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The nuclear hormone receptors liver X receptor α (LXRα) and peroxisome proliferator-activated receptor γ (PPARγ) play key roles in the development of fatty liver. To determine the link between hepatic PPARγ and LXRα signaling and the development of fatty liver, a LXRα-specific ligand, T0901317, was administered to normal OB/OB and genetically obese (ob/ob) mice lacking hepatic PPARγ (PparγΔH). In ob/ob-PparγΔH and OB/OB-PparγΔH mice, as well as ob/ob-PparγWT and OB/OB-PparγWT mice, the liver weights and hepatic triglyceride levels were markedly increased in response to T0901317 treatment. These results suggest that hepatic PPARγ and LXRα signals independently contribute to the development of fatty liver.  相似文献   

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It is well recognized that PGC-1α protein is a key regulator of mitochondrial biogenesis. Mechanical and metabolic perturbations in a skeletal muscle during and after aerobic exercise lead to an increased expression of PGC- gene. This increased expression of PGC- gene after exercise depends on the relative workload intensity and does not depend on the fitness level. The goal of this study was to compare mRNA expression of PGC-, TFAM, and TFB2M regulators of mitochondrial biogenesis and FOXO1 and Atrogin-1 proteolysis-related genes in a skeletal muscle of untrained and trained men after aerobic exercise with the same relative workload. This study showed that PGC- gene expression after exercise was the same in the two groups, but the expression of TFAM and TFB2M genes was higher in untrained muscles than in trained ones. In contrast, the expression of FOXO1 and Atrogin-1 genes increased only in the muscles of trained men.  相似文献   

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The ingestion of capsaicin, the principle pungent component of red and chili peppers, induces thermogenesis, in part, through the activation of brown adipocytes expressing genes related to mitochondrial biogenesis and uncoupling such as peroxisome proliferator‐activated receptor (Ppar) γ coactivator‐1α (Pgc‐1α) and uncoupling protein 1 (Ucp1). Capsaicin has been suggested to induce the activation of brown adipocytes, which is mediated by the stimulation of sympathetic nerves. However, capsaicin may directly affect the differentiation of brown preadipocytes, brown adipocyte function, or both, through its significant absorption. We herein demonstrated that Trpv1, a capsaicin receptor, is expressed in brown adipose tissue, and that its expression level is increased during the differentiation of HB2 brown preadipocytes. Furthermore, capsaicin induced calcium influx in brown preadipocytes. A treatment with capsaicin in the early stage of brown adipogenesis did not affect lipid accumulation or the expression levels of Fabp4 (a gene expressed in mature adipocytes), Pparγ2 (a master regulator of adipogenesis) or brown adipocyte‐selective genes. In contrast, a treatment with capsaicin in the late stage of brown adipogenesis slightly increased the expression levels of Fabp4, Pparγ2 and Pgc‐1α. Although capsaicin did not affect the basal expression level of Ucp1, Ucp1 induction by forskolin was partially inhibited by capsaicin, irrespective of the dose of capsaicin. The results of the present study suggest the direct effects of capsaicin on brown adipocytes or in the late stage of brown adipogenesis.  相似文献   

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In recent years, much attention has been paid by the scientific community to phenolic compounds as active biomolecules naturally present in foods. Pterostilbene is a resveratrol dimethylether derivative which shows higher bioavailability. The aim of the present study was to analyze the effect of pterostilbene on brown adipose tissue thermogenic markers in a model of genetic obesity, which shows reduced thermogenesis. The experiment was conducted with 30 Zucker (fa/fa) rats that were distributed in three experimental groups: control and two groups orally administered with pterostilbene at 15 and 30 mg/kg body weight/day for 6 weeks. Gene expression of uncoupling protein 1 (Ucp1), peroxisome proliferator-activated receptor γ co-activator 1 α (Pgc-1α), carnitine palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor α (Pparα), nuclear respiratory factor 1 (Nfr1), and cyclooxygenase-2 (Cox-2); protein expression of PPARα, PGC-1α, p38 mitogen-activated protein kinase (p38 MAPK), UCP1 and glucose transporter (GLUT4); and enzyme activity of CPT 1b and citrate synthase (CS) were assessed in interscapular brown adipose tissue. With the exception of Pgc-1α expression, all these parameters were significantly increased by pterostilbene administration. These results show for the first time that pterostilbene increases thermogenic and oxidative capacity of brown adipose tissue in obese rats. Whether these effects effectively contribute to the antiobesity properties of these compound needs further research.  相似文献   

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Background

The inverse relationship between exercise capacity and its variation over time and both cardiovascular and all-cause mortality suggests the existence of an etiological nexus between cardiometabolic diseases and the molecular regulators of exercise capacity. Coordinated adaptive responses elicited by physical training enhance exercise performance and metabolic efficiency and possibly mediate the health benefits of physical exercise. In contrast, impaired expression of genes involved in mitochondrial biogenesis or protein turnover in skeletal muscle—key biological processes involved in adaptation to physical training—leads to insulin resistance and obesity. Ingestion of fructose has been shown to suppress the exercise-induced GLUT4 response in rat skeletal muscle. To evaluate in greater detail how fructose ingestion might blunt the benefits of physical training, we investigated the effects of fructose ingestion on exercise induction of genes that participate in regulation of mitochondrial biogenesis and protein turnover in rat’s skeletal muscle.

Methods

Eight-week-old Wistar rats were randomly assigned to sedentary (C), exercise (treadmill running)-only (E), fructose-only (F), and fructose + exercise (FE) groups and treated accordingly for 8 weeks. Blood and quadriceps femoris were collected for biochemistry, serum insulin, and gene expression analysis. Expression of genes involved in regulation of mitochondrial biogenesis and autophagy, GLUT4, and ubiquitin E3 ligases MuRF-1, and MAFbx/Atrogin-1 were assayed with quantitative real-time polymerase chain reaction.

Results

Aerobic training improved exercise capacity in both E and FE groups. A main effect of fructose ingestion on body weight and fasting serum triglyceride concentration was detected. Fructose ingestion impaired the expression of PGC-1α, FNDC5, NR4A3, GLUT4, Atg9, Lamp2, Ctsl, Murf-1, and MAFBx/Atrogin-1 in skeletal muscle of both sedentary and exercised animals while expression of Errα and Pparδ was impaired only in exercised rats.

Conclusions

Our results show that fructose ingestion impairs the expression of genes involved in biological processes relevant to exercise-induced remodeling of skeletal muscle. This might provide novel insight on how a dietary factor contributes to the genesis of disorders of glucose metabolism.
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Exercise training mitigates cardiac pathological remodeling and dysfunction caused by myocardial infarction (MI), but its underlying cellular and molecular mechanisms remain elusive. Our present study in an in vivo rat model of MI determined the impact of post-MI exercise training on myocardial fibrosis, mitochondrial biogenesis, antioxidant capacity, and ventricular function. Adult male rats were randomized into: (a) Sedentary control group; (b) 4-week treadmill exercise training group; (c) Sham surgery group; (d) MI group with permanent ligation of left anterior descending coronary artery and kept sedentary during post-MI period; and (e) post-MI 4-week exercise training group. Results indicated that exercise training significantly improved post-MI left ventricular function and reduced markers of cardiac fibrosis. Exercise training also significantly attenuated MI-induced mitochondrial damage and oxidative stress, which were associated with enhanced antioxidant enzyme expression and/or activity and total antioxidant capacity in the heart. Interestingly, the adaptive activation of the SIRT1/PGC-1α/PI3K/Akt signaling following MI was further enhanced by post-MI exercise training, which is likely responsible for exercise-induced cardioprotection and mitochondrial biogenesis. In conclusion, this study has provided novel evidence on the activation of SIRT1/PGC-1α/PI3K/Akt pathway, which may mediate exercise-induced cardioprotection through reduction of cardiac fibrosis and oxidative stress, as well as improvement of mitochondrial integrity and biogenesis in post-MI myocardium.  相似文献   

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The primary goals of the present study were to investigate the inhibitory effects of bromocriptine (BC) on adipogenesis and lipogenesis in 3T3-L1 adipocyte cells as well as to elucidate its molecular mechanism of action. Adipogenic and lipogenic capacity of BC-treated cells was evaluated by oil red-O staining, triglyceride content assay, real-time RT-PCR and immunoblotting. To determine the mechanism responsible for the anti-obesity effect of BC, we applied two methods. Firstly, we knocked down dopamine D2 receptor (D2R) up to 50 % using siRNA. Secondly, we blocked the activity of α2-adrenergic receptor (α2-AR) by yohimbine treatment and monitored its effects on adipogenic and lipogenic events in 3T3-L1 cells. BC decreased the expression levels of adipogenic activators, including Pparα, Pparγ, and Cebpα, as well as major lipogenic target genes, including Me1, Acc1, 6Pgd, Fasn, and Prkaa1. Moreover, BC markedly reduced intracellular nitric oxide formation in a dose-dependent manner and expression of pro-inflammatory genes, Tnfα and Il6, which reflects attenuated pro-inflammatory responses. Further, upon treatment with BC, D2R-deficient cells displayed a significant decrease in lipogenic activity compared to control cells, whereas yohimbine-treated cells exhibited no reduction in lipogenic activity. BC can effectively attenuate adipogenesis and lipogenesis in 3T3-L1 cells by downregulating the expression of lipogenic genes and proteins. Our current experimental data collectively establish that the anti-obesity effects of BC are not D2R-dependent but result from the action of α2-AR in 3T3-L1 adipocytes.  相似文献   

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PurposeExercise tolerance is impaired in hypoxia. The aim of this study was to evaluate the effects of myricetin, a dietary flavonoid compound widely found in fruits and vegetables, on acute hypoxia-induced exercise intolerance in vivo and in vitro.MethodsMale rats were administered myricetin or vehicle for 7 days and subsequently spent 24 hours at a barometric pressure equivalent to 5000 m. Exercise capacity was then assessed through the run-to-fatigue procedure, and mitochondrial morphology in skeletal muscle cells was observed by transmission electron microscopy (TEM). The enzymatic activities of electron transfer complexes were analyzed using an enzyme-linked immuno-sorbent assay (ELISA). mtDNA was quantified by real-time-PCR. Mitochondrial membrane potential was measured by JC-1 staining. Protein expression was detected through western blotting, immunohistochemistry, and immunofluorescence.ResultsMyricetin supplementation significantly prevented the decline of run-to-fatigue time of rats in hypoxia, and attenuated acute hypoxia-induced mitochondrial impairment in skeletal muscle cells in vivo and in vitro by maintaining mitochondrial structure, mtDNA content, mitochondrial membrane potential, and activities of the respiratory chain complexes. Further studies showed that myricetin maintained mitochondrial biogenesis in skeletal muscle cells under hypoxic conditions by up-regulating the expressions of mitochondrial biogenesis-related regluators, in addition, AMP-activated protein kinase(AMPK) plays a crucial role in this process.ConclusionsMyricetin may have important applications for improving physical performance under hypoxic environment, which may be attributed to the protective effect against mitochondrial impairment by maintaining mitochondrial biogenesis.  相似文献   

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Objective

Enhancing structural and functional integrity of mitochondria is an emerging therapeutic option against endothelial dysfunction. In this study, we sought to investigate the effect of fluid shear stress on mitochondrial biogenesis and mitochondrial respiratory function in endothelial cells (ECs) using in vitro and in vivo complementary studies.

Methods and Results

Human aortic- or umbilical vein-derived ECs were exposed to laminar shear stress (20 dyne/cm2) for various durations using a cone-and-plate shear apparatus. We observed significant increases in the expression of key genes related to mitochondrial biogenesis and mitochondrial quality control as well as mtDNA content and mitochondrial mass under the shear stress conditions. Mitochondrial respiratory function was enhanced when cells were intermittently exposed to laminar shear stress for 72 hrs. Also, shear-exposed cells showed diminished glycolysis and decreased mitochondrial membrane potential (ΔΨm). Likewise, in in vivo experiments, mice that were subjected to a voluntary wheel running exercise for 5 weeks showed significantly higher mitochondrial content determined by en face staining in the conduit (greater and lesser curvature of the aortic arch and thoracic aorta) and muscle feed (femoral artery) arteries compared to the sedentary control mice. Interestingly, however, the mitochondrial biogenesis was not observed in the mesenteric artery. This region-specific adaptation is likely due to the differential blood flow redistribution during exercise in the different vessel beds.

Conclusion

Taken together, our findings suggest that exercise enhances mitochondrial biogenesis in vascular endothelium through a shear stress-dependent mechanism. Our findings may suggest a novel mitochondrial pathway by which a chronic exercise may be beneficial for vascular function.  相似文献   

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We have previously shown that 4 wk of exercise training early in life normalizes the otherwise greatly reduced pancreatic β-cell mass in adult male rats born small. The aim of the current study was to determine whether a similar normalization in adulthood of reduced skeletal muscle mitochondrial biogenesis markers and alterations in skeletal muscle lipids of growth-restricted male rats occurs following early exercise training. Bilateral uterine vessel ligation performed on day 18 of gestation resulted in Restricted offspring born small (P < 0.05) compared with both sham-operated Controls and a sham-operated Reduced litter group. Offspring remained sedentary or underwent treadmill running from 5-9 (early exercise) or 20-24 (later exercise) wk of age. At 24 wk of age, Restricted and Reduced litter offspring had lower (P < 0.05) skeletal muscle peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein expression compared with Control offspring. Early exercise training had the expected effect of increasing skeletal muscle markers of mitochondrial biogenesis, but, at this early age (9 wk), there was no deficit in Restricted and Reduced litter skeletal muscle mitochondrial biogenesis. Unlike our previous observations in pancreatic β-cell mass, there was no "reprogramming" effect of early exercise on adult skeletal muscle such that PGC-1α was lower in adult Restricted and Reduced litter offspring irrespective of exercise training. Later exercise training increased mitochondrial biogenesis in all groups. In conclusion, although the response to exercise training remains intact, early exercise training in rats born small does not have a reprogramming effect to prevent deficits in skeletal muscle markers of mitochondrial biogenesis in adulthood.  相似文献   

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We tested the hypothesis that strength exercise after intermittent aerobic exercise might activate signaling pathways that regulate mitochondrial biogenesis (activation of the AMPK and p38 pathways; the expression of PGC-1α, NT-PGC-1α, TFAM, and VEGFA mRNA), protein synthesis (phosphorylation level of p70S6K1Thr389 and eEF2Thr56; the expression IGF-1Ea, IGF-1Ec (MGF), and REDD1 mRNA) and proteolysis (phosphorylation level of FOXO1Ser256; the expression of MURF1, MAFbx, and Myostatin mRNA) in trained skeletal muscles. Nine amateur endurance-trained athletes performed an intermittent aerobic cycling (70 min), followed by one-leg strength exercise (ES: four sets of knee extensions till exhaustion), while the other leg was resting (E). Gene expression and protein level were evaluated in samples from m. vastus lateralis taken before the exercise, 40 min, 5 and 22 h after the aerobic exercise. The phosphorylation level of the АССSer79/222 (an endogenous marker of AMPK activity) and the expression of PGC-1α-related gene TFAM (a marker of mitochondrial biogenesis) were increased after E exercise and did not changed after ES exercise. The expression of PGC-1α and truncated isoform NT-PGC-1α was increased in both legs as well. Insulin concentration in blood was decreased significantly (7.5-fold) after aerobic exercise; the phosphorylation level of FOXOSer256 (a regulator of ubiquitin-related proteolysis) was decreased in both legs, which means that it was activated in both types of exercises; at the same time, the expression of the E3-ubiquitin ligase gene MURF1, its target, was only increased after E exercise. Neither aerobic or combined exercise had a significant effect on the regulation of protein synthesis: there were no changes in either expression of IGF-1Ea and IGF-1Ec(MGF) mRNA isoforms or the phosphorylation levels of markers of protein synthesis p70S6K1Thr389 and eEF2Thr56. Thus, the performance of strength exercise immediately after aerobic one prevented the activation of mitochondrial biogenesis in endurance-trained muscles: activation of AMPK pathway and the expression of TFAM are decreased, while protein synthesis regulation is not affected. At the same time, the strength exercise inhibited the expression of MURF1 gene (a marker of ubiquitin proteasome system), which was induced by aerobic exercise. We suggest that strength exercise performed immediately after intense intermittent aerobic exercise may have a negative effect on aerobic performance if used chronically.  相似文献   

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