Effects of intermittent fasting combined with physical exercise on cardiometabolic outcomes: systematic review and meta-analysis of clinical studies.

CONTEXT: Different intermittent fasting (IF) protocols have been proven to be efficient in improving cardiometabolic markers, but further research is needed to examine whether or not combining IF regimens plus physical exercise is superior to control diets (ie, nonfasting eating) plus physical exercise in this setting. OBJECTIVE: The aim of this study was to determine whether or not combining IF plus exercise interventions is more favorable than a control diet plus exercise for improving cardiometabolic health outcomes. DATA SOURCE: PubMed, Scopus, and Web of Science were comprehensively searched until April 2023. DATA EXTRACTION: Electronic databases were searched for clinical trials that determined the effect of IF plus exercise vs a control diet plus exercise on body weight, lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol), and systolic and diastolic blood pressure (SBP and DBP, respectively). Analyses were conducted for IF plus exercise vs a nonfasting diet plus exercise to calculate weighted mean differences (WMDs). DATA ANALYSIS: The meta-analysis included a total of 14 studies, with a total sample of 360 adults with or without obesity. The duration ranged from 4 to 52 weeks. IF plus exercise decreased body weight (WMD = -1.83 kg; P = 0.001), LDL (WMD = -5.35 mg/dL; P = 0.03), and SBP (WMD = -2.99 mm Hg; P = 0.003) significantly more than a control diet plus exercise. HDL (WMD = 1.57 mg/dL; P = 0.4) and total cholesterol (WMD = -2.24 mg/dL; P = 0.3) did not change significantly for IF plus exercise vs a control diet plus exercise, but there was a trend for reducing triglycerides (WMD = -13.13 mg/dL; P = 0.07) and DBP (WMD = 2.13 mm Hg; P = 0.05), which shows clinical magnitude. CONCLUSION: IF plus exercise improved some cardiometabolic outcomes (body weight, blood pressure, and lipid profile) compared with a control diet plus exercise. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023423878.

The effects of aerobic exercise on liver function, insulin resistance, and lipid profiles in prediabetic and type 2 diabetic mice.

BACKGROUND AND AIMS: The purpose of the current study was to evaluate the expression of gluconeogenesis and insulin resistance key genes; including insulin receptor substrate 1 (Irs1), a serine/threonine protein kinase (Akt), forkhead box class-O 1 (FoxO1) and phosphoenolpyruvate carboxykinase (Pepck) genes, and lipid profiles following either a standard or a high-fat diet (HFD) and either an aerobic exercise or non-exercise intervention in prediabetic and type 2 diabetic (T2DM) mice. METHODS: 24 male mice were randomly assigned to two groups fed with a normal diet (ND) or a HFD for 12 weeks. The mice in each group were again randomly assigned to two groups to create four groups in total: 1. Prediabetes-exercised (Prediabetes-Exe), 2. Prediabetes-non exercised (Prediabetes-Non exe), 3. Healthy-exercised (Healthy-Exe), and 4. Healthy-non exercised (Healthy-Non exe). Eighteen additional male mice were fed with the HFD for 8 weeks, after which streptozotocin (STZ) was administered. The mice were then fed the HFD for an additional 4 weeks. These T2DM mice were then randomly divided into two groups: 1. Diabetes-exercised (Diabetic-Exe), and 2. Diabetes-Non exe. The three Exe groups all exercised on a treadmill for 8 weeks for 5 sessions/week. After the last training session, liver tissue was extracted, and the expression of Irs1, Akt, FoxO1, and Pepck genes was measured using real time quantitative Polymerase chain reaction tests. Lipid profiles were measured in serum and in the liver. RESULTS: The expression of both Irs1 and Akt was significantly increased in the Healthy-Exe, Prediabetes-Exe, and Diabetes-Exe groups as compared to the Healthy-Non exe, Prediabetes-Non exe, and Diabetes-Non exe groups (p < 0.001). Additionally, the expression of FoxO1 (p < 0.05) and Pepck (p < 0.001) decreased significantly in the Prediabetes-Exe, and Diabetes-Exe groups as compared to the Prediabetes-non exe, and Diabetes-Non exe groups. Aerobic exercise did not lead to reductions in FoxO1 or Pepck expression in the Healthy-Exe mice. CONCLUSIONS: Eight weeks of aerobic exercise (5 sessions/week) significantly increased the expression of key genes that are important for maintaining glucose homeostasis and improving insulin resistance (Irs1 and Akt), and decreased expression of genes that are important for decreasing gluconeogenesis in the liver (FoxO1 and Pepck) in healthy, prediabetic, and T2DM mice. The lipid profiles improved in healthy, prediabetic, and T2DM mice.

Pioglitazone Mediates Cardiac Progenitor Formation through Increasing ROS Levels.

In order to achieve a sufficient population of cardiac-committed progenitor cells, it is crucial to know the mechanisms of cardiac progenitor formation. Previous studies suggested ROS effect on cardiac commitment events to play a key role in the cell signaling and activate cardiac differentiation of pluripotent stem cells. We previously reported that PPARγ activity is essential for cardiac progenitor cell commitment. Although several studies have conducted the involvement of PPARγ-related signaling pathways in cardiac differentiation, so far, the regulatory mechanisms of these signaling pathways have not been discussed and cleared. In this study, we focus on the role of PPARγ agonist in ROS generation and its further effects on the differentiation of cardiac cells from mESCs. The results of this study show that the presence of ROS is necessary for heart differentiation in the precursor stage of cardiac cells, and the coenzyme Q10 antioxidant precludes proper cardiac differentiation. In addition, this antioxidant prevents the action of pioglitazone in increasing oxygen radicals as well as beating cardiomyocyte differentiation properties. In this case, it can be concluded that PPARγ is required to modulate ROS levels during cardiac differentiation.

Noncoding RNAs Associated with PPARs in Etiology of MAFLD as a Novel Approach for Therapeutics Targets.

Background: Metabolic associated fatty liver disease (MAFLD) is a complex disease that results from the accumulation of fat in the liver. MAFLD is directly associated with obesity, insulin resistance, diabetes, and metabolic syndrome. PPARγ ligands, including pioglitazone, are also used in the management of this disease. Noncoding RNAs play a critical role in various diseases such as diabetes, obesity, and liver diseases including MAFLD. However, there is no adequate knowledge about the translation of using these ncRNAs to the clinics, particularly in MAFLD conditions. The aim of this study was to identify ncRNAs in the etiology of MAFLD as a novel approach to the therapeutic targets. Methods: We collected human and mouse MAFLD gene expression datasets available in GEO. We performed pathway enrichment analysis of total mRNAs based on KEGG repository data to screen the most potential pathways in the liver of MAFLD human subjects and mice model, and analyzed pathway interconnections via ClueGO. Finally, we screened disease causality of the MAFLD ncRNAs, which were associated with PPARs, and then discussed the role of revealed ncRNAs in PPAR signaling and MAFLD. Results: We found 127 ncRNAs in MAFLD which 25 out of them were strongly validated before for regulation of PPARs. With a polypharmacology approach, we screened 51 ncRNAs which were causal to a subset of diseases related to MAFLD. Conclusion: This study revealed a subset of ncRNAs that could help in more clear and guided designation of preclinical and clinical studies to verify the therapeutic application of the revealed ncRNAs by manipulating the PPARs molecular mechanism in MAFLD.

Hypothetical molecular interconnection between type 2 diabetes and dyslexia.

BACKGROUND: Dyslexia is one of the most common learning disabilities, especially among children. Type 2 diabetes is a metabolic disorder that affects a large population globally, with metabolic disorders. There have been several genes that are identified as causes of Dyslexia, and in recent studies, it has been found out that some of those genes are also involved in several metabolic pathways. For several years, it has been known that type 2 diabetes causes several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Furthermore, in several studies, it was suggested that type 2 diabetes also has some associations with learning disabilities. This raises the question of whether "Is there a connection between type 2 diabetes and dyslexia?". In this study, this question is elaborated by linking their developmental processes via bioinformatics analysis about these two diseases individually and collectively. RESULT: The literature review for dyslexia and type two diabetes was completed. As the result of this literature review, the genes that are associated to type 2 diabetes and dyslexia were identified. The biological pathways of dyslexia, and dyslexia associated genes, type 2 diabetes, and type 2 diabetes associated genes were identified. The association of these genes, regarding to their association with pathways were analysed, and using STRING database the gene associations were analysed and identified. CONCLUSION: The findings of this research included the interaction analysis via gene association, co-expression and protein-protein interaction. These findings clarified the interconnection between dyslexia and type 2 diabetes in molecular level and it will be the beginning of an answer regarding to the relationship between T2D and dyslexia. Finally, by improving the understanding this paper aims to open the way for the possible future approach to examine this hypothesis.

Aerobic exercise modulates noncoding RNA network upstream of FNDC5 in the Gastrocnemius muscle of high-fat-diet-induced obese mice.

The purpose of the study was to determine the influence of aerobic exercise with a fat-rich diet on ncRNAs expression associated with FNDC5 in the Gastrocnemius muscle of the obese mice. Twenty-five male mice were grouped into two categories of normal diet (ND) and high-fat diet (HF) treatments for three months. For the subsequent treatment, HF-fed animals (obese) were proceeded in four groups: HF-Trained (n = 5), HF-Untrained (n = 5), ND-Trained (n = 5), and ND-Untrained (n = 5). Simultaneously, ND fed mice (n = 5) continued receiving normal diet and being untrained. In the training group, exercise was applied using a treadmill for 2 months. The Gastrocnemius muscle was excised for the assessment of FNDC5 mRNA, protein levels, and ncRNAs. Using bioinformatics tools, two potential miRNAs, miR-129-5p and miR-140-5p, and four lncRNAs constructing a network with FNDC5 were identified. Significant decrease was observed in both miR-129-5p and miR-140-5p in the HF-fed mice vs. ND-fed mice (p < 0.01). Significant increase of lncRNAs Meg3, Malat1, Neat1, and Kcnq1ot1 correlating in the network was also detected (p < 0.001 for all lncRNAs) in HF-fed mice and trained mice (p < 0.001 for Neat1, Meg3, and Kcnq1ot1). The present study suggests that an increase in the muscle FNDC5 of the high-fat diet mice is governed by an expression regulation of suggested ncRNAs, which were revealed by bioinformatics study to be involved in the insulin resistance and glucose homeostasis pathways.

Modulation and bioinformatics screening of hepatic mRNA-lncRNAs (HML) network associated with insulin resistance in prediabetic and exercised mice.

BACKGROUND: Insulin resistance is associated with prediabetes and further progression to type 2 diabetes mellitus (T2DM). This study aims to investigate novel hepatic lncRNAs associated with key genes in insulin resistance in prediabetes. METHODS: In the bioinformatics phase, we have collected screened a pool of lncRNAs and mRNAs according to their potential association to prediabetic condition. We performed pathway analysis of mRNAs, using DAVID tool based on KEGG repository data. Then, we used Python programming language to get a subset of lncRNAs located in 50 kb proximity with high-fat (HF)-responsive mRNAs. In the experimental phase, prediabetic mice model was established by the treatment of HF diets for 12 weeks. After this treatment, HF-fed animals were divided into two groups of endurance exercised or sedentary, both continuing on the HF diet for 8 weeks. Besides, a group of diabetic mice was treated using a HF diet for 8 weeks followed by injection with STZ solution and then a HF diet for another 4 weeks. RESULTS: We found three genes having paired lncRNAs annotated in insulin resistance pathway. Their hepatic expression levels were altered in prediabetic condition as upregulation of Srebf1 was associated with GM38501, upregulation of Pck1 was associated with Ctcflos and GM36691, downregulation of Cpt1b was associated with GM44502. All of these expression patterns were replicated in diabetic mice, correlated positively with their predicted lncRNAs. Interestingly, exercise reversed their expression patterns. CONCLUSIONS: We suggest that the expression pattern of the hepatic mRNA-lncRNA (HML) network in prediabetic state undergoes similar modification to that of diabetes.