scholarly journals Leptin-Mediated Changes in the Human Metabolome

2020 ◽  
Vol 105 (8) ◽  
pp. 2541-2552 ◽  
Author(s):  
Katherine Lawler ◽  
Isabel Huang-Doran ◽  
Takuhiro Sonoyama ◽  
Tinh-Hai Collet ◽  
Julia M Keogh ◽  
...  
Keyword(s):  
Amino Acids ◽  
Caloric Restriction ◽  
Severe Obesity ◽  
Caloric Intake ◽  
Branched Chain Amino Acids ◽  
Endocrine Function ◽  
Acid Oxidation ◽  
Obese People ◽  
Leptin Deficiency ◽  
Branched Chain

Abstract Context While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. Objective The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. Design Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. Results Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. Conclusion Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin’s effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.

Effect of carnitine on branched-chain amino acid oxidation by liver and skeletal muscle.

1978 ◽  
Vol 234 (5) ◽  
pp. E494 ◽  
Author(s):  
H S Paul ◽  
S A Adibi
Keyword(s):  
Amino Acids ◽  
Liver Mitochondria ◽  
Branched Chain Amino Acids ◽  
Diabetic Rats ◽  
Acid Oxidation ◽  
Acyltransferase Activity ◽  
Remarkable Effect ◽  
Carnitine Acyltransferase ◽  
Branched Chain Amino Acid ◽  
Branched Chain

The effect of L-carnitine (0.5-2.0 mM) on the rates of alpha-decarboxylation of 1-14C-labeled branched-chain amino acids by gastrocnemius muscle and liver homogenates of fed rats was investigated. Carnitine increased the rate of alpha-decarboxylation of leucine (125%) and valine (28%) by muscle, but it was without effect on the oxidation of these amino acids by liver. Carnitine increased the rate of alpha-decarboxylation of alpha-ketoisocaproate by both tissues. This effect was more pronounced in muscle (130% increase) than in liver (41% increase). The activity of carnitine acyltransferase, with isovaleryl-CoA as a substrate, was 18 times higher in muscle mitochondria than in liver mitochondria. Both starvation and diabetes increased the rate of alpha-decarboxylation of leucine by muscle without having a remarkable effect on the concentration of carnitine or the activity of carnitine acyltransferase. We conclude that: a) carnitine stimulates decarboxylation of branched-chain amino acids by increasing the conversion of their ketoanalogues into carnitine esters, b) a greater carnitine acyltransferase activity in muscle than in liver may be responsible for the greater carnitine effect in muscle, c) carnitine does not appear responsible for the enhancement of leucine oxidation by muscle of starved and diabetic rats.

scholarly journals The Role of Skeletal Muscle in The Pathogenesis of Altered Concentrations of Branched-Chain Amino Acids (Valine, Leucine, and Isoleucine) in Liver Cirrhosis, Diabetes, and Other Diseases

2021 ◽  
pp. 293-305
Author(s):  
M Holeček
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Liver Cirrhosis ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Branched Chain Amino Acids ◽  
Acid Oxidation ◽  
Amino Group ◽  
Branched Chain

The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to α-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (α-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.

Oxidation of 2-oxoisocaproate and 2-oxoisovalerate by the perfused rat heart. Interactions with fatty acid oxidation

1990 ◽  
Vol 68 (1) ◽  
pp. 260-265 ◽  
Author(s):  
Joan Letto ◽  
John T. Brosnan ◽  
Margaret E. Brosnan
Keyword(s):  
Amino Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Branched Chain Amino Acids ◽  
Acid Oxidation ◽  
Perfused Heart ◽  
Acid Dehydrogenase ◽  
Liver And Kidney ◽  
Labelled Compound ◽  
Branched Chain

The interactions between fatty acid oxidation and the oxidation of the 2-oxo acids of the branched chain amino acids were studied in the isolated Langendorff-perfused heart. 2-Oxoisocaproate inhibited the oxidation of oleate, but 2-oxoisovalerate and 2-oxo-3-methylvalerate did not. This difference was not attributable to the magnitude of the flux through the branched chain 2-oxo acid dehydrogenase, which was slightly higher with 2-oxoisovalerate than with 2-oxoisocaproate. Oxidation of 2-oxoisocaproate in the perfused heart was virtually complete, since more than 80% of the isovaleryl-CoA formed from 2-oxo[1-14C]isocaproate was further metabolized to CO2, as determined by comparing 14CO2 production from 2-oxo[14C(U)]isocaproate with that from the 1-14C-labelled compound. Only twice as much 14CO2 was produced from 2-oxo[14C(U)]isovalerate as from the 1-14C-labelled compound, indicating incomplete oxidation. This was confirmed by the accumulation in the perfusion medium of substantial quantities of labelled 3-hydroxyisobutyrate (an intermediate in the pathway of valine catabolism), when hearts were perfused with 2-oxo[14C(U)]isovalerate. The failure of 2-oxoisovalerate to inhibit fatty acid oxidation, then, can be attributed to the fact that its partial metabolism in the heart produces little ATP. We have previously shown that 3-hydroxyisobutyrate is a good gluconeogenic substrate in liver and kidney, and postulate that 3-hydroxyisobutyrate serves as an interorgan metabolite such that valine can serve as a glucogenic amino acid, even when its catabolism proceeds beyond the irreversible 2-oxo acid dehydrogenase in muscle.Key words: branched chain amino acids, branched chain 2-oxoacids, perfused heart, fatty acid metabolism, 3 -hydroxyisobutyrate.

scholarly journals Effects of Administration of Oral Branched-Chain Amino Acids on Anorexia and Caloric Intake in Cancer Patients

1996 ◽  
Vol 88 (8) ◽  
pp. 550-552 ◽  
Author(s):  
C. Cangiano ◽  
A. Laviano ◽  
M. M. Meguid ◽  
M. Mulieri ◽  
L. Conversano ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cancer Patients ◽  
Caloric Intake ◽  
Branched Chain Amino Acids ◽  
Branched Chain

scholarly journals Regulation of branched-chain amino acid oxidation in isolated muscles, nerves and aortas of rats

1975 ◽  
Vol 148 (3) ◽  
pp. 363-374 ◽  
Author(s):  
M G Buse ◽  
S Jursinic ◽  
S S Reid
Keyword(s):  
Amino Acids ◽  
Spinal Cord ◽  
Peripheral Nerves ◽  
Branched Chain Amino Acids ◽  
The Other ◽  
Acid Oxidation ◽  
Amino Acid Oxidation ◽  
Branched Chain Amino Acid ◽  
14Co2 Production ◽  
Branched Chain

1. The oxidation of the three branched-chain amino acids was regulated in parallel fashion in rat tissues studied in vitro. 2. With 0.1 mM-[1-14C]isoleucine as substrate in the presence of 5.5 mM-glucose, 14CO2 production was 0.6 mumol/2 h per g in the aorta, 0.3 in peripheral nerve, 0.2 in muscle and 0.13 in spinal cord. 3. The ratio 14C oxidized/14C incorporated into proteins with 0.1 mM-[1-14C]leucine was 1.3 in hemidiaphragms, 3.3 in sciatic nerve and 1.0 in nerves undergoing Wallerian degeneration. Leucine oxidation decreased only slightly during degeneration, but protein synthesis doubled. 4. Hemidiaphragms incubated with [1-14C]leucine or 4-methyl-2-oxo[1-14C]pentanoate increased 14CO2 production 7-9-fold as substrate concentration was increased from 0.1 to 0.5 mM; under the same conditions 14CO2 production by nerves increased only 2-3-fold. 5. 2-Oxoglutarate stimulated the oxidation of the branched-chain amino acids by muscles and peripheral nerves and the oxidation of 4-methyl-2-oxopentanoate by hemidiaphragms but not by nerves. 6. Octanoate (0.1-1.0 mM) markedly stimulated the oxidation of branched-chain amino acids and of 4-methyl-2-oxopentanoate in hemidiaphragms, but inhibited oxidation of both by peripheral nerves and spinal cord. In aortas, oxidation of isoleucine (the only substance tested) was inhibited by octanoate. 7. The effects of octanoate and 2-oxoglutarate on leucine oxidation by hemidiaphragms were additive at low concentrations. When maximally stimulating concentrations of either agent were used, addition of the other was ineffective. 8. Pyruvate inhibited the oxidation of branched-chain amino acids and 4-methyl-2-oxopentanoate in all tissues tested. 9. Insulin did not affect the oxidation of 4-methyl-2-oxopentanoate by muscles or nerves. 10. The oxidative decarboxylation of the branched-chain alpha-oxo acids is suggested as a regulatory site of branched-chain amino acid oxidation. Differences in regulation between muscle on the one hand, and nerve and aorta on the other, are discussed.

Total branched-chain amino acids requirement in patients with maple syrup urine disease by use of indicator amino acid oxidation with l-[1-13C]phenylalanine

2004 ◽  
Vol 287 (1) ◽  
pp. E142-E149 ◽  
Author(s):  
Roya Riazi ◽  
Mahroukh Rafii ◽  
Joe T. R. Clarke ◽  
Linda J. Wykes ◽  
Ronald O. Ball ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Maple Syrup Urine Disease ◽  
Branched Chain Amino Acids ◽  
Acid Oxidation ◽  
Maple Syrup ◽  
Amino Acid Oxidation ◽  
Urine Disease ◽  
The Mean ◽  
Branched Chain

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by defects in the mitochondrial multienzyme complex branched-chain α-keto acid dehydrogenase (BCKD; EC 1.2.4.4 ), responsible for the oxidative decarboxylation of the branched-chain ketoacids (BCKA) derived from the branched-chain amino acids (BCAA) leucine, valine, and isoleucine. Deficiency of the enzyme results in increased concentrations of the BCAA and BCKA in body cells and fluids. The treatment of the disease is aimed at keeping the concentration of BCAA below the toxic concentrations, primarily by dietary restriction of BCAA intake. The objective of this study was to determine the total BCAA requirements of patients with classical MSUD caused by marked deficiency of BCKD by use of the indicator amino acid oxidation (IAAO) technique. Five MSUD patients from the MSUD clinic of The Hospital for Sick Children participated in the study. Each was randomly assigned to different intakes of BCAA mixture (0, 20, 30, 50, 60, 70, 90, 110, and 130 mg·kg−1·day−1), in which the relative proportion of BCAA was the same as that in egg protein. Total BCAA requirement was determined by measuring the oxidation of l-[1-13C]phenylalanine to 13CO2. The mean total BCAA requirement was estimated using a two-phase linear regression crossover analysis, which showed that the mean total BCAA requirement was 45 mg·kg−1·day−1, with the safe level of intake (upper 95% confidence interval) at 62 mg·kg−1·day−1. This is the first time BCAA requirements in patients with MSUD have been determined directly.

PSX-A-5 Late-Breaking: Branched chain amino acid and threonine requirements for puppy (>14 wk-9mo) Labrador Retrievers using the indicator amino acid oxidation (IAAO) technique

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 363-364
Author(s):  
Jessica L Varney ◽  
Heather Adams ◽  
Sarah Cox ◽  
Kevin Cline ◽  
Rhianna Bailey ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Control Diet ◽  
Branched Chain Amino Acids ◽  
Acid Oxidation ◽  
Gut Health ◽  
Isoleucine Leucine ◽  
Amino Acid Oxidation ◽  
Branched Chain ◽  
Labrador Retrievers

Abstract Branched chain amino acids are heavily involved in protein synthesis and turnover, emphasizing the need to establish requirement for growing animals. On the other hand, threonine is vital for supporting proteins necessary for gut health. Thus, it is very important to supply branched chain amino acids and threonine in appropriate amounts to growing animals. In this experiment, the indicator amino acid oxidation (IAAO) technique was utilized to determine valine, isoleucine, leucine, and threonine requirements in six puppy Labrador Retrievers (>14wk-9mo). Puppies were subjected to diets ranging from deficient to excess, with each of the indispensable amino acids formulated at 1.6x NRC values. The control diet was fed for two days of adaptation, followed by one experimental day in which the test diet was fed. On the test day, a breath sample was collected using a using a respiration mask (Oxymax, Columbus Instruments). A priming dose of L-[1-^13C]phenylalanine (Cambridge Isotope Laboratories, Inc.) based on body weight was supplied to each puppy, followed by [1-^13C]Phe doses every 30 minutes, for a four hour period. ^13CO[2] was collected after each dose and enrichment was determined by isotope ratio mass spectrometry (IRMS). Results from IRMS were converted to atom percent excess (APE) and analyzed using a segmented line model (JMP^® Pro 16). Each of the Four Rivers mean and population requirements were as follows: 1.72 ± 0.11 g/1000 kcal ME for valine; 1.43 ± 0.24 g/1000 kcal ME for isoleucine; 2.25 ± 0.15 g/1000 kcal ME for leucine; 1.74 ± 0.16 g/1000 kcal ME for threonine (mean ± 2SD). The knowledge gained from this study is highly useful as the lean mass deposited as a puppy influences the animal throughout their lifetime.

Sign in / Sign up

Export Citation Format

Share Document