RESUMO
BACKGROUND AND AIMS: Excess energy intake can lead to metabolic dysfunction-associated steatotic liver disease (MASLD), but the relationship between dietary carbohydrate intake and liver fat content remains unclear. This study aimed to examine the associations between types and sources of dietary carbohydrates and liver fat content. METHODS: UK Biobank participants with no pre-existing diabetes, liver disease or cardiovascular disease reported dietary intake of types and sources of carbohydrates (total carbohydrates, free sugars, non-free sugars, starch from whole grains, starch from refined grains, and fibre) on at least two 24-h dietary assessments. In cross-sectional analyses, (n = 22,973), odds ratios (OR) of high liver fat content (defined as a score of ≥ 36 in the hepatic steatosis index) by quintiles of carbohydrate intakes were estimated using multivariable logistic regression models. In prospective analyses, a second sample (n = 9268) had liver proton density fat fraction (PDFF) measured by magnetic resonance imaging (2014-2020). Multivariable linear regression models estimated geometric means of PDFF (%) by quintiles of carbohydrate intakes. Models were adjusted for demographic and lifestyle confounders, including total energy intake. RESULTS: In the cross-sectional analyses, 6894 cases of high liver fat content were identified. Inverse associations between intakes of fibre (OR of highest vs. lowest quintile 0.46 [95% CI: 0.41-0.52]), non-free sugars (0.63 [0.57-0.70]) and starch from whole grains (0.52 [0.47-0.57]) with liver fat were observed. There were positive associations between starch from refined grains and liver fat (1.33 [1.21-1.46]), but no association with free sugars (p=0.61). In prospective analyses, inverse associations with PDFF (%) were observed for intakes of fibre (- 0.48 geometric mean difference between highest and lowest quintile of intake [- 0.60 to - 0.35]), non-free sugars (- 0.37 [- 0.49 to - 0.25]) and starch from whole grains (- 0.31 [- 0.42 to - 0.19]). Free sugars, but not starch from refined grains, were positively associated with PDFF (0.17 [0.05 to 0.28]). CONCLUSION: This study suggests that different carbohydrate types and sources have varying associations with liver fat, which may be important for MASLD prevention. Non-free sugars, fibre, and starch from whole grains could be protective, while associations with free sugars and starch from refined grains are less clear.
Assuntos
Carboidratos da Dieta , Hepatopatias , Humanos , Dieta/efeitos adversos , Estudos Prospectivos , Estudos Transversais , Bancos de Espécimes Biológicos , Amido , Açúcares , Reino UnidoRESUMO
PURPOSE OF REVIEW: Prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing, and as pharmacological treatment does not exist, lifestyle interventions (i.e. diet and exercise) represent the cornerstone management and treatment strategy. Although the available data clearly demonstrate that changes in lifestyle influence intrahepatic triglyceride (IHTG) content, the mechanisms through which this is achieved are seldom investigated. Here, we review recent evidence demonstrating the influence of lifestyle interventions on hepatic fatty acid metabolism and IHTG content. RECENT FINDINGS: Diet and exercise influence IHTG content through various, and often interrelated factors. These include alterations in whole-body and tissue-specific insulin sensitivity, which may influence the flux of fatty acid and lipogenic substrates to the liver, and changes in intrahepatic fatty acid synthesis and partitioning. Notably, there are only a few studies that have investigated intrahepatic fatty acid metabolism in vivo in humans before and after an intervention. SUMMARY: Lifestyle interventions represent an effective means of influencing hepatic fatty acid metabolism. IHTG content is decreased without weight-loss either through exercise or by changing the macronutrient composition of the diet, although what the optimal macronutrient composition is to achieve this has yet to be defined.
Assuntos
Ácidos Graxos/metabolismo , Estilo de Vida , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Dietoterapia/métodos , Gorduras na Dieta/metabolismo , Ingestão de Alimentos/fisiologia , Exercício Físico/fisiologia , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/metabolismo , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking. OBJECTIVE: The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses. METHODS: In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m2), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons. RESULTS: Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%; P ≤ 0.040), LECT2 at 3 d (17%) and 7 d (32%; P ≤ 0.004), and fetuin-A at 7 d (7%; P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021). CONCLUSIONS: Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145.
Assuntos
Dieta Hiperlipídica , Ingestão de Energia , Fatores de Crescimento de Fibroblastos/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , alfa-2-Glicoproteína-HS/metabolismo , Adulto , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Adulto Jovem , alfa-2-Glicoproteína-HS/genéticaRESUMO
Obesity is undoubtedly caused by a chronic positive energy balance. However, the early metabolic and hormonal responses to overeating are poorly described. This study determined glycaemic control and selected gut hormone responses to nutrient intake before and after 7 d of high-fat overfeeding. Nine healthy individuals (five males, four females) performed a mixed meal tolerance test (MTT) before and after consuming a high-fat (65 %), high-energy (+50 %) diet for 7 d. Measurements of plasma glucose, NEFA, acylated ghrelin, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and serum insulin were taken before (fasting) and at 30-min intervals throughout the 180-min MTT (postprandial). Body mass increased by 0·79 (sem 0·14) kg after high-fat overfeeding (P<0·0001), and BMI increased by 0·27 (sem 0·05) kg/m2 (P=0·002). High-fat overfeeding also resulted in an 11·6 % increase in postprandial glucose AUC (P=0·007) and a 25·9 % increase in postprandial insulin AUC (P=0·005). Acylated ghrelin, GLP-1 and GIP responses to the MTT were all unaffected by the high-fat, high-energy diet. These findings demonstrate that even brief periods of overeating are sufficient to disrupt glycaemic control. However, as the postprandial orexigenic (ghrelin) and anorexigenic/insulintropic (GLP-1 and GIP) hormone responses were unaffected by the diet intervention, it appears that these hormones are resistant to short-term changes in energy balance, and that they do not play a role in the rapid reduction in glycaemic control.
Assuntos
Glicemia/metabolismo , Gorduras na Dieta/administração & dosagem , Trato Gastrointestinal/metabolismo , Refeições , Área Sob a Curva , Peso Corporal , Relação Dose-Resposta a Droga , Esquema de Medicação , Exercício Físico , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Glucose/metabolismo , Glucose/farmacocinética , Humanos , Insulina/metabolismo , Insulina/farmacocinética , Masculino , Adulto JovemRESUMO
OBJECTIVE: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR, defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. DESIGN: Cross-sectional study in men and women across a range of adiposity. METHODS: Medication-free participants (n = 177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. RESULTS: Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. CONCLUSIONS: Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF, and these pathways should be considered for therapeutic targeting.
Assuntos
Jejum , Resistência à Insulina , Fígado , Humanos , Masculino , Feminino , Resistência à Insulina/fisiologia , Adulto , Fígado/metabolismo , Estudos Transversais , Jejum/metabolismo , Pessoa de Meia-Idade , Gluconeogênese/fisiologia , Lipogênese/fisiologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Glicemia/metabolismo , Triglicerídeos/metabolismo , Triglicerídeos/sangue , Hiperinsulinismo/metabolismoRESUMO
BACKGROUND: It has been suggested that dietary polyunsaturated fatty acids (PUFA) are partitioned into oxidation pathways to a greater extent than dietary saturated fatty acids (SFA). Whilst this has been demonstrated in animal models, evidence in humans is lacking. The potential divergence in the metabolic fate of these dietary fatty acids (FA) may explain some of the reported differences in ectopic fat deposition with SFA and PUFA enriched diets. AIMS: To compare whole-body oxidation of dietary palmitate and linoleate after consumption of a single test meal. METHODS: In a randomized, crossover design 24 healthy volunteers (12 males and 12 females, matched for age and BMI) underwent two study days separated by 2-week washout period. During each study day participants consumed a standardized test meal which contained [U13C]palmitate or [U13C]linoleate. Blood and breath samples were collected over the 6 h postprandial period and the 13C enrichment in breath CO2 samples and plasma lipid fractions was determined. RESULTS: Appearance of 13C in expired CO2 was significantly (p < 0.05) increased after consumption of the meal containing [U13C]linoleate compared to the meal containing [U13C]palmitate. The recovery of tracer was 8.9 ± 1.2% [U13C]linoleate vs. 5.6 ± 0.4% [U13C]palmitate (p < 0.05). The incorporation of 13C from [U13C]palmitate was greater in plasma triacylglycerol and non-esterified fatty acids than [U13C]linoleate, whereas the incorporation of 13C from [U13C]linoleate was greater than [U13C]palmitate in plasma phospholipids. Although 13CO2 was significantly (p < 0.05) higher in females compared to males after consumption of [U13C]palmitate, there was no difference in 13CO2 between sexes after consumption of [U13C]linoleate. CONCLUSIONS: We demonstrate that whole-body oxidation of dietary linoleate is comparatively higher than that of dietary palmitate in humans following consumption of a single mixed-test meal. We found indications of sexual dimorphism for dietary palmitate but not dietary linoleate. STUDY REGISTRATION: http://www.clinicaltrials.org/ ID number NCT03587753.
Assuntos
Gorduras na Dieta/farmacologia , Ácido Linoleico/farmacologia , Refeições/fisiologia , Oxirredução/efeitos dos fármacos , Palmitatos/farmacologia , Adolescente , Adulto , Idoso , Testes Respiratórios , Dióxido de Carbono/análise , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Adulto JovemRESUMO
BACKGROUND: The fatty acid (FA) composition of blood can be used as an objective biomarker of dietary FA intake. It remains unclear how the nutritional state influences the FA composition of plasma lipid fractions, and thus their usefulness as biomarkers in a non-fasted state. OBJECTIVES: To investigate the associations between palmitate, oleate and linoleate in plasma lipid fractions and self-reported dietary FA intake, and assess the influence of meal consumption on the relative abundance of these FA in plasma lipid fractions (i.e. triglyceride [TG], phospholipids [PLs] and cholesterol esters [CEs]). DESIGN: Analysis was performed in plasma samples collected from 49 (34 males and 15 females) participants aged 26-57 years with a body mass index (BMI) between 21.6 and 34.2 kg/m2, all of whom had participated in multiple study visits, thus a pooled cohort of 98 data sets was available for analysis. A subset (n = 25) had undergone nutritional interventions and was therefore used to investigate the relationship between the FA composition of plasma lipid fractions and dietary fat intake. RESULTS: Significant (P < 0.05) positive associations were observed between dietary polyunsaturated fat and linoleate abundance in plasma CE. When investigating the influence of meal consumption on postprandial FA composition, we found plasma TG palmitate significantly (P < 0.05) decreased across the postprandial period, whereas oleate and linoleate increased. A similar pattern was observed in plasma PL, whereas linoleate abundance decreased in the plasma CE. CONCLUSION: Our data demonstrate that the FA composition of plasma CE may be the lipid fraction to utilise as an objective biomarker when investigating recent (i.e. previous weeks-months) dietary FA intakes. In addition, we show that the consumption of a high-fat meal influences the FA composition of plasma TG, PL and CE over the course of the postprandial period, and therefore, suggest that fasting blood samples should be utilised when using FA composition as a biomarker of dietary FA intake.
Assuntos
Ácidos Graxos , Lipídeos , Biomarcadores , Gorduras na Dieta , Feminino , Humanos , Masculino , TriglicerídeosRESUMO
The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.g. hypertriglyceridemia), and increased mortality rates relative to those with only NAFLD or T2D in isolation; therefore, effective treatment strategies are required. Here we review the available intervention studies that have investigated the effects of changes in lifestyle (diet and exercise/physical activity) on NAFLD in patients with both NAFLD and T2D. On the basis of the available evidence, it appears that the addition of any kind of exercise (i.e. resistance, aerobic, or high-intensity intermittent exercise) is beneficial for patients with both NAFLD and T2D. These effects appear to occur independently of changes in body weight. Hypocaloric diets leading to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and T2D, with data indicating that ~ 7-10% weight loss is required in order to observe beneficial effects. It is unclear if multidisciplinary interventions incorporating changes in both diet and physical activity levels are a more effective treatment strategy in this population than diet or exercise interventions in isolation. In conclusion, it is clear that lifestyle interventions are an effective treatment strategy in patients with both NAFLD and T2D, although further research is required to optimise these interventions and determine their scalability.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Estilo de Vida , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Peso Corporal , Dieta , Exercício Físico , Feminino , Humanos , Redução de PesoRESUMO
Non-alcoholic fatty liver disease encompasses a spectrum of conditions from hepatic steatosis through to cirrhosis; obesity is a known risk factor. The liver plays a major role in regulating fatty acid metabolism and perturbations in intrahepatic processes have potential to impact on metabolic health. It remains unclear why intra-hepatocellular fat starts to accumulate, but it likely involves an imbalance between fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver and TAG export from the liver. As man spends the majority of the day in a postprandial rather than postabsorptive state, dietary fatty acid intake should be taken into consideration when investigating why intra-hepatic fat starts to accumulate. This review will discuss the impact of the quantity and quality of dietary fatty acids on liver fat accumulation and metabolism, along with some of the potential mechanisms involved. Studies investigating the role of dietary fat in liver fat accumulation, although surprisingly limited, have clearly demonstrated that it is total energy intake, rather than fat intake per se, that is a key mediator of liver fat content; hyperenergetic diets increase liver fat whilst hypoenergetic diets decrease liver fat content irrespective of total fat content. Moreover, there is now, albeit limited evidence emerging to suggest the composition of dietary fat may also play a role in liver fat accumulation, with diets enriched in saturated fat appearing to increase liver fat content to a greater extent when compared with diets enriched in unsaturated fats.
Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado , Adulto , Feminino , Humanos , Fígado/metabolismo , Fígado/fisiologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Adulto JovemRESUMO
Background: Hepatic de novo lipogenesis (DNL) is ideally measured in very low-density lipoprotein (VLDL)-triacylglycerol (TAG). In the fasting state, the majority of plasma TAG typically represents VLDL-TAG; however, the merits of measuring DNL in total plasma TAG have not been assessed. This study aimed to assess the performance of DNL measured in VLDL-TAG (DNLVLDL-TAG) compared to that measured in total plasma TAG (DNLPlasma-TAG).Methods: Using deuterated water, newly synthesised palmitate was determined in fasting plasma VLDL-TAG and total TAG in 63 subjects taking part in multiple studies resulting in n = 123 assessments of DNL (%new palmitate of total palmitate). Subjects were split into tertiles to investigate if DNLPlasma-TAG could correctly classify subjects having 'high' (top tertile) and 'low' (bottom tertile) DNL. Repeatability was assessed in a subgroup (n = 16) with repeat visits.Results: DNLVLDL-TAG was 6.8% (IQR 3.6-10.7%) and DNLPlasma-TAG was 7.5% (IQR 4.0%-11.0%), and the correlation between the methods was rs = 0.62 (p < 0.0001). Bland-Altman plots demonstrated similar performance (mean difference 0.81%, p = 0.09); however, the agreement interval was wide (-9.6% to 11.2%). Compared to DNLVLDL-TAG, 54% of subjects with low DNL were correctly classified, whilst 66% of subjects with high DNL were correctly classified using DNLPlasma-TAG. Repeatability was acceptable (i.e. not different) at the group level, but the majority of subjects had an intra-individual variability over 25%.Conclusion: DNL in total plasma TAG performed similarly to DNL in VLDL-TAG at the group level, but there was large variability at the individual level. We suggest that plasma TAG could be useful for comparing DNL between groups.
Assuntos
Lipoproteínas VLDL/sangue , Lipoproteínas VLDL/fisiologia , Fígado/metabolismo , Triglicerídeos/sangue , Adulto , Feminino , Humanos , Lipogênese , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Triglicerídeos/fisiologiaRESUMO
OBJECTIVE: Debate continues regarding the influence of dietary fats and sugars on the risk of developing metabolic diseases, including insulin resistance and nonalcoholic fatty liver disease (NAFLD). We investigated the effect of two eucaloric diets, one enriched with saturated fat (SFA) and the other enriched with free sugars (SUGAR), on intrahepatic triacylglycerol (IHTAG) content, hepatic de novo lipogenesis (DNL), and whole-body postprandial metabolism in overweight males. RESEARCH DESIGN AND METHODS: Sixteen overweight males were randomized to consume the SFA or SUGAR diet for 4 weeks before consuming the alternate diet after a 7-week washout period. The metabolic effects of the respective diets on IHTAG content, hepatic DNL, and whole-body metabolism were investigated using imaging techniques and metabolic substrates labeled with stable-isotope tracers. RESULTS: Consumption of the SFA diet significantly increased IHTAG by mean ± SEM 39.0 ± 10.0%, while after the SUGAR diet IHTAG was virtually unchanged. Consumption of the SFA diet induced an exaggerated postprandial glucose and insulin response to a standardized test meal compared with SUGAR. Although whole-body fat oxidation, lipolysis, and DNL were similar following the two diets, consumption of the SUGAR diet resulted in significant (P < 0.05) decreases in plasma total, HDL, and non-HDL cholesterol and fasting ß-hydroxybutyrate plasma concentrations. CONCLUSIONS: Consumption of an SFA diet had a potent effect, increasing IHTAG together with exaggerating postprandial glycemia. The SUGAR diet did not influence IHTAG and induced minor metabolic changes. Our findings indicate that a diet enriched in SFA is more harmful to metabolic health than a diet enriched in free sugars.
Assuntos
Glicemia/efeitos dos fármacos , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Ácidos Graxos , Fígado/efeitos dos fármacos , Período Pós-Prandial/efeitos dos fármacos , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Dieta , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/metabolismo , Masculino , Refeições , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fatores de RiscoRESUMO
CONTEXT: The mechanisms responsible for dietary fat-induced insulin resistance of skeletal muscle and its microvasculature are only partially understood. OBJECTIVE: To determine the impact of high-fat overfeeding on postprandial glucose fluxes, muscle insulin signaling, and muscle microvascular endothelial nitric oxide synthase (eNOS) content and activation. DESIGN: Fifteen non-obese volunteers consumed a high-fat (64%) high-energy (+47%) diet for 7 days. Experiments were performed before and after the diet. Stable isotope tracers were used to determine glucose fluxes in response to carbohydrate plus protein ingestion. Muscle insulin signaling was determined as well as the content and activation state of muscle microvascular eNOS. RESULTS: High-fat overfeeding impaired postprandial glycemic control as demonstrated by higher concentrations of glucose (+11%; P = 0.004) and insulin (+19%; P = 0.035). Carbohydrate plus protein ingestion suppressed endogenous glucose production to a similar extent before and after the diet. Conversely, high-fat overfeeding reduced whole-body glucose clearance (-16%; P = 0.021) and peripheral insulin sensitivity (-26%; P = 0.006). This occurred despite only minor alterations in skeletal muscle insulin signaling. High-fat overfeeding reduced eNOS content in terminal arterioles (P = 0.017) and abolished the increase in eNOS Ser1177 phosphorylation that was seen after carbohydrate plus protein ingestion. CONCLUSION: High-fat overfeeding impaired whole-body glycemic control due to reduced glucose clearance, not elevated endogenous glucose production. The finding that high-fat overfeeding abolished insulin-mediated eNOS Ser1177 phosphorylation in the terminal arterioles suggests that impairments in the vasodilatory capacity of the skeletal muscle microvasculature may contribute to early dietary fat-induced impairments in glycemic control.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/patologia , Resistência à Insulina , Músculo Esquelético/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Adulto , Biomarcadores/análise , Glicemia/análise , Feminino , Seguimentos , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Humanos , Masculino , Músculo Esquelético/metabolismo , Fosforilação , Prognóstico , Adulto JovemRESUMO
Background: Observational studies often infer hepatic de novo lipogenesis (DNL) by measuring circulating fatty acid (FA) markers; however, it remains to be elucidated whether these markers accurately reflect hepatic DNL. Objectives: We investigated associations between fasting hepatic DNL and proposed FA markers of DNL in subjects consuming their habitual diet. Methods: Fasting hepatic DNL was assessed using 2H2O (deuterated water) in 149 nondiabetic men and women and measuring the synthesis of very low-density lipoprotein triglyceride (VLDL-TG) palmitate. FA markers of blood lipid fractions were determined by gas chromatography. Results: Neither the lipogenic index (16:0/18:2n-6) nor the SCD index (16:1n-7/16:0) in VLDL-TG was associated with isotopically assessed DNL (r = 0.13, P = 0.1 and r = -0.08, P = 0.35, respectively). The relative abundances (mol%) of 14:0, 16:0, and 18:0 in VLDL-TG were weakly (r ≤ 0.35) associated with DNL, whereas the abundances of 16:1n-7, 18:1n-7, and 18:1n-9 were not associated. When the cohort was split by median DNL, only the abundances of 14:0 and 18:0 in VLDL-TG could discriminate between subjects having high (11.5%) and low (3.8%) fasting hepatic DNL. Based on a subgroup, FA markers in total plasma TG, plasma cholesteryl esters, plasma phospholipids, and red blood cell phospholipids were generally not associated with DNL. Conclusions: The usefulness of circulating FAs as markers of hepatic DNL in healthy individuals consuming their habitual diet is limited due to their inability to discriminate clearly between individuals with low and high fasting hepatic DNL.
Assuntos
Jejum , Ácidos Graxos/sangue , Lipogênese , Fígado/metabolismo , Avaliação Nutricional , Adulto , Biomarcadores/sangue , Cromatografia Gasosa/métodos , Deutério , Óxido de Deutério , Dieta , Feminino , Humanos , Lipoproteínas VLDL/metabolismo , Masculino , Pessoa de Meia-Idade , Palmitatos/metabolismo , Reprodutibilidade dos Testes , Triglicerídeos/metabolismoRESUMO
GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.
Assuntos
Ingestão de Energia/fisiologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Adulto , Animais , Linhagem Celular , Dieta Hiperlipídica/métodos , Fator 15 de Diferenciação de Crescimento/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto JovemRESUMO
Context and Objectives: Spillover of fatty acids (FAs) into the plasma nonesterified fatty acid (NEFA) pool, because of an inability of adipose tissue (AT) to accommodate sufficient fat uptake, has been suggested to contribute to obesity-related insulin resistance. Using specific labeling techniques, we compared the proportion of spillover-derived NEFA across a range of adiposity. Participants and Methods: Seventy-one healthy men and women were fed a mixed meal (40 g fat) containing [U13C]palmitate to assess the contribution of chylomicron-derived spillover FAs. To investigate subcutaneous abdominal-specific spillover, arteriovenous difference and stable-isotope methodologies were used in substudy (six men, six women). Results: Chylomicron-derived FA spillover was higher in individuals with a BMI <25 kg/m2 (n = 18) compared with those with a BMI ≥25 kg/m2 (n = 53) (22.2 ± 1.6% vs 18.6 ± 0.7%, P = 0.02). Women had higher chylomicron-derived FA spillover than age- and BMI-matched men (21.9 ± 1.1% vs 15.0 ± 1.6%, P = 0.001). Assessing spillover across subcutaneous abdominal AT showed higher proportions in women than in men (28.5 ± 6.1% vs 9.9 ± 1.3%, P = 0.01). Conclusion: There is a considerable degree of spillover FA into the systemic NEFA pool in the postprandial state; this process is greater and more dynamic in lean individuals and women. Contrary to general perception, spillover of chylomicron-derived FA into systemic circulation is a physiologically normal feature most easily observed in people with a higher capacity for clearance of plasma triglycerides, but does not appear to be a pathway providing excess NEFA in obesity.
Assuntos
Tecido Adiposo/metabolismo , Quilomícrons/metabolismo , Ácidos Graxos/metabolismo , Resistência à Insulina , Obesidade/fisiopatologia , Magreza/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Período Pós-PrandialRESUMO
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.
RESUMO
Obese individuals exhibit a diminished muscle protein synthesis response to nutrient stimulation when compared with their lean counterparts. However, the effect of obesity on exercise-stimulated muscle protein synthesis remains unknown. Nine lean (23.5 ± 0.6 kg/m2 ) and 8 obese (33.6 ± 1.2 kg/m2 ) physically active young adults participated in a study that determined muscle protein synthesis and intracellular signaling at rest and following an acute bout of resistance exercise. Mixed muscle protein synthesis was determined by combining stable isotope tracer ([13 C6 ]phenylalanine) infusion with serial biopsies of the vastus lateralis. A unilateral leg resistance exercise model was adopted so that resting and postexercise measurements of muscle protein synthesis could be obtained simultaneously. Obesity was associated with higher basal levels of serum insulin (P < 0.05), plasma triacylglycerol (P < 0.01), plasma cholesterol (P < 0.01), and plasma CRP (P < 0.01), as well as increased insulin resistance determined by HOMA-IR (P < 0.05). However, resting and postexercise rates of muscle protein synthesis were not significantly different between lean and obese participants (P = 0.644). Furthermore, resistance exercise stimulated muscle protein synthesis (~50% increase) in both groups (P < 0.001), with no difference between lean and obese (P = 0.809). Temporal increases in the phosphorylation of intracellular signaling proteins (AKT/4EBP1/p70S6K) were observed within the exercised leg (P < 0.05), with no differences between lean and obese. These findings suggest a normal anabolic response to muscle loading in obese young adults.
Assuntos
Músculo Esquelético/metabolismo , Obesidade/metabolismo , Biossíntese de Proteínas , Treinamento Resistido , Adulto , Estudos de Casos e Controles , Colesterol/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Músculo Esquelético/fisiologia , Triglicerídeos/sangueRESUMO
The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the available observational and intervention studies that have investigated the influence of dietary macronutrients on liver fat content. Findings from observational studies are conflicting with some reporting that relative to healthy controls, patients with NAFLD consume diets higher in total fat/saturated fatty acids, whilst others find they consume diets higher in carbohydrates/sugars. From the limited number of intervention studies that have been undertaken, a consistent finding is a hypercaloric diet, regardless of whether the excess calories have been provided either as fat, sugar, or both, increases liver fat content. In contrast, a hypocaloric diet decreases liver fat content. Findings from both hyper- and hypo-caloric feeding studies provide some suggestion that macronutrient composition may also play a role in regulating liver fat content and this is supported by data from isocaloric feeding studies; fatty acid composition and/or carbohydrate content/type appear to influence whether there is accrual of liver fat or not. The mechanisms by which specific macronutrients, when consumed as part of an isocaloric diet, cause a change in liver fat remain to be fully elucidated.
Assuntos
Dieta , Metabolismo dos Lipídeos , Fígado/metabolismo , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Fatores de RiscoRESUMO
Consuming excessive amounts of energy as dietary fat for several days or weeks can impair glycemic control and reduce insulin sensitivity in healthy adults. However, individuals who demonstrate binge eating behavior overconsume for much shorter periods of time; the metabolic consequences of such behavior remain unknown. The aim of this study was to determine the effect of a single day of high-fat overfeeding on whole-body insulin sensitivity. Fifteen young, healthy adults underwent an oral glucose tolerance test before and after consuming a high-fat (68% of total energy), high-energy (78% greater than daily requirements) diet for one day. Fasting and postprandial plasma concentrations of glucose, insulin, non-esterified fatty acids, and triglyceride were measured and the Matsuda insulin sensitivity index was calculated. One day of high-fat overfeeding increased postprandial glucose area under the curve (AUC) by 17.1% (p < 0.0001) and insulin AUC by 16.4% (p = 0.007). Whole-body insulin sensitivity decreased by 28% (p = 0.001). In conclusion, a single day of high-fat, overfeeding impaired whole-body insulin sensitivity in young, healthy adults. This highlights the rapidity with which excessive consumption of calories through high-fat food can impair glucose metabolism, and suggests that acute binge eating may have immediate metabolic health consequences for the individual.