Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular adaptations to endurance training are influenced by the intensity and duration of exercise. To examine the impact of exercise intensity and duration on the acute transcriptional regulation of metabolic genes in red (RG) and white (WG) gastrocnemius muscle, rats completed either low-intensity [ approximately 50% maximal O2 uptake (VO2 max)] treadmill exercise (LIE) for 45 min, LIE for 180 min, or high-intensity ( approximately 75% VO2 max) exercise (HIE) for 45 min. LIE for 45 min activated (P < 0.05) transcription of the pyruvate dehydrogenase kinase-4 (PDK4), uncoupling protein-3 (UCP3), heme oxygenase-1 (HO-1), and hexokinase II (HK II) genes in RG within 1 h after exercise. In WG, transcription of PDK4, UCP3, HKII, and lipoprotein lipase (LPL) was also induced, whereas transcription of the HO-1 gene did not change. In RG, extending LIE duration from 45 to 180 min elicited a similar activation of PDK4 and UCP3 ( approximately 15-fold) but a far greater increase in HO-1 (>30-fold) and HKII transcription (>25-fold). In WG, extending LIE for 180 min induced a much greater and prolonged (through 2- to 4-h recovery) activation of PDK4, UCP3 (both >200-fold), and HO-1 (>10-fold). HIE elicited a similar pattern of gene activation to LIE in both RG and WG, with the exception that HIE triggered >10-fold activation of HO-1 in WG. These data provide evidence that both the intensity and the duration of exercise affect the transcriptional regulation of metabolic genes in muscle in a fiber type-specific manner, possibly reflecting the relative stress imposed by the exercise bout.
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PMID:Differential transcriptional activation of select metabolic genes in response to variations in exercise intensity and duration. 1290 22

We searched for the presence of uncoupling protein genes so far unknown in marsupials and monotremes and identified uncoupling protein 2 (UCP2) and UCP3 full-length cDNAs in libraries constructed from the marsupials Antechinus flavipes and Sminthopsis macroura. Marsupial UCP2 is 89-90% identical to rodent UCP2, whereas UCP3 exhibits 80% identity to mouse UCP3. A phylogenetic tree including all known UCPs positions the novel marsupial UCP2 and UCP3 at the base of the mammalian orthologs. In the 5'-untranslated region of UCP2 a second open reading frame encoding for a 36-amino acid peptide was identified which is highly conserved in all vertebrate UCP2 transcripts. Analysis of tissue specificity in A. flavipes with homologous cDNA probes revealed ubiquitous presence of UCP2 mRNA and striated muscle specificity of UCP3 mRNA resembling the known expression pattern in rodents. Neither UCP2 nor UCP3 gene expression was stimulated in adipose tissue and skeletal muscle of cold exposed A. flavipes. However, UCP3 mRNA expression was upregulated 6-fold in heart and 2.5-fold in skeletal muscle as reported for rodents in response to fasting. Furthermore, UCP3 mRNA seems to be coregulated with PDK4 mRNA, indicating a relation to enhanced lipid metabolism. In contrast, UCP2 gene expression was not regulated in response to fasting in adipose tissue and skeletal muscle but was diminished in the lung and increased in adipose tissue. Taken together, the sequence analysis, tissue specificity and physiological regulation suggest a conserved function of UCP2 and UCP3 during 130 million years of mammalian evolution.
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PMID:Uncoupling protein 2 and 3 in marsupials: identification, phylogeny, and gene expression in response to cold and fasting in Antechinus flavipes. 1497 Mar 61

Skeletal muscle possesses a high degree of plasticity and can adapt to both the physical and metabolic challenges that it faces. An acute bout of exercise is sufficient to induce the expression of a variety of metabolic genes, such as GLUT4, pyruvate dehydrogenase kinase 4 (PDK-4), uncoupling protein-3 (UCP3), and peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1). Reducing muscle glycogen levels before exercise potentiates the effect of exercise on many genes. Similarly, altered substrate availability induces transcription of many of these genes. The purpose of this study was to determine whether glucose ingestion attenuates the exercise-induced increase in a variety of exercise-responsive genes. Six male subjects (28 +/- 7 yr; 83 +/- 3 kg; peak pulmonary oxygen uptake = 46 +/- 6 ml.kg(-1).min(-1)) performed 60 min of cycling at 74 +/- 2% of peak pulmonary oxygen uptake on two separate occasions. On one occasion, subjects ingested a 6% carbohydrate drink. On the other occasion, subjects ingested an equal volume of a sweet placebo. Muscle samples were obtained from vastus lateralis at rest, immediately after exercise, and 3 h after exercise. PDK-4, UCP3, PGC-1, and GLUT4 mRNA levels were measured on these samples using real-time RT-PCR. Glucose ingestion attenuated (P < 0.05) the exercise-induced increase in PDK-4 and UCP3 mRNA. A similar trend (P = 0.09) was observed for GLUT4 mRNA. In contrast, PGC-1 mRNA increased following exercise to the same extent in both conditions. These data suggest that glucose availability can modulate the effect of exercise on metabolic gene expression.
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PMID:Effect of carbohydrate ingestion on exercise-induced alterations in metabolic gene expression. 1593 64

Ingestion of carbohydrate during exercise may blunt the stimulation of fat oxidative pathways by raising plasma insulin and glucose concentrations and lowering plasma free fatty acid (FFA) levels, thereby causing a marked shift in substrate oxidation. We investigated the effects of a single 2-h bout of moderate-intensity exercise on the expression of key genes involved in fat and carbohydrate metabolism with or without glucose ingestion in seven healthy untrained men (22.7 +/- 0.6 yr; body mass index: 23.8 +/- 1.0 kg/m(2); maximal O(2) consumption: 3.85 +/- 0.21 l/min). Plasma FFA concentration increased during exercise (P < 0.01) in the fasted state but remained unchanged after glucose ingestion, whereas fat oxidation (indirect calorimetry) was higher in the fasted state vs. glucose feeding (P < 0.05). Except for a significant decrease in the expression of pyruvate dehydrogenase kinase-4 (P < 0.05), glucose ingestion during exercise produced minimal effects on the expression of genes involved in carbohydrate utilization. However, glucose ingestion resulted in a decrease in the expression of genes involved in fatty acid transport and oxidation (CD36, carnitine palmitoyltransferase-1, uncoupling protein 3, and 5'-AMP-activated protein kinase-alpha(2); P < 0.05). In conclusion, glucose ingestion during exercise decreases the expression of genes involved in lipid metabolism rather than increasing genes involved in carbohydrate metabolism.
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PMID:Glucose ingestion during exercise blunts exercise-induced gene expression of skeletal muscle fat oxidative genes. 1603 63

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.
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PMID:Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin. 1644 71

Previous investigations show that intracerebroventricular administration of a potent inhibitor of fatty acid synthase, C75, increases the level of its substrate, malonyl-CoA, in the hypothalamus. The "malonyl-CoA signal" is rapidly transmitted to skeletal muscle by the sympathetic nervous system, increasing fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure. Here, we show that intracerebroventricular or intraperitoneal administration of C75 increases the number of mitochondria in white and red (soleus) skeletal muscle. Consistent with signal transmission from the hypothalamus by the sympathetic nervous system, centrally administered C75 rapidly (< or =2 h) up-regulated the expression (in skeletal muscle) of the beta-adrenergic signaling molecules, i.e., norepinephrine, beta3-adrenergic receptor, and cAMP; the transcriptional regulators peroxisomal proliferator activator regulator gamma coactivator 1alpha (PGC-1alpha) and estrogen receptor-related receptor alpha (ERRalpha); and the expression of key oxidative mitochondrial enzymes, including pyruvate dehydrogenase kinase, medium-chain length fatty acyl-CoA dehydrogenase, ubiquinone-cytochrome c reductase, cytochrome oxidase, as well as ATP synthase and UCP3. The role of PGC-1alpha in mediating these responses in muscle was assessed with C2C12 myocytes in cell culture. Consistent with the in vivo response, adenovirus-directed expression of PGC-1alpha in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration. These effects, coupled with an increased carnitine palmitoyltransferase 1b, led to increased fatty acid oxidation. PGC-1alpha also increased the expression of ERRalpha, PPARalpha, and enzymes that support mitochondrial fatty acid oxidation, ATP synthesis, and thermogenesis, apparently mediated by an increased expression of UCP3.
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PMID:Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1alpha. 1703 Jul 88

High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)beta inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and (13)C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.
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PMID:Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. 1736 43

Corticosteroids (CS) effects on insulin resistance related genes in rat skeletal muscle were studied. In our acute study, adrenalectomized (ADX) rats were given single doses of 50 mg/kg methylprednisolone (MPL) intravenously. In our chronic study, ADX rats were implanted with Alzet mini-pumps giving zero-order release rates of 0.3 mg/kg/h MPL and sacrificed at various times up to 7 days. Total RNA was extracted from gastrocnemius muscles and hybridized to Affymetrix GeneChips. Data mining and literature searches identified 6 insulin resistance related genes which exhibited complex regulatory pathways. Insulin receptor substrate-1 (IRS-1), uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), fatty acid translocase (FAT) and glycerol-3-phosphate acyltransferase (GPAT) dynamic profiles were modeled with mutual effects by calculated nuclear drug-receptor complex (DR(N)) and transcription factors. The oscillatory feature of endothelin-1 (ET-1) expression was depicted by a negative feedback loop. These integrated models provide testable quantitative hypotheses for these regulatory cascades.
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PMID:Pharmacodynamic/pharmacogenomic modeling of insulin resistance genes in rat muscle after methylprednisolone treatment: exploring regulatory signaling cascades. 1978 81

This study aimed to assess the effects of carbohydrate (CHO) and fat intake on the expression of key genes related with nutrient partitioning and metabolism in main tissues involved in energy metabolism (white adipose tissue, liver, and skeletal muscle). Rats were studied under different conditions: feeding state, 24 h fasting, and 12 h refeeding after 24 h fasting with isocaloric amounts of CHO or fat. Fat, but not CHO, refeeding was associated with an increase in serum and liver triglyceride content. Main changes in gene expression elicited by CHO compared with fat refeeding were: 1) higher expression levels of genes related with lipogenesis (PPARgamma2, ChREBP, FAS), glucose uptake and metabolism (GLUT4, HKII), fatty acid uptake (LPL, CD36), and lipolysis (ATGL, HSL) in white adipose tissue; 2) higher expression levels of genes related with lipogenesis (FAS, SCD1) but lower ones related with fatty acid uptake (CD36) and oxidation (PPARalpha, CPT1, PDK4) in liver; and 3) higher expression levels of GLUT4 but lower ones related with fatty acid oxidation (PDK4 and UCP3) in muscle. It is worth mentioning that both CHO and fat refeeding resulted in a robust increase in both hepatic mRNA and circulating levels of fibroblast growth factor-21, compared with fasted levels. In summary, these results, showing marked differences in gene expression after CHO and fat refeeding, can explain diet-associated differences in fuel handling and partitioning between tissues; in addition, a role of fibroblast growth factor-21 in metabolic adaptations, not only in the ketotic state but also to face an unbalanced nutritional situation, is suggested.
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PMID:Response to carbohydrate and fat refeeding in the expression of genes involved in nutrient partitioning and metabolism: striking effects on fibroblast growth factor-21 induction. 1983 71

Knowledge of in vivo relationship between the coactivator PPARGC1A and its target genes is very limited, especially in the pig. In this study, a real-time PCR experiment was performed on longissimus dorsi muscle (MLD) and backfat with 10 presumed PPARGC1A downstream target genes, involved in energy and fat metabolism, to identify possible relationships with PPARGC1A mRNA expression in vivo in the pig (n = 20). Except for UCP3 and LPL, a very significant difference in expression was found between MLD and backfat for all genes (P < 0.01). Hierarchical cluster analysis and the significant pairing of mRNA expression data between sampling locations suggested a genetic regulation of the expression of several target genes. A positive correlation with PPARGC1A was found for CPT1B, GLUT4, PDK4, and TFAM (P < 0.0001). A negative correlation was found for UCP2, FABP4, LEP (P < 0.0001), and TNF (P = 0.0071). No significant correlation was detected for UCP3 and LPL. This study provides evidence for a clear difference in mRNA expression of crucial genes in fat and energy metabolism between 2 important tissues. Our data suggest a clear impact of PPARGC1A on energy and lipid metabolism in vivo in the pig, through several of these downstream target genes.
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PMID:Correlation between porcine PPARGC1A mRNA expression and its downstream target genes in backfat and longissimus dorsi muscle. 1987 86


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