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PubMed1993

Is dehydroepiandrosterone an antiobesity agent?

The steroid hormone intermediate, DHEA, has been proposed as a therapeutic agent for the treatment of obesity. Its effects on lipogenesis, substrate cycling, peroxisome proliferation, mitochondrial respiration, protein synthesis, and thyroid hormone function have been reported. The results of these studies suggest that the antiobesity function of DHEA is not simply one of inhibiting fat synthesis and deposition but is one of affecting a number of pathways that contribute to the maintenance of the isoenergetic state rather than the promotion of positive energy balance.

Animals↗
PubMed2006

A role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis.

An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose tissue fat stores exert a suppressive effect on thermogenesis. Using a previously described rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se, we report here that the gene expression of stearoyl-coenzyme A desaturase 1 (SCD1) is elevated in skeletal muscle after 2 wk of semistarvation and remains elevated in parallel to the phase of suppressed thermogenesis favoring catch-up fat during refeeding. These elevations in the SCD1 transcript are skeletal muscle specific and are associated with elevations in microsomal Delta9 desaturase enzyme activity, in the Delta9 desaturation index, and in the relative content of SCD1-derived monounsaturates in several lipid fractions extracted from skeletal muscle. An elevated skeletal muscle SCD1, by desaturating the products of de novo lipogenesis and diverting them away from mitochondrial oxidation, would inhibit substrate cycling between de novo lipogenesis and lipid oxidation, thereby leading to a state of suppressed thermogenesis that regulates the body's fat stores.

Animals↗
PubMed1999

Magnetic resonance spectroscopy in toxic encephalopathy and neurodegeneration.

Magnetic resonance spectroscopy allows neurochemistry to be probed noninvasively in vivo. Recent advances in our understanding of the biochemical significance of the various neurochemicals that are observable allow a variety of pathologic states of relevance to encephalopathies and neurodegenerative disorders to be observed. Measurements of brain glutamate and glutamine allow observation of neuronal/glial substrate cycling and ammonia detoxification. Myo-inositol allows changes in cerebral osmolarity and gliosis to be observed. N-acetylaspartate is a marker of neuronal health and number. Lactate allows nonoxidative glycolysis to be observed. These molecules are now being used to ask etiologic questions that are of relevance to encephalopathies and neurodegeneration, as well to probe longitudinally both natural history and therapeutic interventions in these conditions. Combined with recent advances in anatomic magnetic resonance imaging as well as perfusion magnetic resonance imaging, magnetic resonance spectroscopy has the potential to aid greatly in our understanding of neuronal dysfunction in a wide variety of neurologic pathologies, even in single patients.

Animals↗
PubMed1995

Alternative Oxidase Activity in Tobacco Leaf Mitochondria (Dependence on Tricarboxylic Acid Cycle-Mediated Redox Regulation and Pyruvate Activation).

Transgenic Nicotiana tabacum (cv Petit Havana SR1) containing high levels of mitochondrial alternative oxidase (AOX) protein due to the introduction of a sense transgene(s) of Aox1, the nuclear gene encoding AOX, were used to investigate mechanisms regulating AOX activity. After purification of leaf mitochondria, a large proportion of the AOX protein was present as the oxidized (covalently associated and less active) dimer. High AOX activity in these mitochondria was dependent on both reduction of the protein by DTT (to the noncovalently associated and more active dimer) and its subsequent activation by certain [alpha]-keto acids, particularly pyruvate. Reduction of AOX to its more active form could also be mediated by intramitochondrial reducing power generated by the oxidation of certain tricarboxylic acid cycle substrates, most notably isocitrate and malate. Our evidence suggests that NADPH may be specifically required for AOX reduction. All of the above regulatory mechanisms applied to AOX in wild-type mitochondria as well. Transgenic leaves lacking AOX due to the introduction of an Aox1 antisense transgene or multiple sense transgenes were used to investigate the potential physiological significance of the AOX-regulatory mechanisms. Under conditions in which respiratory carbon metabolism is restricted by the capacity of mitochondrial electron transport, feed-forward activation of AOX by mitochondrial reducing power and pyruvate may act to prevent redirection of carbon metabolism, such as to fermentative pathways.

Journal Article↗
PubMed1978

Organic Acid Metabolism by Isolated Rhizobium japonicum Bacteroids.

Rhizobium japonicum bacteroids isolated from soybean (Glycine max L.) nodules oxidized (14)C-labeled succinate, pyruvate, and acetate in a manner consistent with operation of the tricarboxylic acid cycle and a partial glyoxylate cycle. Substrate carbon was incorporated into all major cellular components (cell wall + membrane, nucleic acids, and protein).

Journal Article↗
PubMed1992

Metabolism of 2'-carboxyarabinitol in leaves.

Results presented here indicate that 2'-carboxyarabinitol (CA) is the in vivo precursor and product of 2'-carboxyarabinitol 1-phosphate (CA1P) metabolism in leaves. When [2-(14)C]CA was fed in the light to leaves of five species known to be highly active in CA1P metabolism (Phaseolus vulgaris, Lycopersicon esculentum, Helianthus annuus, Petunia hybrida, and Beta vulgaris), [(14)C]CA1P was formed in the dark. Reillumination of a Phaseolus leaf caused this [(14)C]CA1P to be rapidly metabolized to [(14)C]CA (t((1/2)) = 1 min). The epimer 2'-carboxyribitol could not substitute for CA in the dark synthesis of CA1P, and CA in the anionic form was a better substrate than CA in the lactone form. In leaves of Phaseolus vulgaris, the active CA pool size used in the dark synthesis of CA1P is between about 70 and 110 nanomoles per milligram of chlorophyll. The photosynthetic electron transport inhibitor diuron did not affect the dark synthesis of [(14)C]CA1P, but did greatly reduce the rate of its subsequent light degradation (t((1/2)) = approximately 10 min). Dark synthesis of [(14)C]CA1P was inhibited by dithiothreitol and NaF. From the present data, we suggest that CA1P and CA participate in a metabolic substrate cycle in vivo.

Journal Article↗
PubMed1989

Hydroxyurea increases the phosphorylation of 3'-fluorothymidine and 3'-azidothymidine in CEM cells.

The triphosphates of the nucleoside analogues 3'-azidothymidine and 3'-fluorothymidine inhibit reverse transcriptase and are of therapeutic interest for the treatment of retrovirus infections. At equimolar concentrations 3'-fluorothymidine was more effectively transformed to the triphosphate by human CEM cells than azidothymidine which mainly accumulates as the monophosphate. Hydroxyurea, a drug that inhibits de novo synthesis of deoxyribonucleotides, considerably increased the ability of cells to phosphorylate both analogues. Addition of as little as 50 microM hydroxyurea decreased the amount of dideoxynucleoside required to attain a given intracellular concentration of its triphosphate by an order of magnitude. Hydroxyurea is known to shift the balance of substrate cycles between natural deoxynucleosides and their 5'-phosphates in the direction of synthesis and thereby to increase the import and intracellular phosphorylation of the nucleoside. The present results demonstrate a similar effect for the two analogues and raise the possibility of using this effect in therapy.

Antiviral Agents↗
PubMed1993

The role of the NAD-dependent glutamate dehydrogenase in restoring growth on glucose of a Saccharomyces cerevisiae phosphoglucose isomerase mutant.

Phosphoglucose isomerase pgi1-deletion mutants of Saccharomyces cerevisiae cannot grow on glucose as the sole carbon source and are even inhibited by glucose. These growth defects could be suppressed by an over-expression on a multi-copy plasmid of the structural gene GDH2 coding for the NAD-dependent glutamate dehydrogenase. GDH2 codes for a protein with 1092 amino acids which is located on chromosome XII and shows high sequence similarity to the Neurospora crassa NAD-glutamate dehydrogenase. Suppression of the pgi1 deletion by over-expression of GDH2 was abolished in strains with a deletion of the glucose-6-phosphate dehydrogenase gene ZWF1 or gene GDH1 coding for the NADPH-dependent glutamate dehydrogenase. Moreover, this suppression required functional mitochondria. It is proposed that the growth defect of pgi1 deletion mutants on glucose is due to a rapid depletion of NADP which is needed as a cofactor in the oxidative reactions of the pentose phosphate pathway. Over-expression of the NAD-dependent glutamate dehydrogenase leads to a very efficient conversion of glutamate with NADH generation to 2-oxoglutarate which can be converted back to glutamate by the NADPH-dependent glutamate dehydrogenase with the consumption of NADPH. Consequently, over-expression of the NAD-dependent glutamate dehydrogenase causes a substrate cycling between 2-oxoglutarate and glutamate which restores NADP from NADPH through the coupled conversion of NAD to NADH which can be oxidized in the mitochondria. Furthermore, the requirement for an increase in NADPH consumption for the suppression of the phosphoglucose isomerase defect could be met by addition of oxidizing agents which are known to reduce the level of NADPH.

Amino Acid Sequence↗
PubMed1984

Determination of glutathione and ATP in ganglia and individual neurons of Aplysia californica.

The levels of two gamma-glutamyl cycle substrates, glutathione and ATP, were determined in single identified nerve cell bodies from the CNS of Aplysia californica. The glutathione content of single cells averaged 30 +/- 4.9 mumol/g protein. Glutathione levels were similar in identified cholinergic, serotonergic, and histaminergic cells, as well as in neurons whose transmitters are not yet identified. The abdominal rostral white cells, which are enriched in glycine, a component amino acid of glutathione, did not possess distinctively higher glutathione concentrations. The ATP content of single Aplysia nerve cell bodies averaged 15.0 +/- 1.5 mumol/g protein. Despite the vast chemical, anatomical, and functional heterogeneity between Aplysia central neurons, no cells were found that contained unusually high or low ATP levels.

Adenosine Triphosphate↗
PubMed2006

Molecular cloning and transcriptional expression analysis of an intracellular beta-glucosidase, a family 3 glycosyl hydrolase, from the edible straw mushroom, Volvariella volvacea.

A beta-glucosidase, with a molecular mass of 95 kDa, was isolated from extracts of Volvariella volvacea mycelium grown on crystalline cellulose. Degenerate primers based on the N-terminal sequences of purified beta-glucosidase and two protease-generated peptides were used to generate cDNA fragments encoding a portion of the beta-glucosidase gene (bgl), and rapid amplification of cDNA ends was used to obtain full-length cDNA clones. The cDNA of bgl contained an ORF of 2586 bp coding for 862 amino acids. Alignment of the deduced amino-acid sequence of beta-glucosidase with deduced amino acid sequences of other microbial beta-glucosidases showed the highest overall homology with glycoside hydrolase family 3 beta-glucosidases from fungi. Transcripts of bgl were detected in total RNA extracted from mycelium grown on cellulose and cellobiose, and from mycelium pre-grown for 72 h in basal medium containing 1% (w/v) sorbitol following addition of alpha-lactose, beta-lactose, cellobiose, d- xylose, l-sorbose, beta-gentiobiose, sophorose or d-galactose. Addition of l-sorbose and d-glucosamine to mycelium grown on 1% (w/v) crystalline cellulose greatly increased the level of bgl expression. bgl Was expressed at various stages of the mushroom developmental cycle (substrate colonization to mature fruit body), although the number of bgl transcripts in pinhead and button stages was slightly smaller.

Agaricales↗
PubMed1989

Changes of high-energy phosphorous compounds in skeletal muscle during glucose-induced thermogenesis in man. A 31P MR spectroscopy study.

By the use of invasive techniques, skeletal muscle has been shown to contribute to thermogenesis induced by glucose in humans. In an attempt to study this phenomenon by a non-invasive method, this study investigated intracellular high-energy phosphorous compounds in calf muscle by 31P MR spectroscopy during an oral glucose load in healthy lean subjects. The inorganic phosphate concentration increased gradually (P less than 0.05) after glucose intake. The phosphocreatine/inorganic phosphate rate decreased (P less than 0.05) and the estimated ADP concentration increased. ATP and intracellular pH remained unchanged after the glucose administration. No changes were seen in the control experiments. The processes responsible for the decreased energy state of the skeletal muscle cell may be an obligatory conversion of glucose to glycogen. Also, facultative processes, such as sodium/potassium pumping and substrate cycles stimulated by the sympatho-adrenal system, may be partly responsible.

Adenosine Diphosphate↗
PubMed1986

Resistance of Candida parapsilosis to drugs.

Several strains of Candida parapsilosis, isolated independently in our laboratory, had their resistance compared to a series of inhibitors which act either at the level of mitochondrial ribosomes (chloramphenicol, erythromycin, paromomycin) or at the level of mitochondrial respiration and oxidative phosphorylation (oligomycin, antimycin A, diuron, carbonylcyanide m-chlorophenylhydrazone). Cells were grown on glycerol media supplemented with one of these inhibitors, and it was demonstrated that the resistance of these yeasts to a large spectrum of antibiotics was due to several features: a resistance to oligomycin was found at the permeation level; the resistance to the other drugs was correlated to the relative insensitivity of cytochrome biosynthesis to the drugs; the cells developed, at the same time, two types of alternative pathways: the one branched at the ubiquinone level which drove electrons from Krebs cycle substrates to oxygen, and the other, antimycin A-insensitive but inhibited by amytal, salicylhydroxamic acid and high cyanide concentrations. This secondary mitochondrial pathway, driving reducing equivalents from cytoplasmic NADH to cytochrome c and then to cytochrome aa3 or to alternate oxidase, allowed the growth of Candida parapsilosis on a non fermentescible medium, supplemented with these drugs.

Antimycin A↗
PubMed1994

Quantitative aspects of glucose and glutamine metabolism by intestinal cells.

Gut fuel utilisation has several unique features. Arterial and luminal fuels provide nutrition for the enterocyte, the former being of more importance. This factor, and the heterogeneity of cell types within the gut makes it difficult to define its fuel utilisation. Metabolic control logic suggests that modulation of the maximal activity of any pathway resides in those enzymes that operate in vivo at rates far below their maximal capacity and that catalyse non-equilibrium reactions. On this basis, although enterocyte hexokinase activity is much higher than in other 'glycolytic' cells (for example, brain), potentially high rates of glucose utilisation are modulated by substrate cycling of glucose 6-phosphate back to glucose through glucose 6-phosphatase. Glutamine metabolism proceeds by glutaminase to produce glutamate, which may then be transaminated (aspartate-aminotransferase and alanine-amino transferase) to produce alpha-ketoglutarate, alanine, and aspartate. The end products of glutamine metabolism by incubated gut preparations in vitro (mainly alanine), suggests that enterocytes, not immune cells, are responsible for most gut glutamine metabolism. High flux rates of glucose and glutamine metabolism in the enterocyte may result from the need for de novo synthesis of purines and pyrimidines and ribose sugars for nucleic acid synthesis. Sepsis reduces rates of glucose and glutamine metabolism, perhaps to preserve the increased consumption of these fuels by activated lymphocytes and macrophages in the gut wall.

Bacterial Infections↗
PubMed1977

ATP utilization associated with recovery metabolism in anaerobic frog muscle.

The ATP turnover during single isometric 0.5-, 1-, and 3-s tetani in anaerobic frog sartorii was measured at 20 degrees C. In parallel experiments, we measured the lactate production by sartorii during their metabolic recovery from such tetani. From these measurements, we obtained an experimental P/lactate ratio which was less than 1.5, the expected value for simple Embden-Meyerhof glycolysis when glycogen is metabolized to lactate. We interpreted these results as indicating a substantial amount of suprabasal ATP breakdown occurred during metabolic recovery. The operation of the fructose phosphate substrate cycle is suggested as a cause of this additional ATP breakdown.

Adenosine Triphosphate↗
PubMed1987

Effect of short-term fasting on lipolytic responsiveness in normal and obese human subjects.

In this study the rate of lipolysis (fatty acid and glycerol release into blood) has been quantified in both normal weight and obese volunteers after both 15 and 87 h of fasting. In each study, the basal rate and subsequent response to epinephrine infusion (0.015 microgram X kg-1 X min-1) were determined. The rate of appearance (Ra) of free fatty acids (FFA) and glycerol were quantified by infusion of [1-13C]palmitate and D-5-glycerol, respectively. Substrate flux rates per unit of body fat mass and lean body mass were calculated from total body water measurements using H2(18)O dilution. In normal volunteers, the basal Ra FFA and Ra glycerol rose markedly with 87 h of fasting, whereas the increases were more modest in the obese subjects. However, the rate of mobilization of fat, in relation to the lean body mass, was higher in the obese subjects than in the normal subjects after 15 h of fasting, and the values were similar in both groups after 87 h of fasting. There was an increased lipolytic response to epinephrine after fasting in both groups. This increased sensitivity may have resulted from the enhancement of fatty acid-triglyceride substrate cycling that occurred after fasting.

Adult↗
PubMed1987

Lipolytic response to glucose infusion in human subjects.

We have determined the effect of various rates of glucose infusion on the rates of release of glycerol (Ra glycerol), free fatty acids (Ra FFA), and on energy metabolism in normal human volunteers. Plasma kinetics were determined with use of the stable isotopic tracers D-5-glycerol and [1-13C]palmitate, and energy metabolism was determined by indirect calorimetry. The effect of glucose infusion on Ra glycerol and Ra FFA was dose-dependent. At an infusion rate of 1 mg X kg-1 X min-1, no effect on either kinetic factor was noted. At 4 mg X kg-1 X min-1, both Ra glycerol and Ra FFA were suppressed; at 8 mg X kg-1 X min-1, Ra FFA was even more depressed, but Ra glycerol was similar to the value during the 4 mg X kg-1 X min-1 infusion. At all infusion rates tested, the amount of potential energy available from the sum of the glucose infusion and endogenously mobilized fat was always greater than when no glucose was infused. Glucose decreased fat mobilization by both inhibiting lipolysis and stimulating reesterification, thus causing a significant increase in triglyceride-fatty acid substrate cycling within the adipose tissue.

Adult↗
PubMed1994

Metabolic interactions between surplus dietary energy intake and cigarette smoking or its cessation.

Cigarette smoking (CS) alters lipid metabolism and is associated clinically with an atherogenic lipid profile. We recently showed that, under controlled eucaloric dietary conditions, CS stimulates lipolysis without increasing oxidation of fat and that cessation of CS does not result in a rebound tendency to synthesize or store fat. We asked here whether the ad libitum intake of surplus dietary energy interacts with the metabolic effects of CS or its cessation. Eight male heavy smokers were allowed ad libitum food intake in a metabolic ward, 1 wk in CS phase and 1 wk in non-CS phase, followed by 4 wk of outpatient non-CS and a repeat 7-day study. De novo hepatic lipogenesis (DNL), lipolysis, substrate cycling of free fatty acids (FFA), hepatic glucose production, and energy expenditure were measured by using a multiple stable-isotope infusion protocol and indirect calorimetry. Surplus dietary energy intake (> 150% of predicted energy needs) occurred in five of eight subjects (2 subjs > 5,500 kcal/day, 3 subjs > 4,000 kcal/day) with weight gain of 1-4 kg/wk, but with no difference between CS and non-CS phases. Acute CS significantly increased (P < 0.05) serum FFA concentrations (58%), FFA flux (63%), and glycerol flux (36%); nonsignificantly increased extra-adipocyte (hepatic) esterification of FFA (125%, P = 0.10) and resting energy expenditure (4.1%, P = 0.22); and did not change adipocyte reesterification of FFA or whole body oxidation of fat. Basal metabolic parameters (after overnight abstention from CS) did not differ between phases. Fractional DNL correlated significantly with excess energy intake (r2 = 0.39) and with percentage of total energy needs provided by carbohydrate (r2 = 0.47). The absence or presence of CS did not affect the increase in fractional DNL in subjects with excess energy intake, however. We conclude that cessation of CS does not result in a rebound tendency to synthesis or storage of fat, even in the presence of positive short-term energy balance, contrary to previous suggestions. Moreover, stimulation of lipolysis by CS does not increase oxidation of fat and thereby protect against fat deposition under conditions of surplus energy intake. The prevention of weight gain after cessation of CS, whether or not nicotine is provided, should focus on energy balance (calorigenesis as well as intake) rather than specific alterations in lipid metabolism.

Adult↗
PubMed1983

Renal ammoniagenesis and acid excretion in the dogfish, Squalus acanthias.

Renal ammoniagenesis and acid excretion were investigated in normal dogfish (Squalus acanthias) and dogfish made acidotic by HCl injection (0.65 meq X kg-1). After acid loading, renal ammonia excretion doubled, rising from 0.11 to 0.25 mueq X h-1, and titratable acid output increased from 28.6 to 44.9 mueq X h-1. Trimethylamine excretion averaged 23.2 mueq X h-1 and did not change in response to the acidosis. During the first 24 h postinjection, the increase in renal acid excretion accounted for the elimination of 15% of the acid load. In vitro studies with kidney slices demonstrated that the dogfish kidney has the capacity to synthesize ammonia from a number of amino acids including glutamine, glutamate, alanine, aspartate, and glycine, with the greatest ammonia production resulting from glutamine. The relatively high glutamine concentration in the kidney, compared with the blood, suggested a high renal capacity for glutamine synthesis. In renal homogenates, enzymatic activities for both the deamidation (glutaminase) and synthesis (glutamine synthetase) of glutamine were investigated. The Michaelis constant (Km) values for the two enzymes were found to be almost equal (4.48 mM glutamine and 4.33 mM glutamate) and at the same levels as the substrate concentrations in the kidney (3.69 mM glutamine and 3.36 mM glutamate). Subcellular localization revealed that both enzymes occur predominantly in the mitochondria. The activities of glutaminase and glutamine synthetase in the renal mitochondria suggest the presence of a substrate cycle that could be modulated to increase ammonia production during acidosis.

Amino Acids↗