Testosterone prevents protein loss via the hepatic urea cycle in human

ContextThe urea cycle is a rate-limiting step for amino acid nitrogen elimination. The rate of urea synthesis is a true indicator of whole-body protein catabolism. Testosterone reduces protein and nitrogen loss. The effect of testosterone on hepatic urea synthesis in humans has not been studied.ObjectiveTo determine whether testosterone reduces hepatic urea production.DesignAn open-label study.Patients and interventionEight hypogonadal men were studied at baseline, and after two weeks of transdermal testosterone replacement (Testogel, 100 mg/day).Main outcomes measuresThe rate of hepatic urea synthesis was measured by the urea turnover technique using stable isotope methodology, with15N2-urea as tracer. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, were calculated.ResultsTestosterone administration significantly reduced the rate of hepatic urea production (from 544.4 ± 71.8 to 431.7 ± 68.3 µmol/min;P < 0.01), which was paralleled by a significant reduction in serum urea concentration. Testosterone treatment significantly reduced net protein loss, as measured by percent Lox/LRa, by 19.3 ± 5.8% (P < 0.05). There was a positive association between Lox and hepatic urea production at baseline (r2 = 0.60,P < 0.05) and after testosterone administration (r2 = 0.59,P < 0.05).ConclusionTestosterone replacement reduces protein loss and hepatic urea synthesis. We conclude that testosterone regulates whole-body protein metabolism by suppressing the urea cycle.

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Interaction between Testosterone and Growth Hormone on Whole-Body Protein Anabolism Occurs in the Liver

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2521 ◽

2011 ◽

Vol 96 (4) ◽

pp. 1060-1067 ◽

Cited By ~ 17

Author(s):

Vita Birzniece ◽

Udo J. Meinhardt ◽

Margot A. Umpleby ◽

David J. Handelsman ◽

Ken K. Y. Ho

Keyword(s):

Protein Metabolism ◽

Whole Body ◽

Protein Breakdown ◽

Protein Loss ◽

Open Label ◽

Gh Therapy ◽

Body Protein ◽

Gh Replacement ◽

Testosterone Administration ◽

The Impact

Abstract Context: GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. Objective: Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. Design: In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. Patients and Intervention: Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. Main Outcome Measures: Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. Results: In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. Conclusions: In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.

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The mysteries of nitrogen balance

Nutrition Research Reviews ◽

10.1079/095442299108728857 ◽

1999 ◽

Vol 12 (1) ◽

pp. 25-54 ◽

Cited By ~ 84

Author(s):

J. C Waterlow

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Urea Cycle ◽

N Balance ◽

Single Amino Acid ◽

Whole Body ◽

Acid Oxidation ◽

Physiological Level ◽

Body Protein ◽

Urea Production

AbstractThe first part of this review is concerned with the balance between N input and output as urinary urea. I start with some observations on classical biochemical studies of the operation of the urea cycle. According to Krebs, the cycle is instantaneous and automatic, as a result of the irreversibility of the first enzyme, carbamoyl-phosphate synthetase 1 (EC 6.3.5.5; CPS-I), and it should be able to handle many times the normal input to the cycle. It is now generally agreed that acetyl glutamate is a necessary co-factor for CPS-1, but not a regulator. There is abundant evidence that changes in dietary protein supply induce coordinated changes in the amounts of all five urea-cycle enzymes. How this coordination is achieved, and why it should be necessary in view of the properties of the cycle mentioned above, is unknown. At the physiological level it is not clear how a change in protein intake is translated into a change of urea cycle activity. It is very unlikely that the signal is an alteration in the plasma concentration either of total amino-N or of any single amino acid. The immediate substrates of the urea cycle are NH3 and aspartate, but there have been no measurements of their concentration in the liver in relation to urea production. Measurements of urea kinetics have shown that in many cases urea production exceeds N intake, and it is only through transfer of some of the urea produced to the colon, where it is hydrolysed to NH3, that it is possible to achieve N balance. It is beginning to look as if this process is regulated, possibly through the operation of recently discovered urea transporters in the kidney and colon. The second part of the review deals with the synthesis and breakdown of protein. The evidence on whole-body protein turnover under a variety of conditions strongly suggests that the components of turnover, including amino acid oxidation, are influenced and perhaps regulated by amino acid supply or amino acid concentration, with insulin playing an important but secondary role. Molecular biology has provided a great deal of information about the complex processes of protein synthesis and breakdown, but so far has nothing to say about how they are coordinated so that in the steady state they are equal. A simple hypothesis is proposed to fill this gap, based on the self-evident fact that for two processes to be coordinated they must have some factor in common. This common factor is the amino acid pool, which provides the substrates for synthesis and represents the products of breakdown. The review concludes that although the achievement and maintenance of N balance is a fact of life that we tend to take for granted, there are many features of it that are not understood, principally the control of urea production and excretion to match the intake, and the coordination of protein synthesis and breakdown to maintain a relatively constant lean body mass.

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Whole-body urea cycling and protein turnover during hyperphagia and dormancy in growing bears (Ursus americanus and U. arctos)

Canadian Journal of Zoology ◽

10.1139/z97-848 ◽

1997 ◽

Vol 75 (12) ◽

pp. 2129-2136 ◽

Cited By ~ 83

Author(s):

Perry S. Barboza ◽

Sean D. Farley ◽

Charles T. Robbins

Keyword(s):

Protein Turnover ◽

Whole Body ◽

Turnover Rates ◽

Protein Loss ◽

Plasma Urea ◽

Body Protein ◽

Urea Production ◽

Amino Acid Degradation ◽

Urea Kinetics ◽

N Resorption

Subadult bears were studied during their autumn hyperphagia (n = 3) and winter dormancy (n = 6). Urea kinetics were measured with 14C- and 15N-urea, protein turnover was estimated with 15N-glycine, and body composition was assessed with 3H-water. Reduced amino acid degradation in winter was indicated by declines in plasma urea and aminotransferase activities, and lower urea production than in autumn (4.7 vs. 27.5 mmol urea-N∙kg−0.75∙d−1). Only 7.5% of urea produced in hyperphagic bears was degraded and just 1.1% of the degraded N reutilized as amino-N. Dormant bears reutilized 99.7% of urea produced, indicating thorough microbial ureolysis and urea-N resorption. Low rates of body N loss during dormancy suggested losses of non-urea N as creatinine. Protein turnover rates (15.2–21.5 g∙kg−0.75∙d−1) were similar between seasons and reflected the apparent maintenance of hepatic, intestinal, and muscular functions through dormancy. Protein synthesis accounted for 32% of energy expended in dormancy, which was mainly (91.5%) derived from fat oxidation. Consistent organ function and body temperature in dormant bears enables recycling of urea-N, which minimizes body protein loss and conserves mobility. In comparison with heterothermic hibernation, ursid dormancy would provide greater flexibility during winter and facilitate rapid resumption of foraging and growth in spring.

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A potent liver-mediated mechanism for loss of muscle mass during androgen deprivation therapy

Endocrine Connections ◽

10.1530/ec-19-0179 ◽

2019 ◽

Vol 8 (5) ◽

pp. 605-615 ◽

Cited By ~ 1

Author(s):

Teresa Lam ◽

Mark McLean ◽

Amy Hayden ◽

Anne Poljak ◽

Birinder Cheema ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Deprivation Therapy ◽

Protein Metabolism ◽

Exercise Intervention ◽

Muscular Atrophy ◽

Androgen Deprivation ◽

Whole Body ◽

Protein Loss ◽

Body Protein ◽

Urea Production

Context Androgen deprivation therapy (ADT) in prostate cancer results in muscular atrophy, due to loss of the anabolic actions of testosterone. Recently, we discovered that testosterone acts on the hepatic urea cycle to reduce amino acid nitrogen elimination. We now hypothesize that ADT enhances protein oxidative losses by increasing hepatic urea production, resulting in muscle catabolism. We also investigated whether progressive resistance training (PRT) can offset ADT-induced changes in protein metabolism. Objective To investigate the effect of ADT on whole-body protein metabolism and hepatic urea production with and without a home-based PRT program. Design A randomized controlled trial. Patients and intervention Twenty-four prostate cancer patients were studied before and after 6 weeks of ADT. Patients were randomized into either usual care (UC) (n = 11) or PRT (n = 13) starting immediately after ADT. Main outcome measures The rate of hepatic urea production was measured by the urea turnover technique using 15N2-urea. Whole-body leucine turnover was measured, and leucine rate of appearance (LRa), an index of protein breakdown and leucine oxidation (Lox), a measure of irreversible protein loss, was calculated. Results ADT resulted in a significant mean increase in hepatic urea production (from 427.6 ± 18.8 to 486.5 ± 21.3; P < 0.01) regardless of the exercise intervention. Net protein loss, as measured by Lox/Lra, increased by 12.6 ± 4.9% (P < 0.05). PRT preserved lean body mass without affecting hepatic urea production. Conclusion As early as 6 weeks after initiation of ADT, the suppression of testosterone increases protein loss through elevated hepatic urea production. Short-term PRT was unable to offset changes in protein metabolism during a state of profound testosterone deficiency.

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Effects of a Caspase and a Calpain Inhibitor on Resting Energy Expenditures in Normal and Hypermetabolic Rats: a Pilot Study

Physiological Research ◽

10.33549/physiolres.933201 ◽

2016 ◽

pp. 537-541 ◽

Cited By ~ 1

Author(s):

P. G. VANA ◽

H. M. LAPORTE ◽

R. H. KENNEDY ◽

R. L. GAMELLI ◽

M. MAJETSCHAK

Keyword(s):

Whole Body ◽

Calpain Inhibitor ◽

Protein Loss ◽

Body Protein ◽

Physiological Conditions ◽

Energy Expenditures ◽

Calpain Inhibitors ◽

Caspase Cascades ◽

Observation Period ◽

Resting Energy

Several diseases induce hypermetabolism, which is characterized by increases in resting energy expenditures (REE) and whole body protein loss. Exaggerated protein degradation is thought to be the driving force underlying this response. The effects of caspase and calpain inhibitors on REE in physiological and hypermetabolic conditions, however, are unknown. Thus, we studied whether MDL28170 (calpain inhibitor) or z-VAD-fmk (caspase inhibitor) affect REE under physiological conditions and during hypermetabolism post-burn. Rats were treated five times weekly and observed for 6 weeks. Treatment was started 2 h (early) or 48 h (late) after burn. In normal rats, MDL28170 transiently increased REE to 130 % of normal during week 2-4. z-VAD-fmk reduced REE by 20-25 % throughout the observation period. Within 14 days after burns, REE increased to 130±5 %. Whereas MDL28170/early treatment did not affect REE, MDL28170/late transiently increased REE to 180±10 % of normal by week 4 post-burn. In contrast, with z-VAD-fmk/early REE remained between 90-110 % of normal post-burn. z-VAD-fmk/late did not affect burn-induced increases in REE. These data suggest that caspase cascades contribute to the development of hypermetabolism and that burn-induced hypermetabolism can be pharmacologically modulated. Our data point towards caspase cascades as possible therapeutic targets to attenuate hypermetabolism after burns, and possibly in other catabolic disease processes.

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Urea cycle intermediate kinetics and nitrate excretion at normal and "therapeutic" intakes of arginine in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.269.5.e884 ◽

1995 ◽

Vol 269 (5) ◽

pp. E884-E896 ◽

Cited By ~ 19

Author(s):

L. Beaumier ◽

L. Castillo ◽

A. M. Ajami ◽

V. R. Young

Keyword(s):

Urea Cycle ◽

Whole Body ◽

Healthy Young Adult ◽

Adult Men ◽

Acid Diet ◽

Leucine Kinetics ◽

Urea Production ◽

Plasma Insulin Levels ◽

Plasma Arginine ◽

Arginine Supplementation

We investigated the effects of a high dietary supplement of arginine on plasma arginine, ornithine, and leucine kinetics and on urea production and excretion in five healthy young adult men. Subjects received either 56 or 561 mg arginine.kg-1.day-1 for 6 days via a complete L-amino acid diet, and on day 7 a tracer protocol (first 3 h fasted; next 5 h fed) was conducted, involving primed constant intragastric infusions of L-[15N2-guanidino,5,5-2H2]arginine, L-[5-13C]ornithine, L-[5,5,5-2H3]leucine, and [15N2]urea, with a prime of H13CO3. Plasma arginine and ornithine fluxes increased significantly (P < 0.05) with arginine supplementation, as did the rate of conversion of plasma labeled arginine to ornithine (P < 0.05) and rate of ornithine oxidation (P < 0.001). However, absolute changes in ornithine kinetics were less than those for arginine or those based on changes expected from the change in arginine intake, implying a complex compartmentation in both whole body arginine and ornithine metabolism. The plasma NO3 concentration, daily output of total NO3, and conversion of [15N]arginine to NO3 did not differ between the diets. Urea production and excretion were reduced significantly with arginine supplementation, suggesting an anabolic effect on the whole body nitrogen economy, possibly via the raised plasma insulin levels (P = 0.013) during the prandial phase.

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Impact of Growth Hormone and Dehydroepiandrosterone on Protein Metabolism in Glucocorticoid-Treated Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2333 ◽

2008 ◽

Vol 93 (3) ◽

pp. 688-695 ◽

Cited By ~ 8

Author(s):

Morton G. Burt ◽

Gudmundur Johannsson ◽

A. Margot Umpleby ◽

Donald J. Chisholm ◽

Ken K. Y. Ho

Keyword(s):

Protein Metabolism ◽

Dose Finding ◽

Whole Body ◽

Constant Infusion ◽

Leucine Incorporation ◽

Protein Loss ◽

Body Protein ◽

Prednisone Dose ◽

Leucine Oxidation

Abstract Context: Chronic pharmacological glucocorticoid (GC) use causes substantial morbidity from protein wasting. GH and androgens are anabolic agents that may potentially reverse GC-induced protein loss. Objective: Our objective was to assess the effect of GH and dehydroepiandrosterone (DHEA) on protein metabolism in subjects on long-term GC therapy. Design: This was an open, stepwise GH dose-finding study (study 1), followed by a randomized cross-over intervention study (study 2). Setting: The studies were performed at a clinical research facility. Patients and Intervention: In study 1, six subjects (age 69 ± 4 yr) treated with long-term (>6 months) GCs (prednisone dose 8.3 ± 0.8 mg/d) were studied before and after two sequential GH doses (0.8 and 1.6 mg/d) for 2 wk each. In study 2, 10 women (age 71 ± 3 yr) treated with long-term GCs (prednisone dose 5.4 ± 0.5 mg/d) were studied at baseline and after 2-wk treatment with GH 0.8 mg/d, DHEA 50 mg/d, or GH and DHEA (combination treatment). Main Outcome Measure: Changes in whole body protein metabolism were assessed using a 3-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance, leucine oxidation, and leucine incorporation into protein were estimated. Results: In study 1, GH 0.8 and 1.6 mg/d significantly reduced leucine oxidation by 19% (P = 0.03) and 31% (P = 0.02), and increased leucine incorporation into protein by 10% (P = 0.13) and 19% (P = 0.04), respectively. The lower GH dose did not cause hyperglycemia, whereas GH 1.6 mg/d resulted in fasting hyperglycemia in two of six subjects. In study 2, DHEA did not significantly change leucine metabolism alone or when combined with GH. Blood glucose was not affected by DHEA. Conclusion: GH, at a modest supraphysiological dose of 0.8 mg/d, induces protein anabolism in chronic GC users without causing diabetes. DHEA 50 mg/d does not enhance the effect of GH. GH may safely prevent or reverse protein loss induced by chronic GC therapy.

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Modulation of the gut microbiota with antibiotic treatment suppresses whole body urea production in neonatal pigs

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00229.2011 ◽

2013 ◽

Vol 304 (3) ◽

pp. G300-G310 ◽

Cited By ~ 20

Author(s):

Patrycja Puiman ◽

Barbara Stoll ◽

Lars Mølbak ◽

Adrianus de Bruijn ◽

Henk Schierbeek ◽

...

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Gut Microbiota ◽

Whole Body ◽

Synthesis Rate ◽

Protein Synthesis Rate ◽

Urea Synthesis ◽

Plasma Urea ◽

Body Protein ◽

Neonatal Pigs

We examined whether changes in the gut microbiota induced by clinically relevant interventions would impact the bioavailability of dietary amino acids in neonates. We tested the hypothesis that modulation of the gut microbiota in neonatal pigs receiving no treatment (control), intravenously administered antibiotics, or probiotics affects whole body nitrogen and amino acid turnover. We quantified whole body urea kinetics, threonine fluxes, and threonine disposal into protein, oxidation, and tissue protein synthesis with stable isotope techniques. Compared with controls, antibiotics reduced the number and diversity of bacterial species in the distal small intestine (SI) and colon. Antibiotics decreased plasma urea concentrations via decreased urea synthesis. Antibiotics elevated threonine plasma concentrations and turnover, as well as whole body protein synthesis and proteolysis. Antibiotics decreased protein synthesis rate in the proximal SI and liver but did not affect the distal SI, colon, or muscle. Probiotics induced a bifidogenic microbiota and decreased plasma urea concentrations but did not affect whole body threonine or protein metabolism. Probiotics decreased protein synthesis in the proximal SI but not in other tissues. In conclusion, modulation of the gut microbiota by antibiotics and probiotics reduced hepatic ureagenesis and intestinal protein synthesis, but neither altered whole body net threonine balance. These findings suggest that changes in amino acid and nitrogen metabolism resulting from antibiotic- or probiotic-induced shifts in the microbiota are localized to the gut and liver and have limited impact on whole body growth and anabolism in neonatal piglets.

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Effects of the amount and quality of dietary protein on nitrogen metabolism and protein turnover of pigs

British Journal Of Nutrition ◽

10.1079/bjn19870096 ◽

1987 ◽

Vol 58 (2) ◽

pp. 287-300 ◽

Cited By ~ 52

Author(s):

M. F. Fuller ◽

P. J. Reeds ◽

A. Cadenhead ◽

B. Seve ◽

T. Preston

Keyword(s):

Dietary Protein ◽

Protein Turnover ◽

Growing Pigs ◽

Whole Body ◽

Urea Synthesis ◽

Total N ◽

Plasma Urea ◽

Body Protein ◽

N Retention

1. The interrelations between protein accretion and whole-body protein turnover were studied by varying the quantity and quality of protein given to growing pigs.2. Diets with 150 or 290g lysine-deficient protein/kg were given in hourly meals, with or without lysine supplementation, to female pigs (mean weight 47 kg).3. After the animals were adapted to the diets, a constant infusion of [14C]urea was given intra-arterially for 30 h, during the last 6 h of which an infusion of [4,5-3H] leucine was also infused at a constant rate. At the same time, yeast-protein labelled with15N was given in the diet for 50 h.4. The rate of urea synthesis was estimated from the specific radioactivity (SR) of plasma urea. The rate of leucine flux was estimated from the SR of plasma leucine. The irrevocable breakdown of leucine was estimated from the3H-labelling of body water. Total N flux was estimated from the16N-labelling of urinary urea.5. Addition of lysine to the low-protein diet significantly increased N retention, with a substantial reduction in leucine breakdown, but there was no significant change in the flux of leucine or of total N.6. Increasing the quantity of the unsupplemented protein also increased N retention significantly, with concomitant increases in leucine breakdown and in the fluxes of leucine and of total N.7. It is concluded that a doubling of protein accretion brought about by the improvement of dietary protein quality is not necessarily associated with an increased rate of whole-body protein turnover.

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