jejum Intermitente , Sobrepeso , Animais , Feminino , Fator 15 de Diferenciação de Crescimento , Jejum , Obesidade , Ingestão de Energia , Restrição Calórica , Ingestão de AlimentosRESUMO
Preclinical data show that autophagy delays age-related disease. It has been postulated that age-related disease is-at least in part-caused by an age-related decline in autophagy. However, autophagic flux has never been measured in humans across a spectrum of aging in a physiologically relevant context. To address this critical gap in knowledge, the objective of this cross-sectional observational study was to measure basal autophagic flux in whole blood taken from people at elevated risk of developing type 2 diabetes and correlate it with chronological age. During this study, 119 people were recruited and five people were excluded during sample analysis such that 114 people were included in the final analysis. Basal autophagic flux measured in blood and correlations with parameters such as age, body weight, fat mass, AUSDRISK score, blood pressure, glycated hemoglobin HbA1c, blood glucose and insulin, blood lipids, high-sensitivity C-reactive protein, plasma protein carbonylation, and plasma ß-hexosaminidase activity were analysed. Despite general consensus in the literature that autophagy decreases with age, we found that basal autophagic flux increased with age in this human cohort. This is the first study to report measurement of basal autophagic flux in a human cohort and its correlation with age. This increase in basal autophagy could represent a stress response to age-related damage. These data are significant not only for their novelty but also because they will inform future clinical studies and show that measurement of basal autophagic flux in a human cohort is feasible.
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Diabetes Mellitus Tipo 2 , Humanos , Estudos Transversais , Autofagia , GlicemiaRESUMO
AIM: This qualitative study aimed to explore the experiences of participants who were enrolled in 6-month controlled weight loss interventions with 2-month follow-up to better understand the process of behaviour change and maintenance. METHODS: Fifteen participants who completed or dropped out from either a daily energy restriction or intermittent fasting group were recruited using maximum variation purposive sampling. In-depth, semi-structured interviews were conducted at the 2-month follow-up phase. All interviews were transcribed and analysed using thematic analysis, guided by behaviour change models including transtheoretical model, social cognitive theory and integrated model of change. RESULTS: Participants following both diets showed similar behaviour change patterns. Their first motivations were mostly external and relied on 'accountability' to adhere to the diet when initiating the dietary changes. Participants highlighted the importance of frequent reviews and monitoring in assisting their adherence. This feedback system promoted the development of self-efficacy and internalised motivation to encourage an 'ownership'. Participants who transitioned successfully from relying on accountability to take 'ownership' of the intervention were more capable of tackling challenges and tailoring their diet to form a new routine for long-term maintenance. CONCLUSION: External motivations were key to initiate while internalised motivations were more important to sustain the behaviour change. Health professionals can assist this process through routine monitoring and feedback processes in clinical practice.
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OBJECTIVE: Time-restricted eating (TRE) restores circadian rhythms in mice, but the evidence to support this in humans is limited. The objective of this study was to investigate the effects of TRE on 24-hour profiles of plasma metabolites, glucoregulatory hormones, and the subcutaneous adipose tissue (SAT) transcriptome in humans. METHODS: Men (n = 15, age = 63 [4] years, BMI 30.5 [2.4] kg/m2 ) were recruited. A 35-hour metabolic ward stay was conducted at baseline and after 8 weeks of 10-hour TRE. Assessment included 24-hour profiles of plasma glucose, nonesterified fatty acid (NEFA), triglyceride, glucoregulatory hormones, and the SAT transcriptome. Dim light melatonin onset and cortisol area under the curve were calculated. RESULTS: TRE did not alter dim light melatonin onset but reduced morning cortisol area under the curve. TRE altered 24-hour profiles of insulin, NEFA, triglyceride, and glucose-dependent insulinotropic peptide and increased transcripts of circadian locomotor output cycles protein kaput (CLOCK) and nuclear receptor subfamily 1 group D member 2 (NR1D2) and decreased period circadian regulator 1 (PER1) and nuclear receptor subfamily 1 group D member 1 (NR1D1) at 12:00 am. The rhythmicity of 450 genes was altered by TRE, which enriched in transcripts for transcription corepressor activity, DNA-binding transcription factor binding, regulation of chromatin organization, and small GTPase binding pathways. Weighted gene coexpression network analysis revealed eigengenes that were correlated with BMI, insulin, and NEFA. CONCLUSIONS: TRE restored 24-hour profiles in hormones, metabolites, and genes controlling transcriptional regulation in SAT, which could underpin its metabolic health benefit.
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Tecido Adiposo , Ritmo Circadiano , Jejum Intermitente , Obesidade , Humanos , Masculino , Pessoa de Meia-Idade , Ritmo Circadiano/genética , Ácidos Graxos não Esterificados , Hidrocortisona , Insulinas , Melatonina , Obesidade/genética , Transcriptoma , IdosoRESUMO
Intermittent fasting appears an equivalent alternative to calorie restriction (CR) to improve health in humans. However, few trials have considered applying meal timing during the 'fasting' day, which may be a limitation. We developed a novel intermittent fasting plus early time-restricted eating (iTRE) approach. Adults (N = 209, 58 ± 10 years, 34.8 ± 4.7 kg m-2) at increased risk of developing type 2 diabetes were randomized to one of three groups (2:2:1): iTRE (30% energy requirements between 0800 and 1200 hours and followed by a 20-h fasting period on three nonconsecutive days per week, and ad libitum eating on other days); CR (70% of energy requirements daily, without time prescription); or standard care (weight loss booklet). This open-label, parallel group, three-arm randomized controlled trial provided nutritional support to participants in the iTRE and CR arms for 6 months, with an additional 12-month follow-up. The primary outcome was change in glucose area under the curve in response to a mixed-meal tolerance test at month 6 in iTRE versus CR. Glucose tolerance was improved to a greater extent in iTRE compared with CR (-10.10 (95% confidence interval -14.08, -6.11) versus -3.57 (95% confidence interval -7.72, 0.57) mg dl-1 min-1; P = 0.03) at month 6, but these differences were lost at month 18. Adverse events were transient and generally mild. Reports of fatigue were higher in iTRE versus CR and standard care, whereas reports of constipation and headache were higher in iTRE and CR versus standard care. In conclusion, incorporating advice for meal timing with prolonged fasting led to greater improvements in postprandial glucose metabolism in adults at increased risk of developing type 2 diabetes. ClinicalTrials.gov identifier NCT03689608 .
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Restrição Calórica , Diabetes Mellitus Tipo 2 , Humanos , Adulto , Jejum Intermitente , Jejum , GlucoseRESUMO
BACKGROUND: Autophagy is a cellular process that cleanses cells and is particularly important during ageing. Autophagy has been extensively studied in vitro and in animal models and is known to be sensitive to nutrition. However, human data are limited because autophagic flux (autophagic degradative activity) has been challenging to measure in humans. This protocol paper describes the Break-Fast study, in which autophagic flux will be measured using a recently developed blood test, before and after ingestion of whey protein. This aims to determine whether an acute nutritional intervention can change autophagy in humans. METHODS: A minimum of forty healthy participants (both male and female) aged 20-50 years, BMI 18.5-29.9 kg/m2 will be recruited into this single arm pre-post study. Participants will visit the clinic after an overnight fast for a first blood collection after which they will consume a whey protein-rich drink. A second blood collection will be performed 60 minutes after consumption of the drink. The primary outcome is the change in autophagic flux at 60 minutes post drink. Secondary outcomes include changes in blood glucose, autophagy-related proteins and mRNA, plasma hormones (e.g. insulin, C-peptide, adiponectin, GLP-1, GIP, ghrelin), cytokines, amino acids and lipids, protein synthesis, and correlation between molecular cell damage and autophagic flux. DISCUSSION: This study will provide information about whether autophagy responds to nutrients in humans, and if nutritional strategies could be used to treat or prevent autophagy-related diseases such as Alzheimer's disease or cancer. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), anzctr.org.au ACTRN12621001029886. Registered on 5 August 2021.
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OBJECTIVES: Intermittent fasting (IF) activates autophagy in cardiac muscle and pancreatic islets. We examined the effect of IF on markers of autophagy in liver and skeletal muscle in mice and in humans. METHODS: Ten-wk-old C57 BL/6 J male mice were ad libitum (AL) fed a high-fat diet (HFD) or chow diet for 8 wk, before randomization to AL or IF (24-h fast, 3 non-consecutive days per week) for 8 wk (8-16 per group). Tissue was collected in the fed or 22-h fasted state. Fifty women (51 ± 2 y, 31.8 ± 4.3 kg/m2) were randomly assigned to one of two IF protocols (24-hfast, 3 non-consecutive days per week) and fed at 70% (IF70) or 100% (IF100) of energy requirements for 8 wk. Vastus lateralis muscle was collected at 0800 after 12- and 24-h fasts. Microtubule-associated protein light chain 1 (Map1 lc3 b), Beclin1 (Becn1), Sequestosome 1 (Sqstm1/p62), and Lysosomal associated membrane protein 2 (Lamp2) were assessed by quantitative polymerase chain reaction and LC3, BECLIN1 and LAMP1 protein content by immunoblotting. RESULTS: Fasting increased hepatic LC3 I protein and Map1 lc3 b mRNA levels in IF mice fed chow or HFD. LAMP1 protein and Beclin1 mRNA levels in liver were also increased by fasting, but only in chow-fed mice. IF did not activate markers of autophagy in mouse muscle. In humans, a 24-h fast increased SQSTM1. BECLIN1, SQSTM1 and LAMP2 mRNA levels were decreased in IF70 after a 12-h overnight fast . CONCLUSION: Markers of autophagy in liver, but not in muscle, were elevated in response to IF in mice. In humans, autophagy markers in muscle were reduced, likely in response to weight loss.
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Jejum , Fígado , Músculo Esquelético , Animais , Autofagia , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Proteína Beclina-1/farmacologia , Biomarcadores , Jejum/metabolismo , Feminino , Humanos , Fígado/citologia , Fígado/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , RNA Mensageiro , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismoRESUMO
OBJECTIVE: We sought to examine the effects of 8 wk of time-restricted eating (TRE) on glucose metabolism and the adipose tissue transcriptome during a metabolic ward stay in men with obesity. METHODS: In a single-arm, pre-post trial, 15 men (ages 63 ± 4 y, body mass index = 30.5 ± 2.4 kg/m2, waist circumference = 113 ± 4 cm) with obesity but no history of diabetes were enrolled and underwent 2 wk of baseline monitoring before they were instructed to eat their regular diets within a contiguous 10-h time frame each day for 8 wk. Metabolic testing was performed at baseline and week 8 during a 35-h metabolic ward stay, during which all food intake was strictly timed and controlled. Identical meal-tolerance tests were performed at breakfast and dinner. Blood glucose, glucoregulatory hormones, and subjective appetite score were measured. Subcutaneous adipose tissue biopsies were performed and the transcriptome was assessed. RESULTS: The primary outcome, plasma glucose area under the curve, was altered by TRE, being unchanged at breakfast but increased at dinner. However, TRE reduced fasting glucose, glycated hemoglobin, body weight, and body fat, and increased glucose-dependent insulinotropic peptide area under the curve at dinner. In subcutaneous adipose tissue, 117 genes were up-regulated and 202 genes down-regulated by TRE. Pathway analysis revealed down-regulation of genes involved in proteasome function and mitochondrial regulation. CONCLUSIONS: TRE had a net effect of reducing glycemia and dampening energy-consuming pathways in adipose tissue.
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Jejum , Controle Glicêmico , Tecido Adiposo/metabolismo , Idoso , Glicemia/metabolismo , Peso Corporal , Jejum/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismoRESUMO
Human trials that compare intermittent fasting (IF) to calorie restriction (CR) with psychological, behavioral and cognition outcomes are limited. We hypothesized that there would be no difference between CR and IF on perceived eating behaviors, mood, sleep quality, quality of life (QOL) and cognition in women with overweight and obesity. In this prespecified secondary analysis of an open-label, single center, parallel assignment, randomized controlled trial, healthy women with overweight or obesity (N = 46, mean [SD] age 50 [9] years, BMI 32.9 [4.4] kg/m2), without a diagnosed eating disorder and who were randomized into 2 weight loss groups (prescribed 70% of calculated energy requirements as IF or CR) were included. Measurements were assessed in both IF and CR groups following a 12-hour overnight fast during baseline and week 8 and additionally following a 24-hour fast in the IF group only at week 8. We observed that IF produced greater weight and body fat loss than CR (P < .001). We did not detect any statistical difference between groups for the change in dietary restraint, disinhibition, hunger, mood, sleep quality, and QOL. An increase in cognitive performance was found in both IF (P = .036) and CR (P = .006) groups in one of the cognitive tasks, but there was no statistical difference between groups. Perceived eating behaviors, mood, sleep quality and cognitive performance were not changed by an acute 24-hour fast within the IF group (all P > .05). IF may be a viable alternative to CR for weight loss, in the short-term, without adversely impacting eating behaviors, mood, sleep quality, QOL or cognition in healthy women with overweight or obesity. However, larger and long term trials are required.
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Afeto , Restrição Calórica , Cognição , Jejum , Comportamento Alimentar , Obesidade/psicologia , Qualidade do Sono , Atividades Cotidianas , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Sobrepeso , Qualidade de VidaRESUMO
Time-restricted feeding (TRF) initiated early during the dark phase prevents the metabolic consequences of a high-fat diet in rodent models. However, the metabolic consequences of delaying the initiation of TRF, akin to breakfast skipping in humans, is unclear. We assigned 8-week-old male C57BL/6J mice (n = 192) to chow or high-fat diet ad libitum (AL) for 4 weeks, before randomization to continue AL or 10 h of TRF, initiated at lights off (TRFe) or 4-h after lights off (TRFd) for a further 8 weeks. Oral glucose tolerance tests (1 g/kg), metabolic monitoring and body composition by echoMRI were performed, and tissues were collected at six time points. TRF reduced weight and fat mass vs AL, with a greater reduction in TRFe vs TRFd. TRF improved glucose tolerance and protected mice from high-fat diet-induced hepatosteatosis vs AL, with no difference between TRFe and TRFd. TRF increased the amplitude of Bmal1, Cry1, Per2, Nampt, and Nocturnin mRNA levels in liver. A phase delay in Bmal1, Cry1, Per2, Reverbα, Nampt, NAD, Sirt1, and Nocturnin was observed in TRFd. Thus, delaying TRF limited the weight benefit and induced a phase delay in the hepatic clock, but improved metabolic health. Allowing more flexibility in when TRF is initiated may increase the translational potential of this dietary approach in humans.
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Ritmo Circadiano , Jejum , Fígado/metabolismo , Obesidade/prevenção & controle , Animais , Dieta Hiperlipídica , Fígado Gorduroso/prevenção & controle , Glucose/metabolismo , Teste de Tolerância a Glucose , Masculino , Camundongos Endogâmicos C57BL , NAD/metabolismo , Distribuição AleatóriaRESUMO
CONTEXT: Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR). OBJECTIVE: In a secondary analysis of a randomized controlled trial, we compared the effects of intermittent fasting (IF) and CR on markers of lipid metabolism in muscle. DESIGN: Seventy-six women (body mass index, 25-40 kg/m2) were randomly assigned to 1 of 3 diets for 8 weeks and provided foods at 70% (CR70 and IF70) or 100% (IF100) of energy requirements. IF groups ate breakfast prior to a 24-hour fast on 3 nonconsecutive days per week. On nonfasting days, IF70 ate at 100% and IF100 ate at 145% of energy requirements to achieve the prescribed target. Weight, body composition, insulin sensitivity by clamp, nonesterified fatty acids (NEFAs), ß-hydroxybutyrate (BHB), and markers of lipid metabolism and oxidative stress in muscle by quantitative polymerase chain reaction were measured at baseline and week 8 following a 12-hour overnight fast (all groups) and 24-hour fast (IF groups). RESULTS: IF70 resulted in greater weight and fat loss and reduced NEFAs vs CR70 and IF100 after an overnight fast. IF70 and IF100 induced a greater reduction only in mRNA levels of antioxidant enzymes glutathione peroxidase 1 (GPX1), superoxide dismutase 1, soluble (SOD1), and SOD2 vs CR70. Fasting for 24 hours increased NEFAs and BHB in IF groups, but impaired insulin sensitivity and increased PLIN5 mRNA levels. CONCLUSIONS: In comparison to CR, IF did not increase markers of lipid metabolism in muscle, but reduced expression of antioxidant enzymes. However, fasting-induced insulin resistance was detected, alongside increased PLIN5 expression, potentially reflecting transient lipid storage.
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Jejum/fisiologia , Metabolismo dos Lipídeos/fisiologia , Músculo Esquelético/metabolismo , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/metabolismo , Restrição Calórica/métodos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/química , Obesidade/dietoterapia , Obesidade/metabolismo , Sobrepeso/dietoterapia , Sobrepeso/metabolismo , Oxirredução , Redução de Peso/fisiologiaRESUMO
OBJECTIVE: This study aimed to examine the effects of intermittent fasting (IF) on mRNA levels of peripheral clock genes in skeletal muscle and subcutaneous adipose tissue (SAT) in women with obesity. METHODS: Women were randomized to one of two IF protocols and provided with all foods at 100% or 70% of calculated weekly energy requirements for 8 weeks. Breakfast was consumed before a 24-hour fast, which was initiated on three nonconsecutive days per week. Muscle and SAT biopsies were performed at 8 am after an overnight fast at baseline and at week 8 on a refed day and again following a 24-hour fast at week 8 for analysis of the mRNA levels of key genes involved in circadian regulation. RESULTS: A group-by-time interaction was observed in Per2 in muscle (F = 3.497, P = 0.044) and SAT (F = 6.686, P = 0.008), but significance was lost upon post hoc adjustment. A time effect was observed in Rorα in muscle, which was decreased by refeeding in both groups (F = 7.225, P = 0.003). CONCLUSIONS: There was no universal effect of IF to alter peripheral clocks, which may be partly because of the alignment of the fasting/feeding cycle with the biological clock. Optimizing intermittent fasting protocols could be important to prevent circadian misalignment in humans.
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Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Jejum/fisiologia , Músculo Esquelético/metabolismo , Obesidade/genética , Gordura Subcutânea/metabolismo , Adulto , Idoso , Animais , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/terapiaRESUMO
BACKGROUND: Intermittent fasting (IF) is proposed as a viable alternative to moderate calorie restriction (CR) for weight loss and metabolic health, but few long term randomized trials have been conducted. This protocol paper describes the rationale and detailed protocol for DIRECT study (Daily versus Intermittent Restriction of Energy: Controlled Trial to Reduce Diabetes Risk), comparing long term effectiveness of IF versus CR on metabolic health in individuals who are at increased risk of developing type 2 diabetes. METHODS: Anticipated 260 non-diabetic men and women aged 35-75 years, BMI 25-50 kg/m2 with score ≥12 on the Australian Diabetes Risk (AUSDRISK) calculator will be recruited into this open-label, multi-arm, parallel group sequential randomized controlled trial. Participants will be randomized to one of three groups for 18 months: IF (30% of energy needs on fast days), CR (70% of energy needs daily), or standard care (SC) group. All participants will visit the clinic fortnightly for weight assessments during active intervention phase (6 months), followed by a 12-month follow-up phase. IF and CR groups will receive further diet counselling by dietitian. Two primary outcomes are the changes in glycated haemoglobin (HbA1c) and postprandial glucose area under the curve (AUC) at week 24 post-randomization. Secondary outcomes include changes in weight, body composition via dual-energy X-ray absorptiometry, gastro-intestinal hormones, cardiovascular risk factors, and dietary record by a smartphone-based application. DISCUSSION: This study will provide substantial evidence as to whether IF is an effective nutrition intervention for glycaemic control in a population at risk of developing type 2 diabetes.
Assuntos
Restrição Calórica/métodos , Diabetes Mellitus Tipo 2/prevenção & controle , Jejum , Controle Glicêmico/métodos , Absorciometria de Fóton , Adulto , Idoso , Área Sob a Curva , Austrália , Glicemia/metabolismo , Composição Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: This study compared the effects of daily calorie restriction (DR) versus intermittent fasting (IF) on markers of inflammation and extracellular matrix deposition in adipose tissue and skeletal muscle in a controlled feeding trial in women with overweight or obesity. METHODS: Women (Nâ¯=â¯76) were randomised to one of three diets and provided with all foods at 100% (IF100) or 70% (IF70 and DR70) of calculated energy requirements for 8â¯weeks. IF groups ate breakfast prior to fasting for 24-h on 3 non-consecutive days/week. Weight, body composition, serum non-esterified fatty acids (NEFA), tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), M1- and M2-macrophage markers by qPCR and immunohistochemistry in adipose tissue and skeletal muscle were measured following a 12-h overnight fast (fed day, all groups) and a 24-h fast (IF groups only). RESULTS: IF70 resulted in greater weight and fat losses and reductions in serum NEFA versus DR70 and IF100 (Pâ¯<â¯0.05) after fed days. Markers of inflammation in serum (TNFα, IL6 and IL10), subcutaneous adipose tissue and skeletal muscle (CD68, CD40 and CD163) were unchanged by DR or IF after fed days. After fasting, NEFA, M1-macrophages (CD40+) in adipose tissue, and M2-macrophages (CD163+) in muscle were increased in IF70 and IF100 (all Pâ¯<â¯0.05) and the changes in NEFA and mRNA of pan-macrophage marker CD68 in adipose tissue were positively correlated (râ¯=â¯0.56, Pâ¯=â¯0.002). CONCLUSIONS: Unlike caloric restriction, IF transiently elevated markers of macrophage infiltration in adipose tissue and skeletal muscle, possibly in response to marked increases in adipose tissue lipolysis.
Assuntos
Biomarcadores/metabolismo , Sobrepeso/dietoterapia , Paniculite/diagnóstico , Adulto , Idoso , Restrição Calórica , Citocinas/metabolismo , Jejum/sangue , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Macrófagos/fisiologia , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Obesidade/sangue , Obesidade/dietoterapia , Sobrepeso/sangue , Gordura Subcutânea/metabolismoRESUMO
OBJECTIVE: Intermittent fasting (IF) may limit metabolic adaptations that reduce energy expenditure, potentially by stimulating white adipose tissue (WAT) browning. The aim of this study was to examine the effects of 8 wk of IF on energy metabolism and markers of WAT browning in lean and diet-induced obese mice and in women who were overweight or obese. METHODS: Male C57 BL/6 J mice were fed chow or a high-fat diet (HFD; 43%) for 8 wk before undergoing IF (3 non-consecutive d/wk) for an additional 8 wk. Food intake, energy expenditure, and inguinal and gonadal fat pads were collected in fed or fasted conditions (22 h, IF mice only). Subcutaneous adipose tissue (SAT) was also collected at baseline, and after 8 wk of IF (in the fed state, and after a 24-h fast), in women with overweight or obesity. Uncoupling protein 1 (UCP1) was assessed by quantitative real-time polymerase chain reaction (mice and humans) and immunohistochemistry (mice). RESULTS: IF reduced body weight and energy intake in HFD fed mice and reduced gonadal and inguinal fat pad weights in both diet groups. IF increased energy expenditure, meal number, Ucp1 mRNA levels in inguinal and gonadal fat depots, and UCP1 protein in inguinal fat in both diet groups on fed days. In women, IF reduced body weight and fat mass, but did not alter UCP1mRNA levels. CONCLUSIONS: IF increased energy expenditure and promoted WAT browning in mice but did not alter UCP1 mRNA levels in SAT in women.