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3 School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland; 4 School of Life Sciences, Heriot Watt University, Edinburgh EH14 4AS, Scotland; and 5 School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, England
* To whom correspondence should be addressed. E-mail: d.ball{at}hw.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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Chiolero et al. (13) showed that intravenous sodium acetate (NaAc)6 administration had a large suppressive effect (P < 0.05) upon both fat and carbohydrate utilization (decreases of 81 and 22%, respectively, when compared with preinfusion values). In contrast, Akanji et al. (10) and Burnier et al. (12) both reported that infusion of NaAc did not affect carbohydrate utilization but did result in a small but significant (P < 0.05) decrease in long-chain fatty acid oxidation. One weakness of these studies is the failure to report substrate utilization data from a placebo trial. Another limitation with these investigations was that the amount of acetate oxidized was assumed rather than calculated from experimental data. This could have a profound effect on any subsequent calculation of fat and carbohydrate utilization. Indeed, in these previous studies the amount of acetate oxidized was estimated to be between 90 and 100% of the infused rate (10,12,13).
Although several studies have utilized isotope methods to examine acetate oxidation in the fasted state (2,14,15) when the plasma acetate concentration is low, to the authors' knowledge, only 1 study (9) has measured acetate oxidation when the plasma acetate concentration substantially increased.
Using 14C labeled NaAc, Skutches et al. (9) calculated that from 869 mmol of acetate infused over a 4-h period only 54% was oxidized during this time. The results from this study are, however, confounded by the fact that glucose was simultaneously infused with the acetate. Furthermore, some of the tracer may have been lost during the dialysis, leading to an underestimation of the amount of acetate oxidized (16).
We conducted this study to quantify the amount of acetate oxidized when acetate availability was increased using stable isotope techniques and also to determine the effect of acetate metabolism upon fat and carbohydrate utilization.
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Methods |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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Experimental design. Each subject reported to the laboratory at 0800 on 2 separate occasions, with at least 1 wk between visits. On each occasion, after resting for a period of at least 60 min, subjects ingested 500 mL low-energy cordial drink (42 kJ/500 mL; 2.5 g of carbohydrate/500 mL). The drinks contained either NaAc (trihydrate) or NaHCO3 at a dose of 2 mmol/kg body mass and the sequence of drink administration was subjected to a randomized, crossover, single-blind experimental design.
Diet and activity before testing.
Subjects were instructed to perform a prolonged, intense bout of exercise 
60 min in duration 5 d before each visit to the laboratory in an attempt to minimize 13C glycogen stores. We instructed subjects to record their dietary intake over the 5d period before the initial visit and then replicate this intake before the following visit. During the experimental period, subjects avoided ingesting foodstuffs derived from carbohydrates from C4 plants (e.g. sugar cane, maize) to maintain a low background 13C enrichment in expired CO2. Subjects fasted overnight and consumed 500 mL of tap water 1 h prior to reporting to the laboratory.
13C labeling.
To quantify exogenous acetate oxidation, a dose of 2 mg [1,2-13C] NaAc/kg body mass (Cambridge Isotope Laboratories) was added to the NaAc drink, giving enrichments of 707.6 ± 69.2 
vs. Pee Dee Belemnitella (PDB) determined by elemental analyzer-isotope ratio mass spectrometry (Europa Scientific Geo 20–20). To prime the bicarbonate pool, NaH13CO3 (Cambridge Isotope Laboratories) at a dose of 0.064 mg/kg body mass was infused immediately before ingestion of the acetate drink. Preliminary studies demonstrated that this amount of NaH13CO3 was sufficient to markedly increase breath 13CO2/12CO2 from –25 vs. PDB to approximately –19 vs. PDB over the first 5 to 10 min before returning close to basal levels after 60 min (–24 vs. PDB).
Procedures. Upon entering the laboratory, each subject was asked to void completely before body mass was recorded. During the preingestion period, 2 consecutive 4-min respiratory gas collections were taken using the Douglas bag method after the expired air passed through a mixing chamber (MLA245 Gas Mixing Chamber, ADInstruments). This arrangement allowed the simultaneous collection of a small volume of expired gas in 10-mL Exetainer tubes (Labco) in duplicate directly from the mixing chamber while also collecting whole breaths in the Douglas bag. Preliminary studies revealed that, the fraction of expired O2 and CO2 at rest sampled directly from the mixing chamber took 2.5 min to stabilize. As such, the mouthpiece was inserted at least 3 min before any respiratory collections were taken.
The breath samples stored in the Exetainer tubes were later analyzed for 13C content by continuous flow isotope ratio MS (Europa Scientific). The gas collected in the Douglas bags was immediately analyzed for percentage oxygen and CO2 using a gas analyzer (Servomex 1440, Servomex Group) with the volume measured using a dry gas meter (Harvard dry gas meter, Harvard Apparatus, Edenbridge). The volume of gas collected in the Exetainer tubes was then added to the expired volume collected in the Douglas bag before we performed any respiratory gas calculations. Gas temperature was also recorded during the measurement of gas volume using a thermocouple situated within the dry gas meter (RS components NTA912, Corby). The gas analyzer was calibrated before, during, and immediately after each test using gases of known composition.
Upon completion of the second resting gas sample, a 21-g butterfly needle was introduced into a superficial vein on the dorsal surface of a warmed hand and a 6.5-mL arterialized venous blood sample obtained. The patency of the cannula was maintained by regular flushing with 0.9% sterile saline, the volume of which totaled 5 mL for each trial.
Subjects were then instructed to consume the prepared drink within 5 min and additional blood and respiratory gas samples were taken every 30 min for the next 180-min period. Two urine samples were also collected during each trial, 1 prior to drink ingestion and another at the end of the 180-min period. We instructed subjects to empty their bladders as completely possible; the entire volume of urine was collected from each subject.
Blood analyses.
One portion of each blood sample (1.5 mL) was collected, without contacting air, in a heparinized syringe, capped, placed on ice, and later analyzed for blood pH, base excess, O2 percent saturation of hemoglobin, and the partial pressure of CO2 (PCO2). Sample analysis was performed using a blood gas analyzer (ELG 500, Radiometer Copenhagen). We calculated blood bicarbonate concentration using the Henderson-Hasselbalch equation.
The remaining portion of blood (5 mL) was dispensed into a tube containing K3 EDTA (1.3 g/L). Duplicate aliquots of whole blood (100 µL) were rapidly deproteinized in 1 mL of ice-cold 2.5% perchloric acid. After centrifugation at 17,500 x g; 4 min, the supernatant was frozen at –20°C and subsequently used to determine lactate concentration (17). Approximately 3 mL of blood was also centrifuged (17,500 x g) with the plasma separated and frozen at –20°C and later used to determine glycerol (18), FFA (Wako NEFA C test kit, Wako Chemicals), and acetate (19) concentration.
The remaining blood in the EDTA tube was used to determine hemoglobin concentration using the cyanmethemoglobin method and packed cell volume by microcentrifugation. The values obtained were used to calculate changes in plasma volume using the equations described by Dill and Costill (20).
Urine analyses.
The volume of each urine sample was recorded after an aliquot of urine (2 mL) was drawn into a syringe, immediately capped, and placed on ice for later determination of PCO2 (ELG 500, Radiometer Copenhagen). An aliquot (20 mL) was also taken and subsequently analyzed for pH using a pH electrode (BDH Gelplas, VWR International) attached to a pH meter (Accumett AB15, Fisher Scientific UK). From the urinary pH and PCO2, the urinary bicarbonate concentration was calculated using the Henderson-Hasselbalch equation. A final 5-mL aliquot was frozen at –20°C and used to determine acetate concentration by GC-MS as described above for plasma acetate (19).
Calculations.
The isotopic enrichment in the breath samples was expressed as per mil difference between the 13C:12C ratio of the sample and a known laboratory reference standard according to the formula of Craig (21):
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The 13C was then related to an international standard (PDB).
Acetate oxidation was calculated according to the following formula:
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where Exp is the 13C enrichment of expired air following ingestion of sodium acetate, Ing is the 13C enrichment of the ingested solution, Expbkg is the 13C enrichment of expired air at the matched time point during the bicarbonate trial, and k is the volume of CO2 (in liters) produced by the oxidation of 1 g acetate (2 mol/1 mol = 44.8 L of CO2/136.08 g = 0.329 L of CO2/g). The appearance of 13C is low at rest following administration of carbon-labeled tracers. A correction factor of 54% was therefore used in the acetate trial to account for loss of label within the bicarbonate pool and via nonoxidative pathways (22,23).
Total carbohydrate and fat utilization were calculated according to Frayn (24). During the NaAc trial, postingestion fat and carbohydrate oxidation was calculated after the 
O2 and CO2 values were corrected to account for oxidation of the ingested acetate. The metabolic calculations were performed according to those detailed by Akanji et al. (10). Briefly, the oxidation of 1 mol NaAc consumes 2 mol O2 (44.8 L) and liberates 1 mol CO2 (22.4 L) (10,16,25). These values were then subtracted from the total O2 and CO2 during the 180-min postingestion period to give the nonacetate O2 and CO2 from which postingestion fat and carbohydrate utilization was based. Energy expenditure was also calculated according to Elia et al. (26). A comparison of the substrate oxidation pre- to postingestion was made based upon the assumption that because the subjects were in a fasted state, the preingestion substrate oxidation rates would have remained constant had the sodium salts not been ingested. The preingestion substrate utilization rates were thus converted into an absolute amount that would be oxidized over a similar 180-min period.
Statistical analysis.
After testing for normality of distribution using the Kolmogorov-Smirnov test, the blood gas variables and blood metabolites were analyzed using a 2-way ANOVA (SPSS version 12) with repeated measures (trial x time). Where a significant interaction was found, we performed a Tukey's post-hoc test. Where a significant main effect for time was observed, further 1-way ANOVA was performed with the Tukey's test used to identify the significant mean differences. All other data were analyzed using paired t tests. Results are presented as mean ± SEM. Differences were considered significant at P 
0.05.
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Results |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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–26.50 vs. PDB over the 180-min period postingestion (P > 0.05). In contrast, ingestion of the 2 mmol/kg body mass NaAc drink markedly increased breath enrichment after 30 min before peaking at 46.07 ± 1.83 vs. PDB 90 min postingestion (P < 0.01). Breath enrichment then slowly returned toward the baseline value but was still significantly higher than the preingestion value over the last 90 min. After accounting for retention of 13C in bicarbonate and other nonoxidative pools, we calculated that 80.1 ± 2.3% of the ingested acetate was oxidized during the 180-min postingestion period.
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90%) replaced the additional fat that was oxidized during the bicarbonate trial.
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Following ingestion of NaHCO3, plasma glycerol and FFA increased over the initial 60 min postingestion and remained higher than the preingestion concentration over the next 120 min (Fig. 3). In contrast, during the NaAc trial, neither plasma glycerol nor FFA concentration changed over the first 60 min postingestion, with the values remaining at 53 µmol/L and 190 µmol/L, respectively. Plasma FFA was also significantly lower during the NaAc trial compared with the NaHCO3 trial over this period. Between 60 and 90 min after ingestion of NaAc, plasma glycerol and FFA increased by 14 µmol/L and 110 µmol/L, respectively, and did not differ between trials over the last 90 min (Fig. 3). There was also no difference between trials in the blood lactate response (P = 0.51), with the plasma concentration decreasing over time in both trials (Table 2).
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+10.5% during the NaHCO3 trial and +11.5% following NaAc ingestion. Blood gases and acid-base balance. The mean percentage of blood oxygen saturation was similar during the trials (95.1 ± 0.6 vs. 95.3 ± 0.5% during the NaAc and NaHCO3 trials, respectively). Baseline blood pH, bicarbonate, base excess, and PCO2 also did not differ between the trials (Fig. 4; Table 3).
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Blood bicarbonate and base excess responded similarly to blood pH during both trials (Table 3). In contrast, blood PCO2 remained unchanged following ingestion of either sodium salt (Table 3).
Urine pH and bicarbonate excretion. Following ingestion of the sodium salts, urine pH increased from 6.32 ± 0.26 to 7.93 ± 0.06 (P < 0.001) during the NaAc trial and from 6.15 ± 0.27 to 7.73 ± 0.29 (P = 0.001) during the NaHCO3 trial. This response was mirrored by an increased amount of bicarbonate excreted in the urine from 2.36 ± 1.15 to 40.30 ± 6.02 mmol (P < 0.001) during the NaAc trial and from 1.59 ± 0.53 to 37.49 ± 7.37 mmol (P = 0.002) during the NaHCO3 trial over 180-min periods pre- and postingestion.
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Discussion |
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TOPABSTRACTIntroductionMethodsResultsDiscussionLITERATURE CITED |
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The 8% increase in energy expenditure observed in this study following NaAc ingestion is comparable to the increase (6–12%) observed in previous studies following NaAc infusion (12,13). Ingestion of NaHCO3 also increased resting energy expenditure in this study despite the low energy content of the administered drink. However, in both cases, this increased energy expenditure represents a small (<0.5%) increase in daily energy expenditure. The observed metabolic response during the NaHCO3 trial does, however, support previous work in humans (27) and in canines (28–30), where NaHCO3 administration increased oxygen consumption and/or energy expenditure. The increased energy expenditure during the NaHCO3 trial in our study was entirely attributable to an increase in fat oxidation. This was mirrored by a significant decrease in the respiratory exchange ratio following NaHCO3 ingestion and supports similar findings previously reported in humans (27,31,32). The mechanism(s) for the increase in fat utilization, but not carbohydrate utilization, could not be ascertained from our study. However, we speculate that it was in part attributable to a greater availability of FFA (Fig. 3) as a result of an alkalosis-induced increase in lipolysis.
In contrast to the response observed during the NaHCO3 trial, acetate ingestion did not affect fat oxidation when compared with the preingestion value. The findings from this study also contrast with previous studies (10,12,13), where NaAc administration suppressed fat utilization compared with preadministration values. The difference in findings may be due to the extent to which acetate contributed to energy expenditure. Indeed, in our study, acetate oxidation only contributed 10.9 ± 0.2% of total energy expenditure compared with 36 and 40% as reported by Akanji et al. (10) and Burnier et al. (12), respectively. The present findings did, however, demonstrate for the first time, to our knowledge, that by increasing exogenous acetate availability, the increase in fat oxidation observed following NaHCO3 ingestion is suppressed despite the induction of a comparable metabolic alkalosis.
Importantly, our findings were independent of the correction factor used in the acetate trial to account for label (13C) temporarily lost in the bicarbonate and other nonoxidative pools. Indeed, if a recovery factor of 81% was used, which is known to only account for loss of 13C in the bicarbonate pool (33) and will therefore almost certainly lead to an underestimation of the true rate of acetate oxidation, there still would have been no change in carbohydrate or fat oxidation pre- and postingestion in the acetate trial. Furthermore, fat oxidation would still tend to be lower following acetate when compared with bicarbonate ingestion using the bicarbonate-only recovery factor (570 ± 68 vs. 694 ± 101 kJ, respectively; P = 0.06).
The differences in fat oxidation between trials may be due to the differing lipemic responses following ingestion of the sodium salts. Plasma FFA and glycerol were both lower in the NaAc trial over the first 60 min compared with NaHCO3 ingestion. It is well accepted that pH influences the rate of lipolysis with a reduction in blood pH lowering the rate of lipolysis (34,35). There is also evidence to suggest that a metabolic alkalosis increases plasma FFA concentration (35–37). Despite a slower change in acid-base balance following NaAc ingestion compared with the NaHCO3 trial, 60 min after ingestion of NaAc, blood acid-base status did not differ between trials. At the same time, there was also evidence of renal system compensation in returning normal acid-base homeostasis because of the increased rate of urinary bicarbonate excretion found in the postingestion urine samples in both trials. The convergence in the blood acid-base response occurred at a time when the concentration of glycerol and FFA were still lower during the NaAc trial. It therefore appears that different temporal changes in acid base balance only partly explain the different glycerol and FFA responses between the trials.
It is interesting to note that the glycerol and FFA concentration increased markedly at a time when acetate was returning toward baseline levels, suggesting that the 2 events may be associated. Despite the glycerol and FFA concentrations being lower during the NaAc trial compared with the NaHCO3 trial over the first 60 min postingestion, they did not differ from the preingestion value. As such, there was no evidence to suggest that acetate inhibited lipolysis per se. We propose, therefore, that acetate may suppress the stimulatory effect that increased blood pH has on lipolysis rather than influencing the basal rate of lipolysis.
The differences in fat utilization between experimental trials may have also been due to a greater change in acetyl group availability in the NaAc trial. Following an infusion of acetate, increases in acetyl-CoA and acetylcarnitine have previously been observed in human skeletal muscle (38–40). Furthermore, such changes in acetyl group availability have been postulated to modulate fat oxidation either through a decrease in free carnitine (due to acetylation of the carnitine pool) and/or increased malonyl-CoA content (through carboxylation of acetyl-CoA by the enzyme acetyl-CoA carboxylase producing malonyl-CoA). Either of these mechanisms would limit fatty acyl-CoA translocation across the mitochondrial membranes. To confirm this hypothesis, further studies incorporating muscle sampling techniques are required to examine changes in malonyl-CoA and free carnitine content when acetate availability is increased.
The effects of acetate administration on lipid metabolism observed in this study may help explain the dyslipidemia observed following long-term hemodialysis, where acetate was employed as the primary buffer in uremic subjects (41,42) and following chronic alcohol ingestion (43–45). In both circumstances, significant elevations in plasma acetate concentration were noted. Over the entire 180-min period following acetate ingestion, there appeared to be a mismatch between fat availability and oxidation, with an increase in plasma FFA concentration but no change in fat utilization. This may have resulted in FFA that would have normally been oxidized, as in the NaHCO3 trial, being directed elsewhere. It is conceivable, therefore, that the excess FFA, coupled with any acetate directed toward de novo lipogenesis, may result in increased lipid storage in and/or VLDL-triglyceride secretion from the liver. This hypothesis is strengthened by the fact that repeated administration of NaAc has been shown to result in hyperlipidemia and hepatic lipid accumulation in rats (46).
In contrast to its effect upon lipid metabolism, administration of NaAc did not affect carbohydrate utilization, supporting the findings of Akanji et al. (10) and Burnier et al. (12) but in contrast to the results of Chiolero et al. (13), who reported significantly decreased carbohydrate oxidation. The possibility that a higher dose of NaAc than given in our study might suppress carbohydrate utilization cannot, however, be discounted, because the dose of acetate administered by Chiolero et al. (13) was 69% higher than we used.
In conclusion, over a 3-h period following the ingestion of a bolus of NaAc (2 mmol/kg body mass), 80% of the administered dose was oxidized, which was quantified using stable isotope techniques. Ingestion of NaAc or NaHCO3 at this dose resulted in a similar increase in energy expenditure but did not affect the amount of carbohydrate utilized. In the NaHCO3 trial, the increase in resting energy expenditure was attributable to a significant increase in fat oxidation. In contrast, there was no change in fat catabolism following acetate ingestion, with the oxidation of the exogenous acetate almost entirely accounting for the increase in fat oxidation observed during the bicarbonate trial. The site(s) where NaAc metabolism inhibits fat utilization remains to be elicited.
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FOOTNOTES |
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2 Author disclosures: G. I. Smith, A. E. Jeukendrup, and D. Ball, no conflicts of interest.
6 Abbreviations used: NaAc, sodium acetate; NaNCO3, sodiumbicarbonate; PCO2, partial pressure of carbon dioxide; PDB, Pee Dee Belemnitella.
Manuscript received 28 March 2007. Initial review completed 29 April 2007. Revision accepted 11 May 2007.
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LITERATURE CITED |
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