Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to investigate the relationship between intra-abdominal-obesity susceptibility and the adaptation of skeletal muscle metabolic and histochemical characteristics when fed a high-fat diet (HFD) for a short period of time. Twenty-four male Wistar rats were fed a HFD (39.7% calories of fat) for 5 wk. After the 5-wk dietary period, the rats were sacrificed and divided into intra-abdominal-obesity-prone (OP) or obesity-resistant (OR) groups according to the total intra-abdominal fat pads (epididymal, mesenteric, and perirenal) weights. A superficial portion of the Muscle (M.) gastrocnemius tissue obtained from 2 groups before and after feeding the HFD were analyzed to determine their hexokinase (HK), (beta-hydroxyacyl CoA dehydrogenase (beta-HAD), and citrate synthase (CS) activities. Muscle fiber composition and capillary density were examined in the deep portion of the M. gastrocnemius, soleus, and extensor digitorum longus (EDL) gained after the HFD. While the OP group had more intra-abdominal fat pads and a heavier final body weight than the OR group, there was no significant difference in the energy intake between the two. Due to the HFD, the OP group showed significant increases in beta-HAD and CS activities, while the OR group did not. Change of beta-HAD activity by HFD in the OP group was significantly greater than that in the OR group. The ratio of fat oxidation, expressed as beta-HAD/CS, significantly increased in the OP group, but not in the OR group. No differences were found in either the muscle fiber composition or capillarization. These results suggest that intra-abdominal-obesity-susceptive rats may have a higher adaptation degree in muscle oxidative enzyme activities as characteristic in the early stage of intra-abdominal adipose accumulation.
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PMID:Adaptation of skeletal muscle characteristics to a high-fat diet in rats with different intra-abdominal-obesity susceptibilities. 1459 10

Leptin plays a central role in the regulation of fatty acid homeostasis, promoting lipid storage in adipose tissue and fatty acid oxidation in peripheral tissues. Loss of leptin signaling leads to accumulation of lipids in muscle and loss of insulin sensitivity secondary to obesity. In this study, we examined the direct and indirect effects of leptin signaling on mitochondrial enzymes including those essential for peripheral fatty acid oxidation. We assessed the impact of leptin using the JCR:LA-cp rat, which lacks functional leptin receptors. The activities of marker mitochondrial enzymes citrate synthase (CS) and cytochrome oxidase (COX) were similar between wild-type (+/?) and corpulent (cp/cp) rats. In contrast, several tissues showed variations in the fatty acid oxidizing enzymes carnitine palmitoyltransferase II (CPT II), long-chain acyl-CoA dehydrogenase (LCAD) and 3-hydroxyacyl-CoA dehydrogenase (HOAD). It was not clear if these changes were due to loss of leptin signaling or to insulin insensitivity. Consequently, we examined the effects of leptin on cultured C(2)C(12) and Sol8 cells. Leptin (3 days at 0, 0.2, or 2.0 nM) had no direct effect on the activities of CS, COX, or fatty acid oxidizing enzymes. Leptin treatment did not affect luciferase-based reporter genes under the control of transcription factors involved in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), nuclear respiratory factor-2 (NRF-2)) or fatty acid enzyme expression (peroxisome proliferator-activated receptors (PPARs)). These studies suggest that leptin exerts only indirect effects on mitochondrial gene expression in muscle, possibly arising from insulin resistance.
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PMID:Leptin and the control of respiratory gene expression in muscle. 1473 84

The purpose of this study was to investigate the effect of endurance training (10 weeks) on previously reported alterations of lactate exchange in obese Zucker fa/fa rats. We used sarcolemmal vesicles to measure lactate transport capacity in control sedentary rats, Zucker (fa/fa), and endurance trained Zucker (fa/fa) rats. Monocarboxylate transporter (MCT) 1 and 4 content was measured in sarcolemmal vesicles and skeletal muscle. Training increased citrate synthase activity in soleus and in red tibialis anterior, and improved insulin sensitivity measured by intraperitoneal glucose tolerance test. Endurance training increased lactate influx in sarcolemmal vesicles at 1 mM of external lactate concentration and increased MCT1 expression on sarcolemmal vesicles. Furthermore, muscular lactate level was significantly decreased after training in red tibialis anterior and extensor digitorum longus. This study shows that endurance training improves impairment of lactate transport capacity that is found in insulin resistance state like obesity and type 2 diabetes.
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PMID:Endurance training increases lactate transport in male Zucker fa/fa rats. 1588 22

To understand mechanisms underlying a resistance to obesity, two obesity-resistant inbred mouse strains, SWR/J and A/J, were compared to 3 inbred "control" strains, C3H/HeJ, BALB/cByJ and C57L/J. These 5 strains, studied at 5 weeks of age when similar in body weight, were maintained for 3 weeks on a 3-diet feeding paradigm, with separate jars of carbohydrate, protein and fat, or for 1 week on a single high-fat or low-fat diet. The control strains each chose a balanced diet, with 50% carbohydrate and 15-25% fat, and they had a similar, normal range of scores for measures of body weight, adiposity, endocrine parameters and metabolic enzyme activity. Compared to these control strains, the obesity-resistant SWR/J and A/J strains consumed more total calories and selected a diet with significantly more fat (35-45%) and less carbohydrate (35%). Despite overeating, they weighed less and had significantly reduced adiposity. They also had lower levels of insulin and exhibited increased capacity of skeletal muscle to metabolize fat, as indicated by measures beta-hydroxyacyl-CoA dehydrogenase activity or its ratio to citrate synthase. Measurements of hypothalamic peptides via radioimmunoassay or real-time quantitative PCR revealed markedly enhanced galanin (GAL) in the paraventricular nucleus and reduced neuropeptide Y (NPY) expression in the arcuate nucleus of obesity-resistant mice. These patterns in SWR/J and A/J strains, seen on a low-fat as well as high-fat diet, may reflect mechanisms involving excess GAL and reduced NPY that contribute early, respectively, to the over-consumption of a high-fat diet and a resistance to the obesity-promoting effects of this diet.
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PMID:Phenotypic profile of SWR/J and A/J mice compared to control strains: possible mechanisms underlying resistance to obesity on a high-fat diet. 1589 25

Tests were conducted to determine whether weight gain or nutrient intake measures during the first week of exposure to a macronutrient diet can accurately predict an animal's long-term propensity towards obesity. In multiple groups of normal-weight Sprague-Dawley rats (n=35-70/group), daily weight gain during the first 5 days on a high-fat diet (45-60% fat) was found to be strongly, positively correlated (r=+0.71 to r=+0.82) with accumulated body fat in 4 dissected depots after 4-6 weeks on the diet. This measure consistently identified obesity-prone (OP) rats which, relative to the obesity-resistant (OR) rats, were only slightly heavier (+15 g, 4%) and hyperphagic (+9 kcal, 8%) after 5 days but markedly heavier (+70g) with up to 2-fold greater fat mass after several weeks on the diet. Other dietary conditions and measures revealed weaker relationships to ultimate body fat accrual. The OP rats identified by their 5-day weight-gain score exhibited at this early stage clear disturbances characteristic of markedly obese rats. These included elevated leptin, insulin, triglycerides and glucose, along with increased lipoprotein lipase activity (LPL) in adipose tissue and galanin expression in the paraventricular nucleus. Most notable were significant reductions in muscle of LPL activity and ratio of beta-hydroxyacyl-CoA dehydrogenase to citrate synthase activity, indicating a decline in lipid transport and capacity of muscle to metabolize lipids. By occurring early with initial weight gain, these hypothalamic and metabolic disturbances in OP rats, favoring fat storage in adipose tissue over fat oxidation in muscle, may have causal relationships to long-term accumulation of body fat.
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PMID:Model for predicting and phenotyping at normal weight the long-term propensity for obesity in Sprague-Dawley rats. 1651 48

beta-Ketoacyl-ACP synthases catalyze the condensation steps in fatty acid and polyketide synthesis and are targets for the development of novel antibiotics and anti-obesity and anti-cancer agents. The roles of the active site residues in Streptococcus pneumoniae FabF (beta-ketoacyl-ACP synthase II; SpFabF) were investigated to clarify the mechanism for this enzyme superfamily. The nucleophilic cysteine of the active site triad was required for acyl-enzyme formation and the overall condensation activity. The two active site histidines in the elongation condensing enzyme have different electronic states and functions. His337 is essential for condensation activity, and its protonated Nepsilon stabilizes the negative charge developed on the malonyl thioester carbonyl in the transition state. The Nepsilon of His303 accelerated catalysis by deprotonating a structured active site water for nucleophilic attack on the C3 of malonate, releasing bicarbonate. Lys332 controls the electronic state of His303 and also plays a critical role in the positioning of His337. Phe396 functions as a gatekeeper that controls the order of substrate addition. These data assign specific roles for each active site residue and lead to a revised general mechanism for this important class of enzymes.
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PMID:Roles of the active site water, histidine 303, and phenylalanine 396 in the catalytic mechanism of the elongation condensing enzyme of Streptococcus pneumoniae. 1661 5

Impaired mitochondrial function and structure and intramyocellular lipid (IMCL) accumulation have been associated with obesity and Type 2 diabetes. We examined whether endurance exercise training and sex influenced IMCL and mitochondrial morphology using electron microscopy, whole-body substrate use, and mitochondrial enzyme activity. Untrained men (n = 5) and women (n = 7) were tested before and after 7 wk of endurance exercise training. Testing included 90 min of cycle ergometry at 60% Vo(2 peak) with preexercise muscle biopsies analyzed for IMCL and mitochondrial size/area using electron microscopy and short-chain beta-hydroxyacyl-CoA dehydrogenase (SCHAD) and citrate synthase (CS) enzyme activity. Training increased the mean lipid area density (P = 0.090), the number of IMCL droplets (P = 0.055), the number of IMCL droplets in contact with mitochondria (P = 0.010), the total mitochondrial area (P < 0.001), and the size of individual mitochondrial fragments (P = 0.006). Women had higher mean lipid area density (P = 0.030) and number of IMCL droplets (P = 0.002) before and after training, but higher individual IMCL area only before training (P = 0.013), compared with men. Women oxidized more fat (P = 0.027) and less carbohydrate (P = 0.032) throughout the study. Training increased Vo(2 peak) (P < 0.001), %fat oxidation (P = 0.018), SCHAD activity (P = 0.003), and CS activity (P = 0.042). In summary, endurance exercise training increased IMCL area density due to an increase in the number of lipid droplets, whereas the increase in total mitochondrial area was due to an increase in the size of individual mitochondrial fragments. In addition, women have higher IMCL content compared with men due mainly to a greater number of individual droplets. Finally, endurance exercise training increased the proportion of IMCL in physical contact with mitochondria.
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PMID:Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. 1709 51

A reduction in fatty acid oxidation has been associated with lipid accumulation and insulin resistance in the skeletal muscle of obese individuals. We examined whether this decrease in fatty acid oxidation was attributable to a reduction in muscle mitochondrial content and/or a dysfunction in fatty acid oxidation within mitochondria obtained from skeletal muscle of age-matched, lean [body mass index (BMI) = 23.3 +/- 0.7 kg/m2] and obese women (BMI = 37.6 +/- 2.2 kg/m2). The mitochondrial marker enzymes citrate synthase (-34%), beta-hydroxyacyl-CoA dehydrogenase (-17%), and cytochrome c oxidase (-32%) were reduced (P < 0.05) in obese participants, indicating that mitochondrial content was diminished. Obesity did not alter the ability of isolated mitochondria to oxidize palmitate; however, fatty acid oxidation was reduced at the whole muscle level by 28% (P < 0.05) in the obese. Mitochondrial fatty acid translocase (FAT/CD36) did not differ in lean and obese individuals, but mitochondrial FAT/CD36 was correlated with mitochondrial fatty acid oxidation (r = 0.67, P < 0.05). We conclude that the reduction in fatty acid oxidation in obese individuals is attributable to a decrease in mitochondrial content, not to an intrinsic defect in the mitochondria obtained from skeletal muscle of obese individuals. In addition, it appears that mitochondrial FAT/CD36 may be involved in regulating fatty acid oxidation in human skeletal muscle.
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PMID:Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. 1731 93

Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.
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PMID:The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. 1732 47

There are fewer mitochondria and a reduced oxidative capacity in skeletal muscle in obesity. Moderate-intensity physical activity combined with weight loss increase oxidative enzyme activity in obese sedentary adults; however, this adaptation occurs without a significant increase in mitochondrial DNA (mtDNA), which is unlike the classic pattern of mitochondrial biogenesis induced by vigorous activity. The objective of this study was to examine the hypothesis that the mitochondrial adaptation to moderate-intensity exercise and weight loss in obesity induces increased mitochondrial cristae despite a lack of mtDNA proliferation. Content of cardiolipin and mtDNA and enzymatic activities of the electron transport chain (ETC) and tricarboxylic acid cycle were measured in biopsy samples of vastus lateralis muscle obtained from sedentary obese men and women before and following a 4-mo walking intervention combined with weight loss. Cardiolipin increased by 60% from 47 +/- 4 to 74 +/- 8 microg/mU CK (P < 0.01), but skeletal muscle mtDNA content did not change significantly (1,901 +/- 363 to 2,169 +/- 317 Rc, where Rc is relative copy number of mtDNA per diploid nuclear genome). Enzyme activity of the ETC increased (P < 0.01); that for rotenone-sensitive NADH-oxidase (96 +/- 1%) increased more than for ubiquinol-oxidase (48 +/- 6%). Activities for citrate synthase and succinate dehydrogenase increased by 29 +/- 9% and 40 +/- 6%, respectively. In conclusion, moderate-intensity physical activity combined with weight loss induces skeletal muscle mitochondrial biogenesis in previously sedentary obese men and women, but this response occurs without mtDNA proliferation and may be characterized by an increase in mitochondrial cristae.
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PMID:Characteristics of skeletal muscle mitochondrial biogenesis induced by moderate-intensity exercise and weight loss in obesity. 1743 Oct 90


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