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University of California, Berkeley 94720; Geriatric Research, Education, and Clinical Center, Palo Alto Veterans Affairs Medical Center, Palo Alto, California 95304; University of Colorado Health Sciences Center, Denver, Colorado 80262; and United States Army Research Institute of Environmental Medicine, Natick, Massachusetts 01760
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Roberts, A. C., G. E. Butterfield, A. Cymerman, J. T. Reeves, E. E. Wolfel, and G. A. Brooks. Acclimatization to 4,300-m altitude decreases reliance on fat as a substrate. J. Appl. Physiol. 81(4): 1762-1771, 1996.
We tested
the hypothesis that exposure to altitude decreases reliance on free
fatty acids (FFA) as substrates and increases dependency on blood
glucose. Therefore, the effects of exercise, hypobaric hypoxia, and
altitude acclimatization on FFA, glycerol and net glucose uptake and
release [ = 2(leg blood flow)(arteriovenous concentration)]
and on fatty acid (FA) consumption by the legs (= 3 × glycerol
release + FFA uptake) were measured. Because sympathetic responses have
been implicated, we utilized nonspecific 
-blockade and observed
responses to exercise, altitude, and altitude acclimatization. We
studied six healthy -blocked men () and five matched controls (C)
during rest and cycle ergometry exercise (88 W) at 49% of sea-level
(SL) peak O2 uptake at the same
absolute power output on acute altitude exposure (A1; barometric pressure = 430 Torr) and after 3 wk of chronic altitude exposure to
4,300 m (A2). During exercise at SL, FA consumption rates increased (P < 0.05). On arrival at 4,300 m,
resting leg FFA uptake and FA consumption rates were not significantly
different from those at SL. However, after acclimatization to altitude,
at rest leg FA consumption decreased to essentially zero in both C and
groups. During exercise at altitude after acclimatization, leg FA
consumption increased significantly, but values were less than at SL or
A1 (P < 0.05), whereas glucose
uptake increased relative to SL values. Furthermore, -blockade
significantly increased glucose uptake relative to control. We conclude
that 1) chronic altitude exposure decreases leg FA consumption during rest and exercise;
2) relative to SL, FFA uptake
decreases while glucose uptake increases during exercise at altitude;
and 3) -blockade potentiates
these effects.
exertion; adaptation; metabolism; free fatty acids; glycerol; lipolysis; glucose; hypoxia
INTRODUCTION DURING EXERCISE after acclimatization to high altitude,
the net degradation rate of muscle glycogen decreases compared with that determined for the same exercise power output before
acclimatization (11, 28), and this glycogen-sparing effect of
acclimatization is associated with increased circulating free fatty
acid (FFA) levels during exercise (28-30). These results have been
interpreted to mean that altitude acclimatization causes an enhanced
ability to utilize lipid energy sources (24, 28-30). However, no
direct evidence has been observed for utilization of intramuscular
triglyceride or blood-borne fatty acids to support these
interpretations of increased dependence on lipid energy sources at high
altitude nor was it considered that elevated concentrations of FFA
after acclimatization may be indicative of decreased clearance. The latter possibility was suggested by research that demonstrated that
hypoxia potentiates exercise-induced sympathetic neural activation in
sea-level inhabitants (22) and in high-altitude residents (2). Thus it
is possible that elevated levels of FFA seen with acclimatization are a
function of epinephrine-induced lipolysis and decreased FFA uptake and
are not indicative of an increased dependence on fat. Moreover, it is
recognized that any given exercise task at altitude will be
accomplished at a relatively greater effort than at sea level and that
at exercise intensities beyond ~50% of maximal
O2 uptake
( Recent evidence by Butterfield et al. (8) and Brooks et al. (3, 4, 7)
suggests that previous interpretations of substrate utilization after
altitude exposure have been influenced by cachexia and energy
imbalance, a circumstance in which fat utilization is known to be
involved at sea level. Furthermore, Butterfield et al. (8) demonstrated
that acute altitude exposure to 4,300-m altitude elevates basal
metabolic rate (BMR) by 30% above sea-level values and that after 3 wk
of habituation BMR remains elevated by 17%. When energy balance was
maintained at altitude by increasing food energy intake to meet
increased energy expenditure on a daily basis, Brooks et al. (4)
observed that altitude exposure increased glucose dependency at rest
and during exercise. Specifically, the decreased rate of muscle
glycogenolysis seen after acclimatization to high altitude was
attributed to increased rates of glucose uptake by muscle from blood.
However, in that investigation FFA consumption was not measured. Thus
neither the cause nor effect of elevated circulating FFA in hypobaric hypoxia is clear.
To evaluate the acute and chronic effects of hypobaric hypoxia on leg
FFA and net glycerol uptake and release and on fatty acid utilization,
we sampled arterial and venous blood across the legs during rest and
submaximal exercise at sea level, on acute exposure to high altitude,
and after 3 wk of chronic exposure to 4,300 m in METHODS Subjects
O2 max) less lipid and
more carbohydrate will be used (6).
-blocked and
-unblocked men provided with dietary energy sufficient to meet
needs. Blood glucose kinetics and leg net uptake were also measured but
are reported in detail in our companion paper (21). Under the
experimental conditions we studied, acclimatization to altitude
exposure resulted in decreased leg lipid metabolism and increased
glucose utilization compared with sea level. Furthermore, -blockade
accentuated these effects.
-blocked = 26.7 ± 1.2 yr) were recruited by
advertisements in local newspapers. All subjects gave their written
informed consent before participation. The research protocol was
approved by the Human Subjects Committees of the University of Colorado
Health Sciences Center, Stanford University, the US Army, and the
University of California at Berkeley (CPHS
91-4-68).
Experimental Design
Measurements were made at rest and during steady-state exercise while subjects were breathing ambient air at sea level [barometric pressure (PB) = 751 Torr] within the first 4 h of arrival at 4,300-m altitude (A1; PB = 463 Torr) and after 21 days of residence at altitude (A2). Studies at high altitude began 4 wk after those performed at sea level. Subjects were flown from sea level to Denver, CO, and slept at 1,954 m (Colorado Springs, CO) the night before ascending to 4,300 m (Pikes Peak). To ensure acute exposure on the peak, during the 45-min ascent via automobile, subjects breathed supplemental O2. Subjects' arrival at altitude was staged so that all subjects were studied promptly on arrival and after an equivalent period of residence at altitude (total time from sea level to A1 was
24 h). The sea-level
studies were performed at the Geriatric Research, Education, and
Clinical Center of the Palo Alto Veterans Affairs Medical Center,
whereas the altitude studies were performed at the US Army Maher
Memorial Research Laboratory on the summit of Pikes Peak.
Experimental Conditions
Six subjects were assigned according to age and weight to the experimental (-blocked) group, and five subjects of similar age and
weight were assigned to the control group. Oral propranolol (80 mg) was
administered 3 times/day (total = 240 mg/day) as the experimental
condition. The condition was double-blind; all subjects were
administered a pill (either a placebo or propranolol) with the code
retained by the principal investigator. Pills were taken for a week
before study at sea level, for a week before ascent to altitude, and
continuously at altitude.
Diet
As previously (8), food intake was controlled at sea level and at altitude with a food and formula diet provided in amounts sufficient to cover measured energy needs. Subjects were weighed daily, and energy need was determined from 4-day food records and controlled feeding in the metabolic unit for 9 days before isotope tracer studies. Additionally, for the last week of the 1-mo interim between sea-level and altitude phases of the experiment, subjects were provided with the same rations as consumed in the metabolic unit and on the mountain. During the time at altitude, BMR was measured 3 times/wk and energy intake was adjusted in response to any changes seen. All subjects were given a basal diet that provide 30% of energy from fat, 58% from carbohydrate, and 12% from protein. The same foods were given daily at sea level and at altitude. Carbohydrate-to-fat ratio of added calories was held constant across all conditions. Compliance with the dietary regimen was enforced as well as fluid intake at altitude. Fluid intake at altitude was a minimum of 2 l/day as water in addition to fluid foods. Sea-level weights (control = 74.0 ± 6.6 kg;-blocked = 69.3 ± 2.6 kg) were maintained during the period of altitude exposure (weights at the end of exposure were control = 73.8 ± 6.6 kg; -blocked = 69.5 ± 2.5 kg). Body composition as assessed by
skin folds and underwater weighing did not change significantly. Subsequently, adequacy of dietary energy and protein intakes were established by presence of nitrogen balance. These data are reported in
detail separately.
Preliminary Testing of Subjects
Peak O2 uptake (O2 peak ).
O2 peak was
determined by the use of a progressive protocol on a leg cycle
ergometer. Workload was increased 25 W every 2 min until the subjects
could no longer continue despite strong verbal encouragement.
O2 peak was defined
as the value obtained when an increase in exercise intensity of 25 W
did not result in any further increase in
O2 uptake
(O2; i.e., a decrease, no
change, or an increase <150 ml/min). This procedure resulted in a
plateau in O2 in the
majority of the subjects. Measurements were made at sea level both
before and after drug/placebo administration and on
days 5,
7, and
18 at 4,300 m with subjects breathing
ambient air. Subjects exercised on a Warren Collins (model 1931)
electronically braked cycle ergometer. Respiratory gas exchange was
measured on-line (model RL-H7000W, Panasonic) by the use of standard
open-circuit techniques (AMETEK S-3A
O2, Beckman LB-2
CO2 analyzers, Validyne MP-45
pressure transducer, Fleisch no. 3 pneumotachometer). These measurements were used to calculate
O2,
CO2 production, and minute
ventilation. The same equipment was used for all exercise studies at
sea level and at high altitude.
Steady-state exercise.
A submaximal workload was chosen to produce a
O2 that approximated 50%
of O2 peak at sea
level. This same absolute power output was used for all steady-state
exercise studies at sea level, on acute exposure to altitude, and after
21 days of residence at high altitude. On the basis of previous
experience (4, 27), this protocol was selected so that exercise would
elicit 65% of altitude
O2 peak, a value that
could be maintained at altitude.
Testing Protocol
On each occasion, sea level and acute and chronic altitude, subjects were studied 12 h postabsorptive at either 8:00 A.M. or 2:00 P.M. Blood was sampled 90, 15, and 0 min before exercise as well as at 5, 15, 30, and 45 min during exercise. Resting measurements were made while the subjects sat quietly upright in a hinged bed for 90 min. Catheterization. After local Xylocaine anesthesia, the femoral artery and vein in the same leg were cannulated by the use of standard percutaneous techniques as previously described (27). A 5-Fr, 23-cm catheter (model 91100900, North American Medical Instrument) was positioned in the distal abdominal aorta. A 6-Fr thermodilution venous catheter (model 93-135-6F, American Edwards Laboratories) was passed through a femoral vein sheath to position its tip in the iliac vein 13 cm from the skin. Both catheters were secured by a suture in the skin and a stretch-bandage wrap around the upper thigh and waist over the point of insertion. The external portions of both catheters were directed along the thigh to allow access for sampling during exercise. There were no significant complications from this procedure. Alternate legs were used for each testing period.Blood Measurements and Sampling Time Points
Arterial and venous leg blood samples were drawn simultaneously anaerobically over 5 s whenO2 had reached a steady
state after 75 and 90 min of rest and at 5, 15, 30, and 45 min during exercise. The blood samples were immediately placed on ice and were
analyzed within 30 min for partial pressures of
O2
(PO2) and of
CO2
(PCO2) as well as pH (ABL 300, Radiometer, Copenhagen, Denmark).
O2 content,
O2 saturation
(SO2), and hemoglobin concentration
were measured independently on each blood sample (OSM 3 hemoximeter,
Radiometer), and hematocrit was determined by the microhematocrit
method. The temperatures measured at the venous catheter tip thermistor
were utilized to correct blood gas tension to temperature in vivo.
Hemodynamic measurements.
Heart rate was determined by single-lead electrocardiograph monitoring
on a Soltec recorder (model 8K22, Sun Valley, CA). After blood
sampling, iliac venous blood flow was estimated from a 10-ml bolus
injection of sterile saline cooled to near 0°C through an American
Edwards Laboratories-Set II (93-520) by the thermodilution technique by using a cardiac output computer (model 9520, American Edwards Laboratories). Measurements were made in triplicate at rest and
during each sampling period during exercise. Validity of the
measurements was determined by obtaining appropriate thermodilution morphology curves on the Soltec recorder with each measurement. The
validity and precautions used with this technique have been described
previously (27). Leg blood flow was measured in duplicate or triplicate
immediately after blood sampling.
Chemical Analyses
Sample collection, transportation, and storage. Blood samples obtained for determination of metabolites and hormones (except for FFA and glycerol) were drawn anaerobically into 10-ml heparinized syringes and then immediately mixed with 6 mg EDTA in sterile Vacutainer tubes by gentle inversion and vortexing. The collection of 4-ml blood samples for FFA and glycerol determination were drawn into nonheparinized syringes. The 6-ml blood samples drawn for glucose and lactate determination were additionally mixed (in Vacutainer tubes) with 17.5 mg of sodium fluoride and 14 mg of potassium oxalate to inhibit glycolysis while the 4 ml of blood designated for determination of catecholamines were promptly mixed with 10 mg of reduced glutathione to prevent oxidation. All samples were immediately stored on ice until centrifuged (Sorval RC-5 centrifuge, DuPont Instruments) for 10 min at 1,050 g; the plasma was then removed with transfer pipettes and stored at
20°C until transported for
future analysis. All samples were packed in dry ice and transported
from altitude via automobile or airplane to Berkeley, California, for
subsequent analysis.
Glucose.
Plasma glucose concentrations were determined with a hexokinase
enzymatic kit from Sigma Chemical (St. Louis, MO). The glucose concentration of each sample was calculated from the average of at
least two assays.
FFA.
Plasma FFA concentrations were determined with a kit from Wako
Chemicals (Dallas, TX). Standards were made for a 1.0 mM oleic standard
and analyzed with each set of samples. The absorbance of each assay
resultant was read at 550 nm, and concentration of each sample was
calculated from the average of two or more assays.
Glycerol.
Plasma glycerol was assayed with a triglyceride (GPO-Trinder) kit from
Sigma Chemical. A 250 mg/dl glycerol stock solution was diluted with
doubly distilled H2O to form
standards. The absorbance of the resultant quinoneimine dye in the
samples was determined at 540 nm, and the concentration of glycerol in
each sample was calculated from the average of two or more assays.
Leg Respiratory Quotient (RQ)
RQ of the legs was determined from the ratio of the venous-arterial CO2 difference (v-aDCO2) and the arteriovenous O2 difference (a-vDO2) across the legs
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(1) |
![C<SC>co</SC><SUB>2 blood</SUB> = [C<SC>co</SC><SUB>2 plasma</SUB>]](/content/vol81/issue4/fulltext/1762/img002.gif)
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![&z.ccirf; <FENCE>1 − <FR><NU>(0.0289)([Hb])</NU><DE>[3.352 − (0.456)(S<SC>o</SC><SUB>2</SUB>)](8.142 − pH)</DE></FR></FENCE>](/content/vol81/issue4/fulltext/1762/img003.gif)
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(2) |
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(3) |
[the
apparent dissociation constant
(pK)] are from the equations of Kelman (19).
Calculations of Leg Lipid Exchange
Net glycerol and FFA uptake or release (
lyc and
FA, respectively) by the legs were calculated from
the product of twice one limb's blood flow (
) and
venous-arterial concentration difference for glycerol
([v-a]DGlyc) and
arteriovenous concentration difference for FFA
([a-v]DFFA)
![<A><AC>G</AC><AC>˙</AC></A>lyc(mmol/min) = 2<A><AC>Q</AC><AC>˙</AC></A>[v-a]D<SUB>Glyc</SUB>](/content/vol81/issue4/fulltext/1762/img005.gif)
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(4) |
![<A><AC>F</AC><AC>˙</AC></A>FA(mmol/min) = 2<A><AC>Q</AC><AC>˙</AC></A>[a-v]D<SUB>FFA</SUB>](/content/vol81/issue4/fulltext/1762/img006.gif)
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(5) |
Leg fatty acid consumption (A) was based on
the fact that during exercise there was net release of glycerol and
uptake of FFA. Therefore, for each glycerol released from the legs,
three FFA were mobilized within the muscle. Thus leg
A was calculated as
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(6) |
Leg net glucose uptake [ = 2(a-vD)] was also measured as were
isotopically determined blood glucose kinetics and rates of appearance
and disappearance. These data are reported in detail in our companion
paper (21).
Statistical Analyses
Data are represented as means ± SE. Representative values for arterial metabolite and hormone concentrations as well as for substrate uptake and release in resting subjects were determined from averaging the two preexercise samples, whereas the mean of blood sampled at 30 and 45 min of exercise provided a representative value for exercise. Effects of-blockade and acute and chronic altitude exposure on
substrate uptake and release and leg fatty acid consumption were
assessed by means of 2 × 3 analysis of variance with repeated
measurements. Associations were determined by Pearson product-moment
correlation. An 
of 0.05 was used throughout.
RESULTS
Ergometry and Whole Body Respiratory Responses
O2 peak in control and
-blocked subjects was 45 ± 2.3 and 44.2 ± 1.6 ml · kg
1 · min1,
respectively. After subjects arrived on Pikes Peak,
O2 peak was
significantly depressed 20% on day
4 of exposure.
O2 peak did not change
significantly during acclimatization and represented 81% of sea-level
O2 peak (Table
1).
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At sea level, continuous exercise was 88.6 ± 2.4 and 86.7 ± 3.1 W in control and -blocked subjects, respectively, which elicited O2 values of 21.3 ± 0.09 and 21.9 ± 0.8 ml · kg1 · min1
and represented 47.7 ± 1 and 49.4 ± 2.1% of
O2 peak, respectively (Table 1). Rates of whole body
O2 were elevated at altitude compared with sea level but did not change due to acclimatization. The
altitude values represented 65.8 ± 3.1 and 65.3 ± 4.3% of predrug sea-level
O2 peak in control and
-blocked subjects, respectively, after chronic altitude exposure.
Leg RQ
RQ values observed in subjects resting and exercising at sea level and high altitude are given in Table 2. With the exception of-blocked subjects resting at sea level, none of
these values is significantly different from unity, indicating
dependence on carbohydrate oxidation in the legs during exercise and at
altitude.
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Arterial Metabolite Concentrations
FFA. Arterial FFA concentrations were not different during exercise or after-blockade at sea level (Table 3).
However, on arrival of subjects at 4,300 m and after acclimatization,
both resting and exercise FFA concentrations in controls were
significantly elevated above sea-level values. However, the effect of
altitude in elevating circulating FFA concentrations was not evident in the -blocked subjects; FFA concentrations were approximately one-half of those in control subjects (Table 3).
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-blocked and control arterial glycerol levels were not
different from one another and increased significantly in the
rest-to-exercise transition (Table 3). On acute exposure of subjects to
altitude, in control subjects both resting and exercise glycerol values
were significantly elevated relative to sea level. However, on acute
exposure arterial glycerol did not rise during exercise in -blocked
subjects and values were significantly lower than in control subjects
(Table 3). In control subjects, after acclimatization to altitude,
arterial glycerol levels during both rest and exercise remained
elevated compared with sea level, and during exercise levels in
controls were again significantly greater than in -blocked subjects.
After acclimatization arterial glycerol levels rose in both groups
during exercise, but the rise was greater in control than in
-blocked subjects (Table 3).
Substrate Net Uptake and Release Across the Legs
FFA. At rest in all conditions, the [a-v]DFFA was negative, or essentially zero, indicating FFA release across the legs (Table 4). During exercise the a-vDFFA across the legs was positive, indicating that the legs switched from net release to net FFA uptake. The switch occurred in both control and-blocked subjects during exercise. However, altitude exposure tended to decrease FFA
uptake by the legs during exercise in both control and -blocked groups (Table 4, Fig. 1). This decrement in
FFA uptake during exercise was statistically significant after chronic
altitude exposure compared with sea-level values in both control and
-blocked subjects.
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-blocked subjects (open bars) at rest
( left pairs) and during exercise (right
pairs) at sea level and after acute and chronic (21-day) altitude
exposure. Values are means ± SE of 5 control and 6 -blocked
subjects at each condition. * Significantly different from sea
level (P < 0.05).
Significantly different from control
(P < 0.05).
Significantly different from acute altitude
(P < 0.05).
§ Significantly
different from rest (P < 0.05).
Glycerol. At rest in all conditions the [v-a]DGlyc was positive, or zero, indicating glycerol release by the legs during rest and exercise (Table 4). At sea level and on acute altitude exposure, glycerol release increased in the rest-to-exercise transition in control but not
-blocked subjects (Table 4, Fig. 1). However, after acclimatization
to 4,300 m, neither resting nor exercising glycerol release values were
different from zero in either group. Thus, -blockade did (could) not
affect glycerol release from the legs, either at rest or during
exercise after acclimatization (Table 4, Fig. 1).
Leg fatty acid consumption.
In both control and -blocked subjects at sea level and on acute
exposure, there was significant fatty acid consumption by the legs
(Table 4). However, after acclimatization the fatty acid consumption
was not different from zero at rest (Table 4, Fig.
2). In both groups, exercise
increased leg fatty acid consumption during each phase of the
experiment, although -blockade significantly blunted this effect at
altitude (Table 4, Fig. 2). Moreover, acclimatization to altitude
significantly reduced the consumption of fatty acids by the legs during
exercise in both groups (Fig. 3) relative
to sea-level and acute altitude conditions.
{[a-v]DFFA + 3([v-a] DGlyc)}
during rest, where is blood flow in 1 leg and
a-vDFFA and
v-aDGlyc are arteriovenous and
venous-arterial concentration differences for FFA and glycerol,
respectively (see METHODS). Values
are means ± SE in control (solid bars) and -blocked subjects (open bars) during rest at sea level and at acute and chronic altitude.
* Significantly different from sea level
(P < 0.05). Significantly different from acute altitude
(P < 0.05).
-blocked subjects (open bars)
during rest at sea level and at acute and chronic altitude. Terms are
defined as in Fig. 2. * Significantly different from sea level
(P < 0.05).
Significantly different from control
(P < 0.05).
Significantly different from acute altitude
(P < 0.05).
Glucose. Whereas acclimatization decreased leg fatty acid consumption (Table 4), acclimatization increased blood glucose flux and leg glucose uptake. These data are reported in detail elsewhere (21).
DISCUSSION
Under conditions of energy and nitrogen balance at sea level and at 4,300-m altitude, we observed substantially decreased rates of FFA uptake and glycerol release across the legs during rest and exercise after acclimatization. At the same time, rates of glucose uptake increased significantly over sea-level values. Paradoxically, these findings of decreased reliance on FFA and increased dependence on glucose were accompanied by increased circulating FFA and decreased glucose levels after chronic exposure to altitude. Additionally, this decreased utilization of FFA was accompanied by unchanged insulin, but elevated levels of epinephrine and glucagon (21) possibly accounted for a lipolysis-stimulated increase in levels of FFA in the blood at this time.
Fat Utilization at Sea Level
Arteriovenous concentration difference and blood flow measurements used to estimate lipid exchange across legs correspond to literature values; during rest there is net FFA release and during exercise the legs switch to net uptake of FFA (1, 18, 20). Furthermore, during rest the leg releases glycerol and this release increases during exercise (Table 3). At sea level, there was no effect of blockade on either net uptake or release of FFA and glycerol (Fig. 1). We note also that-blockade
had no significant effect on epinephrine or insulin in resting subjects at sea level (21) (Table 3).
Our calculated leg fatty acid consumption increased in the
rest-to-exercise transition but was not different between control and
-blocked subjects at sea level (Table 4). Increased utilization of
lipid from the rest-to-exercise transition is directly reported in only
a few studies on humans (1, 14, 17, 18, 26). For example, using direct
arteriovenous difference measurements, Ahlborg et al. (1) observed
working human muscle to increase uptake of FFA during low- to
moderate-intensity exercise. By contrast, using tracer palmitate in men
during hard-intensity exercise (
70% O2 max), Hall et al.
(14) and Jones et al. (17) observed no significant increase in plasma
FFA flux over rest. These variable and intensity-dependent results are
consistent with the crossover concept (6), which predicts that lipid
utilization will be maximal during power outputs that elicit
40-50% O2 max. At
greater exercise intensities, there will be a correspondingly greater reliance on carbohydrate and lesser reliance on lipid (see below).
Fat Utilization at Altitude
Acute altitude. Although arterial glycerol and FFA concentrations increased significantly in controls (Table 3), immediate exposure to altitude did not affect rates of fatty acid consumption by the legs, which remained the same as at sea level (Table 4). This result of unchanged lipid utilization in the face of rising concentrations contradicts the usual interpretation of increased levels of arterial glycerol and FFA. Concentrations of FFA and glycerol in the plasma are often taken as indicators of FFA and glycerol turnover. Although there is often a positive correlation between plasma concentration and turnover rates, we and others have demonstrated that this relationship may vary with experimental conditions and the intensity of exercise (1, 4, 7, 13, 23). Thus the mechanism for increasing fatty acid utilization, at least with sudden exposure to altitude, is more complex then concentration-driven muscular uptake. It seems that the increase in FFA and glycerol concentrations seen with acute altitude exposure in control subjects parallels the increase in epinephrine concentration (21) and may indicate increased mobilization that is not compensated for by a corresponding increase in FFA utilization by the legs. Chronic altitude. Our results in subjects maintained in energy and nitrogen balance clearly indicate a reduced reliance by the legs on fatty acids as substrates during rest and exercise after acclimatization to high altitude. Our results are in agreement with those that implicate increased glucose dependency in iron-deficient (5, 15) and acutely anemic animals (12, 25) as well as in hypoxemic (9) and altitude-exposed humans (4, 21). Our results apparently contradict those suggesting enhanced lipid metabolism in mountaineers (24, 28-30) and subjects exposed to acute hypoxia induced by breathing gas containing 10-13% O2 (17) at sea level. We note that the conclusion of increased FFA utilization in subjects acutely exposed to hypoxia (17) was based on a rise in plasma glycerol and the assumption that glycerol clearance was unaffected by hypoxia. Consequently, our results demonstrate both elevated FFA and glycerol concentrations (Table 3) after altitude exposure yet decreased uptake and release, respectively (Table 4, Fig. 1), during exercise after acclimatization. Thus the increased concentrations of FFA and glycerol are indicative of decreased, not increased, utilization after 3 wk of habituation at altitude. Additionally, the studies previously mentioned did not accomplish energy balance in their subjects. Thus their results better show the interactive effects of hypoxia and energy deficit (24, 28-30), whereas our results in subjects in energy and nitrogen balance (4, 6, 8, 21) possibly better isolate the effects of hypoxia on substrate selection without fuel deficit where fat utilization would not be stimulated to cover energy need. Our attempts to determine the leg RQ resulted in significant intraindividual and intratrial variability, with the results clustering around an RQ of 1.0. Estimation of bloodO2 and
CO2 production across the legs is
extremely difficult and, in addition to precision of measurements, is
influenced by the alkalosis of acute altitude, the acidosis of
exercise, and hemoconcentration of acclimatization. Hence the only
reasonable interpretation of the data (Table 2) is that exercise and
altitude cause increased dependence on carbohydrate-derived fuels. As
such, results of attempts to estimate leg RQ are consistent with other
results obtained.
Mechanisms of Decreased Fatty Acid Consumption at High Altitude
Effects of-blockade.
-blockade decreased both arterial FFA and glycerol concentrations
and rates of uptake and release, respectively, as well as rates of
fatty acid consumption by the legs. This effect is not surprising
because lipolysis is, in part, mediated by -adrenergic stimulation
(16), and tissue FFA uptake from blood is, in part, concentration
dependent (13, 17, 23, 26). However, -blockade did not completely
diminish the influences of exercise and acute altitude exposure on
these parameters. Although the values were significantly reduced from
those at sea level, both leg net uptake of FFA and release of glycerol
(Fig. 1), as well as leg fatty acid consumption (Fig. 3) occurred in
-blocked subjects on acute exposure.
Our findings with regard to the effects of propranolol are not
consistent with those of a previous investigation, which showed no
effect of propranolol on FFA concentration during high-altitude exposure (28). Again, in that study nitrogen and energy balance were
not maintained. Thus it becomes difficult to differentiate metabolic
effects of either drug or altitude exposure from those caused by energy
deprivation.
Compartmentation of leg lipid metabolism.
We measured femoral arterial and venous concentration differences of
FFA and glycerol during rest and exercise, at sea level, and at
altitude. Appropriately, we have tried to describe effects of exercise,
altitude, and altitude acclimatization on the leg, which is known to
contain subcutaneous as well as extra- and intracellular triglyceride
depots. Despite absence of precise data on metabolism within these
several depots, knowledge of leg anatomy and biochemistry allows some
reasonable conclusions to be reached.
Acclimatization decreased both fatty acid consumption and glycerol
release by the leg. These results are likely due to intramuscular rather than subcutaneous adipose tissue effects because muscle mass
predominates in the leg. Furthermore, the anatomy of venous drainage in
the leg would result in most glycerol and FFA from subcutaneous fat
entering the femoral venous blood without opportunity for muscle
exchange. Thus lipolysis in subcutaneous adipose tissue would have
resulted in glycerol and fatty acid release into femoral blood. Because
glycerol release decreased to nil with acclimatization, we can
tentatively conclude that lipolysis in both subcutaneous and
intramuscular fat depots was depressed.
Neither adipocytes nor myocytes are known to contain glycerol kinase
(26). Thus it is unlikely that increased reesterification accounted for
the decline in leg glycerol release and FFA uptake after
acclimatization. In any case, the substrate for glycerol kinase is
-glycerol phosphate, which is derived from glucose, not glycerol.
Thus reesterification would not be expected to affect net glycerol
release, which declined with acclimatization. In view of the virtual
absence of glycerol release from the leg after acclimatization, the
results probably can be interpreted to mean that the increase in
glucose uptake was attributable to glycolysis and not triglyceride
synthesis or reesterification. Therefore, it appears from glycerol
exchange data that limb net glycerol release was a valid measure of leg
lipolysis.
Our calculation of fatty acid consumption offered the opportunity to
underestimate fatty acid uptake in leg muscle. Lipolysis in
extracellular (interstitial) triglyceride depots would have resulted in
glycerol and FFA release into venous drainage, with some opportunity
for uptake by muscle cells. However, on balance, there was probably a
corresponding uptake of arterial FFA by muscle cells that was invisible
to our methods. Furthermore, tortuosity of the leg muscle capillary
network probably ensured mixing of FFA from arterial and interstitial
lipid stores. Therefore, the arteriovenous difference method probably
achieved an integrated and representative measure of leg fatty acid
consumption.
In the absence of having performed necessary dissections of many muscle
biopsy samples, we cannot address the issue of whether intra- or
extracellular lipid was mobilized during exercise. However, if we can
assume that various depots behaved similarly, and given the decline in
FFA uptake and fatty acid consumption after acclimatization, then it is
possible to reach the tentative conclusion that acclimatization suppressed net lipolysis in intra- and extracellular muscle lipid stores.
Leg Fatty Acid Consumption After Acclimatization
Our approach to evaluating the effects of exercise, altitude, and-blockade on muscle lipid metabolism involved a computation with
components of limb blood flow, as well as arterial and venous contents
of glycerol and FFA. As such, our estimates are subject to variations
in substrate delivery (i.e., blood flow and arterial concentration) as
well as metabolite extraction (i.e., a-vD).
Although limb blood flow was increased on acute exposure, with acclimatization flow returned to sea-level values as arterial SO2 improved (Table 4). Additionally, arterial FFA and glycerol levels tended to rise with chronic altitude exposure (Table 3). Therefore, the shift in limb substrate use after chronic exposure was probably not due to a decline in vascular conductance of substrate.
Glycerol and FFA Clearance After Altitude Acclimatization
During rest and exercise at altitude, circulating FFA and glycerol levels were increased in comparison with sea level in control but not in-blocked subjects (Table 3). Because after acclimatization it was
clear that limb glycerol release and FFA uptake are nil (Figs. 2 and
3), it is clear that altitude acclimatization results in decreased
glycerol and FFA clearance. However, in the absence of measurements of
glycerol and FFA flux rates, it is not possible to know whether
lipolysis is also affected by altitude or acclimatization.
Energy Balance at Altitude
An important aspect of this investigation was the attempt at maintaining energy and nitrogen balance despite elevated BMR at altitude. Butterfield et al. (8) demonstrated that BMR is increased by 30% on acute exposure to altitude and remains elevated by 17% even after 3 wk at altitude. Thus, in an assessment of the individual or combined effects of exercise and hypoxia on substrate metabolism, it is important to ensure that dietary energy intake meets need. In the present study, in which we fed subjects to maintain energy and nitrogen balance, we observed a shift away from lipid and toward glucose metabolism during both rest and exercise. We caution that the same results might not have been obtained if subjects were in negative nutrient balance, which would have increased use of endogenous lipids.Effects of Altitude and Relative Exercise Intensity
Because it was not feasible to study subjects at several times during acute altitude exposure, we had to decide whether to study subjects at a given absolute or relative exercise intensity. To isolate the effects of altitude on the balance of substrate utilization, we chose to maintain overall metabolic flux constant and observe effects on the patterns of substrate utilization. However, it must be acknowledged that at altitude physical exertion will be accomplished at a relatively greater exercise intensity (e.g., at a greater percentO2 max) than
at sea level and that at exercise power outputs in excess of
45-50% O2 max,
plasma FFA flux and oxidation decrease (6). Therefore, caution needs to
be exercised in making sea level-altitude comparisons of data obtained
in our investigation. However, in this regard we must emphasize that we
observed significant changes in limb glycerol and FFA exchanges across
the legs in our subjects after 3 wk of residence at 4,300 m even when
O2 max did not change
over the course of residence at altitude. Thus we conclude that,
regardless of whether altitude exposure increases the relative exercise
effort or chronic hypoxia signals changes in the patterns of substrate, the ultimate result for a well-nourished sojourner at altitude will be
a shift toward increased glucose and decreased lipid oxidation (6).
Summary
Our results obtained in young men who were in energy and nitrogen balance indicate that acclimatization to high altitude (4,300 m) results in decreased reliance on fat as a fuel. This decreased reliance is apparent under both resting and sustained exercise conditions. Furthermore, we also observed an increased dependence on glucose after altitude exposure (21). These results are in agreement with previous research in which the effects of energy and nitrogen balance on substrate utilization were considered (4, 8). A shift toward increased dependence on glucose metabolism and away from reliance on fatty acid consumption under conditions of acute and chronic hypoxia may be advantageous because glucose is a most O2-efficient fuel. Because our findings of decreased reliance on FFA as fuel and increased dependence on glucose were accompanied by increased levels of arterial FFA and glycerol and decreased levels of arterial glucose after chronic exposure to altitude, we conclude that arterial concentrations may not always indicate rates of utilization. Furthermore, these changes in blood metabolite flux under conditions of high-altitude acclimatization occur with unaltered insulin levels (21), even in the presence of-blockade. Thus the extra- and intracellular signals for altered patterns of lipid and glucose metabolism at altitude remain to be
explained.
ACKNOWLEDGEMENTS
We thank the following individuals for their technical support and assistance: Michael A. Horning, Mark Selland, Gretchen Casazza, Robert F. Grover, Robert E. McCullough, and Rosann G. McCullough. We also thank the US Army Research Institute of Environmental Medicine for allowing us to use the facilities at the summit of Pikes Peak. Finally, we express our appreciation to the 11 subjects whose participation made this study possible.
FOOTNOTES
Address for reprint requests: G. A. Brooks, Exercise Physiology Laboratory, Dept. of Human Biodynamics, 103 Harmon, Univ. of California, Berkeley, CA 94720 (E-mail: GBrooks{at}Violet.Berkeley.Edu).
Received 12 September 1994; accepted in final form 15 February 1996.
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