Project description:BACKGROUND:Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. METHODS:We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. RESULTS:Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. CONCLUSIONS:Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

Project description:Excessive oil addition can easily result in decreased disease resistance in broilers, a drop in meat quality, and disorders of glucose and lipid metabolism. Epigallocatechin gallate (EGCG) is an important bioactive component of tea and has been shown to have promising effects on the metabolism of nutrients. This study was aimed at investigating the impact of EGCG supplementation through a high-fat diet (HFD) on production performance, meat quality, lipid metabolism and the influence of intestinal flora in broiler chickens. During the experimental phase, the broilers were segregated into three groups and provided with distinct diets: a basal diet, a high-fat diet, and a high-fat diet supplemented with EGCG, respectively. The results showed that EGCG increased lightness (L*) 24 h (P < 0.05), and decreased drip loss (P < 0.05) of chicken meat; Enhanced the presence of non-essential and flavor amino acids in muscle tissue and greatly enhanced the antioxidant capacity of broilers, leading to a noteworthy upregulation of antioxidant genes at the genetic level (P < 0.05); Reduced in blood lipids, blood glucose, liver and abdominal fat accumulation in high-fat diet-induced obese chickens (P < 0.05), markedly improved serum and liver biochemical parameters, and histological analysis results also demonstrated that EGCG markedly decreased hepatic lipid accumulation caused by HFD feeding. Compared to high-fat diet-induced obese chickens, supplementation of EGCG significantly lowered hepatic fatty acid synthase (FAS) expression and lipid synthesis metabolites, while fatty acid decomposition enzymes showed no significant changes. Furthermore, EGCG significantly decreased inflammation levels and oxidative damage in high-fat diet-induced obese chickens (P < 0.05). 16S rRNA gene sequencing revealed that dietary supplementation of EGCG reduced the abundance of Bacteroidota and Dielma, while increasing the abundance of Firmicutes, Turiciactor, Romboutsia, and Parasutterella, thereby modulating the microbial composition. Dietary EGCG may have induced some of the alterations due to increased activity of the enzymes catalase (CAT) and superoxide dismutase (SOD), as well as decreased oxidation of proteins and lipids. Collectively, EGCG shows potential as an effective dietary additive for improving the high fat feeding of broiler health, feed nutrient utilization, and meat quality and nutritional value. This experiment provides a powerful new idea for the efficient utilization of oil feed and has important theoretical significance.

Project description:BackgroundRecent experimental studies have shown that vegetable oil supplementation ameliorates high-fat diet- (HFD-) induced hyperlipidemia and oxidative stress in mice via modulating hepatic lipid metabolism and the composition of the gut microbiota. The aim of this study was to investigate the efficacy of the Torreya grandis kernel oil (TKO) rich in unpolysaturated fatty acid against hyperlipidemia and gain a deep insight into its potential mechanisms.MethodsNormal mice were randomly divided into three groups: ND (normal diet), LO (normal diet supplement with 4% TKO), and HO (normal diet supplement with 8% TKO). Hyperlipidemia mice were randomly divided into two groups: HFN (normal diet) and HFO (normal diet supplement with 8% TKO). Blood biochemistry and histomorphology were observed; liver RNA-seq, metabolomics, and gut 16S rRNA were analyzed.ResultsContinuous supplementation of TKO in normal mice significantly ameliorated serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and free fatty acid (FFA) accumulation, decreased blood glucose and malondialdehyde (MDA), and enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. According to GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, most differentially expressed genes (DEGs) were significantly enriched in the biosynthesis of unsaturated fatty acid pathways, and significantly changed metabolites (SCMs) might be involved in the metabolism of lipids. High-dose TKO improved gut alpha diversity and beta diversity showing that the microbial community compositions of the five groups were different.ConclusionSupplementation of TKO functions in the prevention of hyperlipidemia via regulating hepatic lipid metabolism and enhancing microbiota richness in normal mice. Our study is the first to reveal the mechanism of TKO regulating blood lipid levels by using multiomics and promote further studies on TKO for their biological activity.

Project description:BackgroundThromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions are the leading cause of death in the world. The most common and effective means to reduce these major adverse cardiovascular events (MACE), including myocardial infarction (MI) and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, little is known regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering.MethodsSmooth muscle cell (SMC)-lineage tracing Apoe-/- mice were fed a Western diet (WD) for 18 weeks and then switched to a low-fat chow diet for 12 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery (BCA) lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of SMC, and other lesion cells by SMC-lineage tracing combined with scRNA-seq, CyTOF, and immunostaining plus high resolution confocal microscopic z-stack analysis. In addition, to determine if treatment with a potent inhibitor of inflammation could augment the benefits of chow diet-induced reductions in LDL-cholesterol, SMC-lineage tracing Apoe-/- mice were fed a WD for 18 weeks and then chow diet for 12 weeks prior to treating them with an IL-1β or control antibody (Ab) for 8-weeks.ResultsLipid-lowering by switching Apoe-/- mice from a WD to a chow diet reduced LDL-cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1β Ab treatment resulted in multiple detrimental changes including increased plaque burden, BCA lesion size, as well as increased cholesterol crystal accumulation, intra-plaque hemorrhage, necrotic core area, and senescence as compared to IgG control Ab treated mice. Furthermore, IL-1β Ab treatment upregulated neutrophil degranulation pathways but down-regulated SMC extracellular matrix pathways likely important for the protective fibrous cap.ConclusionsTaken together, IL-1β appears to be required for chow diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.

Project description:Detrimental exposures in mothers are recognized as risk factors for the development of metabolic dysfunction in offspring. In contrast, maternal exercise has been reported to be an effective strategy to maintain offspring health. However, the mechanisms underlying the protective effects of maternal exercise on adult offspring metabolic homeostasis are largely unclear. This study aims to investigate whether maternal exercise before and during pregnancy could combat the adverse effects of maternal high-fat diet (HFD) on metabolism in 24-week-old male offspring and to explore the role of miRNAs in mediating the effects. Female C57BL/6 mice were fed with either control diet or HFD 3-week prior to breeding and throughout pregnancy and lactation, among whom half of the HFD-fed mice were submitted to voluntary wheel running training 3-week before and during pregnancy. Male offspring were sedentary and fed with a control diet from weaning to 24 weeks. Body weight, the content of inguinal subcutaneous adipose tissue and perirenal visceral adipose tissue, glucose tolerance, and serum insulin and lipids in offspring were analyzed. Hepatic tissues were collected for transcriptome and miRNA sequencing and reverse transcription-quantitative polymerase chain reaction validation. The results showed that maternal HFD resulted in significant glucose intolerance, insulin resistance, and dyslipidemia in adult offspring, which were negated by maternal exercise. Transcriptome sequencing showed that maternal exercise reversed perinatal HFD-regulated genes in adult offspring, which were enriched in glucose and lipid metabolic-related signaling pathways. At the same time, maternal exercise significantly rescued the changes in the expression levels of 3 hepatic miRNAs in adult offspring, and their target genes were involved in the regulation of cholesterol biosynthesis and epigenetic modification, which may play an important role in mediating the intergenerational metabolic regulation of exercise. Overall, our research pioneered the role of miRNAs in mediating the programming effects of maternal exercise on adult offspring metabolism, which might provide novel insight into the prevention and treatment of metabolic disorders in early life.

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The beneficial effects of exercise on glucose and lipid metabolism during statin therapy is partially mediated by changes of the intestinal flora

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