A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites.

Vitamin B-6 deficiency is associated with impaired tryptophan metabolism because of the coenzyme role of pyridoxal 5'-phosphate (PLP) for kynureninase and kynurenine aminotransferase. To investigate the underlying mechanism, we developed a mathematical model of tryptophan metabolism via the kynurenine pathway. The model includes mammalian data on enzyme kinetics and tryptophan transport from the intestinal lumen to liver, muscle, and brain. Regulatory mechanisms and inhibition of relevant enzymes were included. We simulated the effects of graded reduction in cellular PLP concentration, tryptophan loads and induction of tryptophan 2,3-dioxygenase (TDO) on metabolite profiles and urinary excretion. The model predictions matched experimental data and provided clarification of the response of metabolites in various extents of vitamin B-6 deficiency. We found that moderate deficiency yielded increased 3-hydroxykynurenine and a decrease in kynurenic acid and anthranilic acid. More severe deficiency also yielded an increase in kynurenine and xanthurenic acid and more pronounced effects on the other metabolites. Tryptophan load simulations with and without vitamin B-6 deficiency showed altered metabolite concentrations consistent with published data. Induction of TDO caused an increase in all metabolites, and TDO induction together with a simulated vitamin B-6 deficiency, as has been reported in oral contraceptive users, yielded increases in kynurenine, 3-hydroxykynurenine, and xanthurenic acid and decreases in kynurenic acid and anthranilic acid. These results show that the model successfully simulated tryptophan metabolism via the kynurenine pathway and can be used to complement experimental investigations.

The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice.

BACKGROUND & AIMS: Zinc homeostasis in cells is maintained through tight regulation of zinc influx, efflux, and distribution to intracellular organelles by zinc transporters. The Zrt-Irt-like protein (ZIP) transporters facilitate zinc influx to the cytosol. Expression of the ZIP family member Zip14 can be induced by inflammatory cytokines, which also initiate liver regeneration. Hepatocyte proliferation is required for liver regeneration. Zinc regulates cell proliferation, tissue growth, and many mitogenic signaling pathways; we investigated its role in hepatocytes. METHODS: Wild-type and Zip14(-/-) mice that underwent partial hepatectomy (70% of liver removed) were used as models of liver regeneration. We also analyzed AML12 hepatocytes that overexpressed Zip14. Proliferation was assessed with proliferating cell nuclear antigen, CD1, and Ki67 markers and along with assays of zinc content was related to protein tyrosine phosphatase 1B (PTP1B) and extracellular signal-regulated kinase 1/2 signaling. RESULTS: Zip14 was up-regulated and hepatic zinc content increased during liver regeneration. Increased hepatic zinc inhibited activity of the phosphatase PTP1B and increased phosphorylation of c-Met, which promoted hepatocyte proliferation. AML12 cells that overexpressed Zip14 increased in zinc content and proliferation; PTP1B was inhibited and phosphorylation of c-Met increased. The increases in hepatic levels of zinc and hepatocyte proliferation that occurred following partial hepatectomy were not observed in Zip14(-/-) mice. CONCLUSIONS: The transporter Zip14 mediates hepatic uptake of zinc during liver regeneration and for hepatocyte proliferation. These findings indicate that zinc transporter activity regulates liver tissue growth by sequestering zinc. Reagents that regulate ZIP14 activity might be developed as therapeutics to promote liver regeneration in patients with chronic liver disease.

Early-phase neuroendocrine responses and strength adaptations following eccentric-enhanced resistance training.

The purpose of this study was to evaluate the early-phase muscular performance adaptations to 5 weeks of traditional (TRAD) and eccentric-enhanced (ECC+) progressive resistance training and to compare the acute postexercise total testosterone (TT), bioavailable testosterone (BT), growth hormone (GH), and lactate responses in TRAD- and ECC+-trained individuals. Twenty-two previously untrained men (22.1 +/- 0.8 years) completed 1 familiarization and 2 baseline bouts, 15 exercise bouts (i.e., 3 times per week for 5 weeks), and 2 postintervention testing bouts. Anthropometric and 1 repetition maximum (1RM) measurements (i.e., bench press and squat) were assessed during both baseline and postintervention testing. Following baseline testing, participants were randomized into TRAD (4 sets of 6 repetitions at 52.5% 1RM) or ECC+ (3 sets of 6 repetitions at 40% 1RM concentric and 100% 1RM eccentric) groups and completed the 5-week progressive resistance training protocols. During the final exercise bout, blood samples acquired at rest and following exercise were assessed for serum TT, BT, GH, and blood lactate. Both groups experienced similar increases in bench press (approximately 10%) and squat (approximately 22%) strength during the exercise intervention. At the conclusion of training, postexercise TT and BT concentrations increased (approximately 13% and 21%, respectively, p < 0.05) and GH concentrations increased (approximately 750-1200%, p < 0.05) acutely following exercise in both protocols. Postexercise lactate accumulation was similar between the TRAD (5.4 +/- 0.4) and ECC+ (5.6 +/- 0.4) groups; however, the ECC+ group's lactate concentrations were significantly lower than those of the TRAD group 30 to 60 minutes into recovery. In conclusion, TRAD training and ECC+ training appear to result in similar muscular strength adaptations and neuroendocrine responses, while postexercise lactate clearance is enhanced following ECC+ training.

Neuroendocrine responses to an acute bout of eccentric-enhanced resistance exercise.

PURPOSE: The purpose of this study was to compare the total testosterone (TT), bioavailable testosterone (BT), growth hormone (GH), lactate, and ratings of perceived exertion (RPE) responses between a single bout of traditional (TRAD) and eccentric-enhanced resistance exercise (ECC+) of matched training volumes. METHODS: Twenty-two previously untrained males (21.9+/-0.8 yr) completed one familiarization and one baseline 1RM testing bout, for the bench press and squat exercises, and then two exercise bouts. During exercise bout 1, all subjects completed a TRAD protocol (four sets of six reps at 52.5% 1RM), and the subsequent exercise bout consisted of either a TRAD or an ECC+ protocol (three sets of six reps at 40% 1RM concentric and 100% 1RM eccentric) for the bench press and squat exercises. Blood samples acquired at rest, immediately after (T1), and 15, 30, 45, and 60 min after exercise were assessed for serum TT, BT, GH, and blood lactate concentrations. RESULTS: Resting and postexercise TT, BT, and GH were not significantly different between groups. Postexercise TT was not elevated during either bout or in either group, whereas BT increased 15-16% at T1 in both groups during bout 2. Postexercise GH concentrations were elevated 500-7000% above baseline after both protocols. Postexercise lactate accumulation and RPE were greater with ECC+ than TRAD. CONCLUSION: TRAD and ECC+ show similar neuroendocrine and differing metabolic responses during the early phase of resistance exercise in untrained, college-age men.

Pharmacologic levels of dietary arginine in CB6F1 mice increase serum ammonia in the healthy state and serum nitrite in endotoxemia.

BACKGROUND: Therapeutic or pharmacologic doses of arginine are used to enhance blood flow and immune function despite the lack of dose-response studies and the potential for adverse effects. This study determined the optimal level of oral arginine supplementation required to elevate serum arginine concentrations yet limit adverse effects in healthy and endotoxemic mice. METHODS: Male CB6F1 mice were fed one of the following diets: The standard AIN93G (3 g arginine/100 g of protein) or this diet modified to provide 10 g, 20 g, or 30 g arginine/100 g of protein. On day 14, mice were injected with lipopolysaccharide (endotoxemic) or saline (healthy) and 4 hours later were exsanguinated. RESULTS: Weight gain was reduced 50% in the group fed the 30 g arginine vs standard diet. Serum arginine, ornithine, citrulline, histidine, lysine, serine, threonine, tyrosine, and phenylalanine were greater and glutamate levels were lower in healthy supplemented mice; lipopolysaccharide treatment negated these changes. Serum ammonia concentration was 52% greater in healthy mice fed the 30 g arginine vs standard diet. Serum nitrite and urea were unaffected by supplementation in healthy mice. Serum nitrite was 37% greater in endotoxemic mice fed 30 g vs 10 g arginine, and serum urea was 27% greater in mice fed 20 g or 30 g vs 10 g arginine. CONCLUSIONS: Changes in serum arginine or its metabolites were observed with all of the modified diets; however, a 30-g arginine diet was associated with an initial impairment of growth and potential adverse effects.

Effects of variation in protein and carbohydrate intake on body mass and composition during energy restriction: a meta-regression 1.

BACKGROUND: It is unclear whether low-carbohydrate, high-protein, weight-loss diets benefit body mass and composition beyond energy restriction alone. OBJECTIVE: The objective was to use meta-regression to determine the effects of variations in protein and carbohydrate intakes on body mass and composition during energy restriction. DESIGN: English-language studies with a dietary intervention of > or =4200 kJ/d (1000 kcal/d), with a duration of > or =4 wk, and conducted in subjects aged > or =19 y were considered eligible for inclusion. A self-reported intake in conjunction with a biological marker of macronutrient intake was required as a minimum level of dietary control. A total of 87 studies comprising 165 intervention groups met the inclusion criteria. RESULTS: After control for energy intake, diets consisting of < or =35-41.4% energy from carbohydrate were associated with a 1.74 kg greater loss of body mass, a 0.69 kg greater loss of fat-free mass, a 1.29% greater loss in percentage body fat, and a 2.05 kg greater loss of fat mass than were diets with a higher percentage of energy from carbohydrate. In studies that were conducted for >12 wk, these differences increased to 6.56 kg, 1.74 kg, 3.55%, and 5.57 kg, respectively. Protein intakes of >1.05 g/kg were associated with 0.60 kg additional fat-free mass retention compared with diets with protein intakes < or =1.05 g/kg. In studies conducted for >12 wk, this difference increased to 1.21 kg. No significant effects of protein intake on loss of either body mass or fat mass were observed. CONCLUSION: Low-carbohydrate, high-protein diets favorably affect body mass and composition independent of energy intake, which in part supports the proposed metabolic advantage of these diets.