Exploring recent insights on intermittent fasting in regulating glucocorticoid levels and diet-induced metabolic disorders with focus on MAFLD and hepatic outcomes.

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

Yet more evidence that MAFLD is more than a name change

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Various types of fasting diet and possible benefits in nonalcoholic fatty liver: Mechanism of actions and literature update

Nonalcoholic fatty liver disease (NAFLD), a condition characterized by the accumulation of fat in the liver, is estimated to be the most common liver disease worldwide. Obesity is a major risk factor and contributor, and, accordingly, weight loss can improve NAFLD. Previous studies in preclinical models of diet-induced obesity and fatty liver disease have shown the independent benefits of resistance exercise training (RT) and time-restricted feeding (TRF) in preventing weight gain and hepatic build-up of fat. Here, we tested the combined effect of TRF and RT on obesity and NAFLD in mice fed a high-fat diet. Our results showed that both TRF-8-h food access in the active phase-and RT-consisting of three weekly sessions of ladder climbing-attenuated body weight gain, improved glycemic homeostasis, and decreased the accumulation of lipids in the liver. TRF combined with RT improved the respiratory exchange rate, energy expenditure, and mitochondrial respiration in the liver. Furthermore, gene expression analysis in the liver revealed lower mRNA expression of lipogenesis and inflammation genes along with increased mRNA of fatty acid oxidation genes in the TRF + RT group. Importantly, combined TRF + RT was shown to be more efficient in preventing obesity and metabolic disorders. In conclusion, TRF and RT exert complementary actions compared with isolated interventions, with significant effects on metabolic disorders and NAFLD in mice.NEW & NOTEWORTHY Whether time-restricted feeding (TRF) combined with resistance exercise training (RT) may be more efficient compared with these interventions alone is still unclear. We show that when combined with RT, TRF provided additional benefits, being more effective in increasing energy expenditure, preventing weight gain, and regulating glycemic homeostasis than each intervention alone. Thus, our results demonstrate that TRF and RT have complementary actions on some synergistic pathways that prevented obesity and hepatic liver accumulation.

Background: Approximately 65% of individuals with obesity have nonalcoholic fatty liver disease (NAFLD) . The primary treatment for NAFLD is regulating weight per diet and exercise. Alternate day fasting (ADF) has been shown to improve body composition and cardiometabolic risk factors in animals. This is the first human trial to compare the effects of ADF plus endurance exercise, ADF alone, endurance exercise alone versus a no intervention control, on body weight and metabolic disease risk factors in participants with obesity and NAFLD. Methods: Subjects with obesity and NAFLD (n = 48) were randomized to 1 of 4 groups for 12 weeks:1) ADF (600 kcal “fast day”, alternated with an ad libitum intake “feast day”) ,2) exercise (endurance exercise 5 times/week for 60 min/d) ,3) combination (ADF + exercise) ,or 4) control (usual diet) . Results: Body weight was reduced (P < 0.05) in the ADF group (-5.3 ± 1.0 %) and combination group (-4.9 ± 0.6 %) , but not the exercise group (-1.9 ± 0.6 %) , versus controls (-0.3 ± 1.2 %) . ALT was reduced (P < 0.05) in the combination group (-29 ± 9%) , but not in the ADF group (-9 ± 8%) , exercise group (1 ± 3%) , versus controls (17 ± 10%) . No significant changes were observed for liver fat, body composition, AST, lipid markers, or glucoregulatory factors. Subjects in the ADF and combination groups were adherent with the fast day energy goal (600 kcal) at week 12 (ADF: 548 kcal; combination: 657 kcal) . Subjects in the exercise and combination groups were adherent with attending the 5 workout sessions per week (exercise: 79% attendance; combination: 83% attendance) . Conclusion: These preliminary findings suggest that combination of ADF plus exercise and ADF alone may be effective non-pharmacological therapies to reduce body weight and ALT. However, neither combination intervention nor ADF alone have had any effect on liver fat, metabolic risk factors, or glucoregulatory factors such as insulin. Disclosure K. Gabel: None. K. Varady: None. S. Cienfuegos: None. Funding NIH/NIDDK (R01DK119783-03)

Changing Nomenclature from Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Fatty Liver Disease – Not Only Premature But Also Confusing

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, and it is characterized by a series of fatty liver diseases that can lead to severe liver disease. Although no therapeutic drug has been approved as an effective therapy for NAFLD to date, dietary changes and physical activity are thought to be the cornerstone of NAFLD management. For this reason, some articles are available to analyze the studies done so far using various modifications of intermittent fasting (IF) among animals and patients with NAFLD. Data from preclinical and clinical trials suggested that IF positively impacts inflammatory and metabolic markers in both animals and humans. Inflammation and oxidative stress are the major risk factors involved in the pathogenesis of NAFLD. IF has been shown to have positive benefits in alleviating metabolic disorders, promoting the browning of white tissue, resetting circadian rhythm, and activating autophagy of cells. This review is intended to provide a detailed synopsis of the protocols, potential mechanisms of action, and supporting evidence for IF in NAFLD. We will highlight what is currently known about IF approaches in NAFLD treatments in clinical populations with mechanism insight from animal studies, and the safety concerns in certain patient groups.Graphical The protocols of intermittent fasting (IF) are various. Data from trials suggested that IF positively impacts both humans and animals. IF has been shown to have potential treatments for nonalcoholic fatty liver disease.

BackgroundThe prevalence of metabolic associated fatty liver disease (MAFLD) is high. However, there are few studies on the effects of time-restricted feeding (TRF) and caloric restriction (CR) in MAFLD.ObjectivesTo investigate the efficacy and mechanism of 4 h TRF and 60% CR in MAFLD.MethodsTwelve male Sprague–Dawley rats were randomly assigned to the Normal group (normal diet, 10 kcal% fat), while the remaining 38 rats were assigned to the MAFLD group (high-fat diet, 60 kcal% fat). 10 weeks later, the MAFLD group was randomly divided into the 4 h TRF, 60% CR, 4 h TRF + 60% CR, and Model groups; all rats were then given normal diet. After 4 weeks, weight, blood lipid, and other indicators were detected.ResultsAfter the high-fat diet was discontinued, the liver lipid levels in the rat with MAFLD significantly reduced, while the body weight was not significantly changed. The rats in the Model group were heavier than those in the other four groups (p < 0.01). The triglyceride levels were higher in the TRF + CR group compared with the Model group (p < 0.01). Compared with the Model group, 110 metabolites were decreased in the TRF + CR group, and 83 metabolites were elevated in liver. Kyoto Encyclopedia of Genes and Genomes revealed that the mechanism involved the proliferator–activated receptor alpha signaling pathway, metabolic pathway, and so on. We observed differences in silent information regulator transcript 1 (SIRT1) mRNA levels in all five groups (p = 0.003).Conclusions4 h TRF and 60% CR significantly reduced body weight and liver lipid in rats with MAFLD. 4 h TRF can improve MAFLD, and there is no need to excessively restrict food intake.

Erratic feeding patterns, such as those experienced by shift workers, can exacerbate obesity and metabolic‐associated fatty liver disease (MAFLD). Both nutritional factors and sexual dimorphism influence the progression of MAFLD. Time‐restricted feeding (TRF) has emerged as a promising strategy to mitigate the effects of obesity, supported by evidence of its benefits for metabolic disorders like MAFLD. Regular physical exercise is also recommended as a non‐pharmacological approach to combat obesity and its related conditions. Both TRF and exercise independently show promise in improving metabolic health, weight management and glycaemic control. Thus, combining these approaches may offer a more effective strategy against obesity and MAFLD. In this study, male and female C57BL/6J mice were subjected to an 8‐week obesity induction protocol, followed by TRF (16/8) or TRF combined with aerobic exercise. The results showed that TRF, even during the inactive phase of the mice, had positive effects on weight loss, adiposity, glycaemic homeostasis, insulin sensitivity, liver lipid composition, hepatic fat accumulation and the reduction of lipogenic and inflammatory genes in the liver. The combination of TRF with aerobic exercise provided additional benefits, including improved regulation of hepatic triglycerides and respiratory exchange ratio (RER) in males, enhanced fasting glucose levels in females and reduced Fatp4 gene expression in both sexes. Aerobic exercise performance also improved in both sexes, with males achieving superior results. Notably, the combination of TRF with aerobic exercise provided greater metabolic benefits, with sex‐specific differences observed in metabolic responses.Key pointsEight weeks of western diet induced obesity, an impaired glucose homeostasis and increased hepatic fat accumulation in male and female C57BL/6J mice.Time‐restricted feeding (TRF) 16/8 in the active phase and TRF combined with aerobic exercise reduced weight gain and metabolic disorders in C57BL/6J male and female mice fed a western diet.TRF when combined with aerobic exercise displayed more pronounced improvements in the hepatic metabolism.TRF when combined with aerobic exercise improved liver triglycerides and respiratory exchange ratio in males, fasting glucose in females and decreased lipogenic gene Fatp4 expression in both males and females.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that ultimately leads to cirrhosis and hepatocellular carcinoma. Intermittent fasting has been proposed as a nonpharmacological dietary approach against metabolic diseases, including NAFLD. In this study, we aimed to investigate the effect of alternate day fasting (ADF) on high-fat diet (HFD)-induced NAFLD in C57BL/6 mice. A mouse model of fatty liver disease was established by feeding the mice a HFD for 16weeks. The mice were administered by body weight, lipid accumulation and inflammation. PPARα, FGF21, serum triglycerides (TG), total cholesterol (TC), transaminase and lipogenesis were assessed. The results showed that long-term ADF can attenuate fatty liver disease by reducing hepatic inflammation and lipid accumulation in a mouse model. Meanwhile, fasting elevated the expression of serum and hepatic fibroblast growth Factor 21 (Fgf21), a circulating hormone produced predominantly in the liver, and could effectively prevent and ameliorate the pathogenesis of NAFLD. Serum starvation also enhanced Fgf21 expression and reduced free fatty acid (FFA)-induced lipid storage in hepatocytes. Moreover, refeeding inhibited the increase in Fgf21 expression induced by fasting. This fasted-to-refed transition is closely related to the expression of Fgf21. Further in vitro and in vivo studies showed that fasting-sensitive PPARα is indispensable for the expression of Fgf21 and its protective effect on NAFLD. These findings indicated that long-term ADF protects mouse livers against HFD induced fatty liver disease through controlling PPARα/Fgf21 signaling. In conclusion, ADF can emerge as a non-pharmacological dietary approach against fatty liver disease.

Non-alcoholic fatty liver disease: Not time for an obituary just yet!

Epidemiology of non-alcoholic fatty liver disease in China

Non-alcoholic fatty liver disease (NAFLD) is a predominant health condition across the world due to its rising prevalence and association with various metabolic disorders. Intermittent fasting (IF) has attracted increasing attention as a dietary approach to addressing weight management and enhancing metabolic well-being, and its potential effects on NAFLD have been a topic of growing research interest. This review aims to critically evaluate the current evidence on IF's impact on NAFLD, including the mechanisms underlying the observed effects in older adults (65+). A comprehensive search of Clinicaltrials.gov was conducted to identify relevant studies that investigated the effects of IF on NAFLD in older adults (65+). Data on study design, sample size, intervention details, and outcomes related to NAFLD were extracted and analyzed. As of April 12th, 2023, there were 1304 clinical trials on NAFLD. Most of these were interventional studies. The investigation focused on completed studies and found that limited clinical trials were identified with limited interventional measures. Only five out of the 1304 studies on NAFLD involved IF. Basic and advanced outcome measures were examined. Although some studies suggest that IF may have potential benefits for NAFLD, the evidence is still limited and inconclusive.

The first-line treatment for non-alcoholic fatty liver disease (NAFLD) is lifestyle modification; this should accompany any pharmacological intervention. Intermittent fasting (IF) has shown benefits over metabolic and cardiovascular parameters. Non-religious IF includes Time-Restricted Feeding (TRF), Alternate-Day Fasting (ADF), and 5:2 IF interventions. To evaluate the effects of IF on anthropometric, liver damage, and lipid profile markers in subjects with NAFLD. A bibliographic search was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using PubMed and Scopus databases. Five studies involving 470 patients with NAFLD were included. In relation to anthropometric markers, all the articles reported body weight reduction (2.48-7.63%), but only ADF and 5:2 IF reported a body weight reduction >5%; also, all the articles reported fat mass reduction. Concerning hepatic markers, all the articles reported a reduction in hepatic steatosis and alanine aminotransferase activity, but no changes in fat-free mass and high-density lipoprotein cholesterol levels. There were variable results on fibrosis, other liver enzymes, waist circumference and body mass index, as well as the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol. Any form of IF could be potentially beneficial for NAFLD treatment and some associated cardiometabolic parameters. However, it is necessary to evaluate the effects and safety of IF in long-term studies involving a higher number of participants with different stages of NAFLD. The effect of IF on NAFLD-associated vascular risk also needs evaluation.