Review 293

Fat Metabolism During Exercise: A Review

Part II: Regulation of Metabolism and the Effects of Training

A. E.]eukendrup, W. H. M. Saris, A. 1. M . Wagenmakers

Nutrition Research Center, Department of Human Biology. Maastricht University, Maastricht.The Netherlands

A. Ljeukendmp, W. H. M. Saris, A,]. M. Wagenmakers, Fat Me- Introduction

tabolism During Exercise: A Review- Part 11: RegulationofMe-

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tabolism and the Effects ofTraining, Int. J. Sports Med., Vol. 19, In part Iof this review "Fatty acid mobilization and muscle me-
pp. 293 - 302.1998. tabolism" published in a previous edition of the International
Journal of Sports Medicine (70). the importance of fat as a sub-
strate during exercise has been outlined and i t was described
how fat is mobilized from adipose tissue, transported through
This part discusses the complex regulation of fat metab- the blood. taken up by the muscle and used for oxidation by
olism. Catecholamines as a stimulator of lipolysis and insulin as the muscle. Also the roles of different lipid fuels (plasma fatty
a suppressor play very important roles in the regulation of fat acids, fatty acids derived from plasma lipoproteins, fatty acids
oxidation. The interaction of carbohydrate and fat metabolism from intramuscular triacylglycerols) have been discussed. Part
has been extenslvely studied in the past decennia but the un- I1 will focus on the interaction between carbohydrate and fat
derstanding of this rnultifactorial regulation is complex and still metabolism and the regulation of substrate utilization. In ad-
incompletely understood. In 1963, Randle et al. proposed the dition the effect of exercise intensity and training will be dis-
glucose-fatty acid cycle as a possible mechanism, and more re- cussed. In part III"Effect of nutritional interventions", in a sub-
cently, regulation through malonyl-CoA has been put forward sequent issue of this journal (71), attention will be paid to the
as a possible way to explain shifts in carbohydrate and fat effects of various nutritional manipulations on fatty acid
metabotism at rest and during exercise. The exercise intensity metabolism.
affects fat oxidation mainly by increasing lipolysis and fatty acid
availability during exercise of low to moderate intensity. At
Regulation of Substrate Utilization
high exercise intensities. both a reduction in fatty acid availabil-
ity (decreased RaFa) and intramuscular factors reduce fat oxida- Hormonal regulation
tion. These intramuscular factors are largely unknown. The in-
creased mitochondria1 density after training and increased oxi- Changes in gluconeogenesis, lipolysis and ltetogenesis during
dative enzymes may partly explain the increased fatty acid oxi- exercise can at least partly be explained by changes in hor-
dation during exercise as observed after training. However. also mone concentrations. The catabolic hormone profile as ob-
supply of fatty acids to the mitochondria may be important. served during intense endurance exercise will be promoted
The available evidence suggests that the additional fatty acids after a low-carbohydrate diet or a negative energy balance
oxidized after training are primarily derived from intramuscular (40.41.77.80). Hormones may primarily affect the mobiliza-
triacylglycerols and not from adipose tissue derived fatty acids tion of fatty acids (i.e. lipolysis). The insulin concentration de-
or circulating triacylglycerols. creases while glucagon, epinephrine, norepinephrine but also
growth hormone (GH) and cortisol levels increase. GH has a fa-
Key words: Training, glucose-fatty acid cycle, malonyl-CoA, cilitating effect on the catecholamines and thus also on the re-
epinephrine. insulin, exercise intensity. lease of fatty acids into the bloodstream. Catecholamines have
a potent stimulating effect on lipolysis while insulin is a strong
inhibitor of lipolysis (48): see also part Iof this review section
on "lipolysis i n adipose tissue". Galbo (40) concluded that the
changes i n the plasma concentration of these hormones were
primarily caused by changes in plasma glucose concentrations.
However, a sympathetic stimulation of hormone release could
not be excluded. During exercise plasma catecholamines and
sympathetic neural activity rise exponentially with increasing
exercise intensity. The effect, however, of plasma catechol-
amine concentrations on lipolysis and fat oxidation during ex-
Int.J. Sports Med. 19 (1998) 293 -302 ercise have not been very well described. Romijn et al. (102)
8 Ceorg Thieme Verlag Stuttgart . New York showed that during exercise at low intensity (25% ~ 0 ~ m a x )
Int. j. Sports Med. 19 (1998) A. E, leukendruo. W. H. M.Saris. A. I. M. Wooenmakeis

fatty acid turnover is increased tive times while plasma cate-

cholamine concentration rose only 50%above resting values.
When exercise intensity was increased to 65 and 85%~ 0 , m a x
plasma catecholamine levels increased 3 - 6 and 17- 19 times,
respectively, but fatty acid turnover actually decreased.There-
fore, other factors such as adipose tissue blood flow (11,12),
plasma lactate concentration (67) plasma insulin concentra- fructose 1.6 b i P
tion (63) and increased glycolytic flux (111) may play a major FFA

role during exercise at moderate to high exercise intensities.

The role of hormones during exercise and their influence on
t
{any acyuhn +4
0vruVBtB
\
\
1
substrate utilization has been extensively reviewed in several
recent publications (34,38,39,100,120).

The glucose-fatty acid cycle a t rest

The interaction between carbohydrate and fat metabolism
could partly be explained by the existence of the so-called glu-
cose-fatty acid cycle proposed by Randle in 1963 (94) (Fig.1).
An increased plasma fatty acid concentration would lead to,
an increased fat oxidation. The accelerated flux through the p-

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oxidation pathway would result in accumulation of acetyl-CoA
and NADH, which in turn would inhibit the activity of the en-
zyme pyruvate dehydrogenase (PDH)and thus inhibit pyru-
vate oxidation. Inhibition of pyruvate dehydrogenase would Fig. 1 Glucose-fatty acid cycle (Randle cycle). This cycle describes the
lead to a sparing of carbohydrates as once pyruvate has been mechanisms by which fatty acid oxidation may inhibit glucose oxida-
converted into acetyl-CoA it is committed to oxidation. In ad- tion. When fatty acids enter the cytosol they may be activated t o fatty
dition, an increased acetyl-CoAconcentration and in fact an in- acyl-CoA and subsequently transported into the mitochondria. Via P-
crease in the acetyl-CoAICoA ratio would result in an increased oxidation fatty acyl-CoA units will be broken down t o acetyl-CoA. An
increased cytosolic acetyl-CoA concentration or acetyl-CoAICoA ratio
citrate concentration leading to an inhibition of the enzyme will inhibit PDH activity and thus inhibit the decarboxylation of pyru-
phosphofructokinase (PFK), a key (rate-determining) enzyme vate t o acetyl-CoA. Also increased citrate concentration may lead t o in-
in the glycolytic pathway. These effects would result in a de- hibition of PFK. Increased cytosolic glucose-6-P concentrations may in-
creased rate of glycolysis and glycogenolysis. Lower fatty acid hibit glucose transport into the muscle cell. (PDH = pyruvate dehydro-
concentration would of course result in the opposite adapta- genase; PFK = phosphofructokinase: P = phosphate).
tions.

Although evidence in favour of the existence of this glucose- ies in which glucose tolerance was investigated with high and
fatty acid cycle has been obtained in rat cardiac muscle (42, low plasma fatty acid levels suggest a direct inhibiting effect of
43,94,95) and in rat diaphragm (42,43,94,95) initial studies fatty acids on glucose transport (35). Wolfe e t al. (128). on the
in rat skeletal muscle suggested that availability of fatty acids other hand, observed that elevated fatty acid levels did not af-
did not inhibit glucose disposal or oxidation (8.49.101). How- fect plasma glucose oxidation when glucose uptalte was kept
ever, results were rather conflicting since other studies report- constant. Instead, elevated fatty acid levels suppressed the oxi-
ed decreased glucose utilization after adding fatty acids to the dation of glycogen. Baron et al. (7) administered IntralipidQ
perfusion medium in isolated rat skeletal muscle (91,98,99). and heparin and observed that insulin-mediated whole body
Rennie et al. (99) found that increasing the fatty acid availabil- glucose utilization at rest was inhibited.
ity decreased the rate of glycogen degradation in stimulated
rat skeletal muscle. Citrate concentrations increased in slow Most studies in resting human subjects support the concept
twitch (ST; soleus) and fast twitch oxidative (no; deep por- that an increased availability of fatty acids affects the utiliza-
tion of vastus lateralis) but not in fast twitch glycolytic muscle tion of intracellular or extracellular glucose or both. However,
(FTG; superficial portion of vastus lateralis). So the differences the underiying mechanisms are largely unltnown and al-
in the above mentioned studies may be in part explained by though there are indications that the Randle cycle is operative
the different muscle types studied. Another difference be- in resting human skeletal muscle, there is little support for the
tween the studies, which may explain part of the conflicting cycle in exercising conditions.
results, could be the time point of the measurement. Zorzano
et al. (130) concluded that the glucose-fatty acid cycle does The glucose-fatty ucid cycle during exercise
not operate in the resting state in the soleus muscle of a
starved rat, but it does operate in the post-exercise period. In one of the first studies lookingat the glucose-fatty acid cycle
in man during exercise, it was observed that glucose uptake
Although most (5,35.36,115.123.129). but not all (49.130), during exercise was inhibited by an increase in plasma fatty
studies provide data that support the existence of the Randle acid concentrations (23). In a classical study Costill et al. (23)
cycle in resting skeletal muscle, this issue still remains a mat- fed their subjects a high-fat meal and gave them a heparin in-
ter of continuous debate. Ferrannini et al. (36) showed that fusion to elevate plasma fatty acids. Subjects exercised 30 min
elevated plasma fatty acid levels inhibited glucose uptalte, a on a treadmill at 70% \iO,max. The eIevation of plasma fatty
finding which was later confirmed by Walker e t al. (123). Stud- acids to approximately 1 mmol .I-' decreased the rate of mus-
Fat Metabolism During Exercise: A Review Int. 1. Sports Med. 19 (1998)

cle glycogen breakdown by 40%as compared to a control trial in which glycogen sparing was observed with elevated fatty
in which the plasma fatty acid concentration was approxi- acid levels (23,30,121),had very low plasma fatty acid levels
mately 0.2 mmol I-'. Vukovich et al. (121) observed similar in their control groups (below -0.2 mmol. I-') which may
glycogen sparing effects with fat feeding and Intralipida infu- have deprived the muscle of a plasma substrate. On the other
sion in combination with heparin infusion. These findings hand, the FFA levels in those studies not able to demonstrate
were further confirmed by Dyclc et al. (30) who infused Intrali- this effect, were somewhat higher (above -0.4mmol.l-I)
pid@and heparin to elevate plasma fatty acids and observed (96). This is analogous to the finding that nicotinic acid, a
significant glycogen sparing after 15 min of cycling at 85% strong inhibitor of fatty acid mobilization which decreases fat-
V0,max. However, the latter did not observe any differences ty acid availability usually below -0.2 mmol .I- increased'
in muscle citrate, acetyl-CoA and PDH between the Intralipide muscle glycogenolysis (9.92). This view is further supported
and the control trials, suggesting that another mechanism by observations by Dyck et al. (30)who showed a poor energy
than the glucose-fatty acid cycle must be responsible for the status of the muscle (low AMP, PCr) in the control trials in
regulation of fuel utilization. The authors suggest regulation which fatty acid availability was low compared to the lntra-
at the level of glycogen phosphorylase (30). Hargreaves et al. lipid" trials with very high plasma fatty acid concentrations.
(51)elevated plasma fatty acid concentration by infusion of In-
rralipid" and heparin. During exercise (knee extensions). arte- In conclusion, there is no evidence that the glucose-fatty acid
riovenous differences of different substrates were measured cycle as originally proposed is operative in exercising human
and muscle biopsies were taken. They observed that the up- skeletal muscle. Although several studies showed decreased
take of glucose was inhibited. while no differences could be glucose utilization when fatty acids are elevated, regulation
found in the muscle respiratory quotient and glucose-dphos- may not be through the classical glucose-fatty acid cycle. The

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phate. Elevated fatty acid concentration did not result in a de- question remains; If the glucose-fatty acid cycle is not the reg-
creased glycogen breakdown. fhe authors suggested that fatty ulating mechanism during exercise then what determines car-
acids have a direct effect on the uptake ofglucose from thevas- bohydrate and fat utilization?
cular space. These results were obtained during low-intensity
exercise with no changes in hormone concentrations (51). Regulation through rnalonyl-CoA
However, Romijn et al. (103) showed that during intense exer-
cise, glucose uptake was not inhibited by increasing plasma Another possible mechanism is regulation through malonyl-
fatty acid concentrations. To further illustrate the contradict- CoA. Carnitine acyl transferase I (CAT I), the rate-limiting step
ing findings Ravussin et al. (96) could not find a change in the for the transport of LCFA-CoA into the mitochondria has been
relative contribution of fat and carbohydrates to total oxida- suggested to be an important regulating site of fatty acid oxi-
tion during exercise at 44% VO,max, although plasma fatty dation (Fig. 2). CAT I-activity in turn is regulated by malonyl-
acids were significantly elevated by providing a pre-exercise CoA, which is formed by acetyl-CoA carboxylase (ACC) in the
medium-chain triacylglycerol (MCl') containing meal. rate limiting step of fatry acid synthesis. CAT I is very sensitive
to changes in the malonyl-CoA concentration (83). In starved
The results of several studies are far from consistent, especially
during exercise (17.23.55.96.98.99). However, some of the Inner
differences in the results can be explained by the experimental mitochondrial
set-up. Some studies have been performed in situations with membrane
very low rates of fatty acid oxidation (79). These low rates of
fatty acid oxidation can be found for instance during either
very low or very high exercise intensities. Some studies admin-
istered only small amounts of exogenous fat, which might have
been insufficient to significantly elevate fat oxidation (19.79).
Also other factors may have caused the non-uniformity in the
results. In addition, the glucose-fatty acid cycle is probably
subjected to influences of several hormones which makes
comparison of different investigations difficult. In the litera-
ture, the different findings of studies, some of which observed
"glycogen sparing" and others which did not, are generally ex-
plained by the extent to which plasma fatty acid levels were
elevated. carnitme transferase
transport system

However, more important may be the extent to which plasma MCFA 4 MCFA
fatty acid levels were lowered in the control situation. If the F"9
muscle is deprived from plasma fatty acids as a fuel (concen- inner space 1: 4 outer space
trations below approximately 0.2 mmol .I- I ) , the energy status
of the muscle cell may be decreased leading to accelerated gly- Fig. 2 Mechanism by which malonyl-COAmay regulate fatty acid flux
cogenolysis. into the mitochondria. Glucose and insulin may stimulate acetyl-CoA
carboxylase (ACC) leading to an accumulation of malonyl-CoA which
in turn may inhibit carnitine dependent long chain fatty acid (LCFA)
Another way of looking at the seemingly conflicting results is transport across the mitochondrial membrane. Medium chain fatty
that the glycogen sparing effect seen in some of the studies is acid transport across the rnitochondrial membrane which is less sensi-
not a result of a reduction in glycogen breakdown but rather an tive for changes in rnalonyl-CoA concentration may be inhibited to a
accelerated glycogen breakdown in the control trials. Studies lesser extent (25).
Int.] Sports Med. 19 (1998)

and diabetic rats. hepatic malonyl-CoA levels are decreased in vivo both at rest and during exercise (84). At the concentra-
and fatty acid oxidation as well as ketosis is increased (85). Jn tion present i n vivo full inhibition of CAT I in fact would be
situations of glucose paucity such as fasting, ACC is inactivat- expected. but this does not seem to prevent that fatty acids in
ed, and the result is a decreased malonyl-CoA concentration time become an increasingly important fuel during mild to
and an increased rate of B-oxidation. After refeeding. the pre- moderate exercise intensities. A possibility is that the concen-
viously starved rats have increased malonyl-CoA levels and de- tration seen by CAT I in the outer mitochondrial membrane in
creased fatty acid oxidation (85). fact is much lower than the malonyl-CoA concentration meas-
ured in the whole muscle extract. but it also cannot be exclud-
These observations suggest that malonyl-CoA may play an im- ed that the malonyl-CoA mechanism is not as important as
portant role in the regulation of fatty acid oxidation (84). Al- suggested in recent exercise literature. In addition malonyl-
though these effects have been shown in studies of liver (82, CoA concentrations have yet to be directly linked to changes
84) and heart (105), there is also evidence for the regulation in fat oxidation during exercise in either human or rat muscle
through malonyl-CoA in skeletal muscle (31,84.106 -108.124. (122).
125). Evidence collected in isolated and perfused skeletal mus-
cle suggest that the availability of carbohydrates may be an The Effect of Exercise Intensity on Fat Metabolism
important factor determining the utilization of fatty acids
(107). Ln liver, heart, and also in muscle, increases in glucose The intensity of exercise is the main factor determining the de-
or insulin and especially the two in combination will lead to gree of fat or carbohydrate oxidation during exercise. Relative-
an increased activity of ACC and an increased formation of ly, fatty acids will be more important during low-intensity ex-
malonyl-CoA (28,107).In addition, acetoacetate (108). exercise ercise. During exercise at 25%V0,max almost all of the energy

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(124.125) and contractions induced by electrical stimulation expenditure was derived from fat (102). During exercise at 65 %
(28,107) have been shown to decrease acutely the concentra- V0,max fat oxidation accounted for 50%of the energy expen-
tion of malonyl-CoA in rat skeletal muscle. Animal models in- diture but since the energy turnover was so much higher, the
dicate that when the muscle is supplied with a surplus of fuels absolute fat oxidation rates were greater. The absolute rates
other than fatty acids, malonyl-CoA levels increase (28,107, of energy provision from fat seem to have an optimum a t exer-
124,125). Conversely, rnalonyl-CoA levels decrease when the cise levels between 50 and 70%~ 0 ~ m aRomijn x. e t al. (102) in-
muscle is fuel-deprived or energy use is increased by contrac- vestigated plasma fatty acid uptake and estimated IMTG utili-
tion (28,107,124,125). zation using stable isotopes. They found that during low-in-
tensity exercise (25%i/02max) IMTC contribute minimally to
However, all these findings are in animal models and no direct energy provision. Plasma fatty acids and glucose appeared to
measures were made of fatty acid oxidation or any aspect of fat be the most important substrates at this intensity where fat is
metabolism. Recently, we reported that increased glycolytic by far the predominant fuel. At a moderate exercise intensity
flux during exercise, from hyperglycemia and hyperinsulin- (65%V0,max) substrates in the muscle (IMTG and glycogen)
emia, reduced long-chain plasma fatty acid oxidation but not became more important (Fig.3). IMTG were oxidized a t high
medium-chain fatty acid oxidation (25). This was interpreted rates at this exercise intensity while plasma fatty acids were
to suggest that increased glycolytic flux actively reduces long- used at a slightly lower rate compared to low-intensity exer-
chain fatty acid entry into mitochondria because the transport cise (Fig. 3).When the exercise intensity was further increased
of long-chain fatty acids through the mitochondrial membrane to 85%\ j ~ , m a x ,the contribution of plasma fatty acids became
appears to be less dependent on CAT J(106). It was suggested even smaller, while also IMTG oxidation decreased. The de-
that the increased glycolytic flux may have increased the con- creasing contribution of plasma fatty acids as observed in this
centration of malonyl-CoA in muscle as shown by Elayan and study may be caused by a decreased availability of fatty acids
Winder (31 ) which may have inhibited CAT I and thereby the which in turn may be caused by lower rates of appearance of
entry of long-chain fatty acids into the mitochondria. Similar fatty acids into the plasma (RaFA) (71,72).This decreased RaFA
findings were reported by Sidossis e t al. ( I l l ) who increased (71) without a simultaneous reduction in lipolysis (102) may
glycolytic flux by increasing the exercise intensity from 40% indicate that fatty acids are trapped within the adipocyte
to 80%~ 0 , m a xand observed specific inhibition of long-chain
fatty acid oxidation compared to medium-chain fatty acid at
the high exercise intensity. Again these results suggest that
long-chain fatty acid transport into the mitochondria is inhib-
ited ar the level of CAT I which may be regulated through
malonyl-CoA (111). Although this is an attractive hypothesis, C
Ji Muscle Glycogen
direct evidence for a malonyl-CoA mediated mechanism couId
VI
not be provided since muscle malonyl-CoA concentrations Y Muscle Triglycerides
were not measured in these studies (25.171). Odland et al.
(90) were the first to measure malonyl-CoA in human slieIetal 400 Plasma 'FA
muscle. They reported low levels at rest (compared to the val-
ues reported in rat skeletal muscle) and a 20%decline during Plasma Glucose
exercise that failed to be statistically significant (90). So, the 0
first data in humans are not very conclusive and further re-
search is needed to elucidate the role of malonyl-CoA in the
regulation of fat oxidation. Another unresolved problem is that Fig. 3 Substrate utilization at different exercise intensities (25%VO,
the Ki of malonvl-CoA for CAT I measured in viho is much low- rnax. 65%~ 0 ~ r n and
a x 80%i/O,max). Data adapted from Romijn et al.
er than the concentration measured in rat and human muscle (102).
Fat Metabolism Durina Exercise: A Review Int.]. Sports Med. 19 (1998)

(56). maybe as a result of increased lactateconcentrations (67) derstood. Several adaptations may contribute to a stimulation
or as a result of vasoconstriction in adipose tissue (12.13.104). of fat oxidation in trained subjects: I ) an increase in the num-
However, although fatty acid n~obilizationfrom adipose tissue ber of oxidative enzymes, and mitochondrial content in
is one of the factors which may be partially responsible for the trained muscle. 2) increased muscle triacylglycerol oxidation.
decreased fatty acid oxidation during exercise at high intensi- 3) increased fatty acid uptake. 4) alterations in mobilization
ties, this may not be the only factor. When plasma fatty acid of fatty acids from adipose tissue. Not only the cause of the in-
levels were elevated to high levels during exercise at 85%~ 0 ~creased. fatty acid oxidation after training is uncertain, also the
max by Intralipida and heparin infusion, fat oxidation rates source of these fatty acids is still not completely Itnown.
were somewhat increased (103) but still lower than during ex-
ercise at 65%~ 0 , m a x(102). This indicates that other (intra- An increase in the number of oxidative enzymes
muscular) factors may reduce fatty acid oxidation during and mitochondrial content
high-intensity exercise. A possible mechanism may be that
high rates of glycolysis and high rates of acetyl-CoA formation Studies on whole muscle homogenates have shown that rat
from glucose-G-phosphate at those exercise intensities inhibit skeletal muscle undergoes adaptive increases in the capacities
long-chain fatty acid transport into the mitochondria at the to oxidize fatty acids (6,8G) and ketones (126). Based on en-
level of CAT I by increasing malonyl-CoA concentrations (111). zyme Icinetics, Gollnick and Saltin (46) calculated that en-
hanced activity of enzymes involved in fatty acid oxidation
In addition, during intense exercise, more fast-twitch (FT)fi- may be the prime cause of the increased fat oxidation after
bers will be recruited and less slow-twitch (ST) fibers (110). training. Increased levels of enzymes involved in the activa-
Since the FT-fibers have a smaller capacity to oxidize fatty tion. transport and P-oxidation of long chain fatty acids have

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acids, fat oxidation will decrease and concomitantly carbohy- been frequently reported (6.15.24.57.86). Increased levels of
drate oxidation will increase when more of these fibers will 3-hydroxyacyl CoA dehydrogenase have been found in endur-
be recruited (110). It has also been suggested that during ance-trained rats (27) and in man (64.68). Other fatty acid
hig11-intensity exercise there is an increased competition of handling enzymes of which the activity or content is increased
pyruvate derived acetyl-CoA with fatty acid derived acetyl- after training include: carnitine palmitoyl transferase 1 (86).
CoA for entry into the TCA-cycle (60). carnitine acyl transferase (86) and fatty acyl-CoA synthetase
(86). However, not only the enzymes involved in fatty acid ac-
The contribution of fatty acids can increase markedly when tivation. transport and oxidation are increased in trained
glycogen stores in the muscle become depleted (1). This im- muscle, but also the enzymes involved in the TCA-cycle and re-
plies, however, that the "high" exercise intensity cannot be spiratory chain (15,24,54).Since endurance training increases
sustained and that exercise has to be continued at a lower level the capacity to oxidize fatty acids as well as pyruvate, the ques-
(92) because the rate of ATP production will decrease. tion remains: why are proportionally more fatty acids and less
carbohydrates oxidized? This may be explained by the mito-
Training and Fatty Acid Oxidation chondrial density as discussed by Gollnick and Saltin (46).

Endurance training affects both substrate utilization and the Endurance training increases both the size and the number of
exercise capacity. A large number of studies, both in animal the mitochondria (58).This increases the surface area where
and man, have established a marked adaptive increase in oxi- exchange of substrates and ADP can take place and possibly
dative potential in response to an increased physical activity also the number of transport proteins. Gollnick and Saltin
(57.58). A notable consequence and probably contributing fac- (46) proposed that the increased total mitochondrial volume
tor to the enhanced exercise capacity after endurance training as seen after endurance training, increases the capacity to
is the shift of metabolism to a greater use of fat and concomi- transport ADP formed by the contractile cycle into the mito-
tant sparing of the glycogen stores (6.18.21.46.47.57-59.64. chondria. Consequently, free ADP (ADPf) levels are lower in
69,109,110). The increased performance and the shift to fat muscles of exercise-trained compared to untrained muscles
metabolism during submaximal exercise are more pro- at the same contractile activity (22). The ADPf concentration.
nounced than the change in total-body maximal oxygen up- ATP/ADPf ratio and the ATP/(ADPfx Pi) ratio in the cytosol
take (i/o2max) (45) and it seems unlikely that other training and in the mitochondria have been shown to be key regulatory
adaptations such as an increased maximal cardiac output or factors of metabolism (4,29.114).Besides these factors also ex-
pulmonary function will be a major factor in explaining the tramitochondrial Pi and the supply ofhydrogen have been pro-
shift from carbohydrate to fat metabolism in the trained skele- posed as important regulatory factors of mitochondrial res-
tal muscle (47). The contribution of fat to total energy expen- piration (114). According to the model of Gollnick and Saltin
diture increases after training at both the same relative and ab- (46) by maintaining lower levels of ADPf or increases in the
solute exercise intensity (23.54.58,64.68,69). This is of ut- ATP/ADPf ratio, a greater entry of acetyl-CoA from fatty acids
most importance during prolonged exercise of moderate to into the oxidative pathways would be favoured because ADPf
high intensity (50-90% \i02max) since carbohydrates are re- and ATP/ADPf have a stimulating influence on glycolysis (88).
quired to maintain those levels of exercise. As soon as glycogen
stores become depleted and carbohydrate oxidation falls be- Compared to untrained, trained subjects have a higher mito-
low a critical level, the exercise intensity has to be reduced chondrial content (i.e. higher oxidative capacity) and during
since ATP cannot be generated at a sufficient rate (87). exercise at a certain workload less ADPf will be formed (along
with higher ATPIADPf and ATP/(ADPfx Pi) ratios). These
Although the advantages of increased fat oxidation during ex- changes will directly control energy metabolism by stirnulat-
ercise are obvious, the cellular and molecular mechanisms un- ing glycogen phosphorylase. PFK and PDH resulting in an in-
derlying this beneficial effect of training are incompletely un- creased glycolytic flux.
Int. 1. Sports Med. 19 (1998) A. E. leukendrup, W. H. M. Saris, A. 1. M. Wagenmakers

Although the enzyme activity and mitochondrial density are fatty acids. So, although fat oxidation is marltedly increased it
increased after training, it remains to be determined whether is unlikely that plasma fatty acids are the main source of fatty
the enzyme activity is the main limitation in lipid oxidation in acids that explain this increased fat oxidation. The above men-
the exercising muscle cell. An increase in the oxidative capaci- tioned studies (54.64.68,81) support the concept that training
ty should be accompanied by a quantitatively similar increase does not increase extraction of plasma fatty acids by the mus-
in the supply of fatty acids to the mitochondria (119). Evidence cle. However. Turcotte et al. (117) reported that, above certain
to support this view is the observation that runners with sim- plasma fatty acid levels, thigh uptake of plasma fatty acids was
ilar rates of fat oxidation during a 60 min run at 70%W,max. limited in untrained compared to trained during the third hour
displayed considerable differences in carnitine palmitoyl of single-leg knee extension exercise at 60%k 2 m a x . Whereas
transferase I and succinyl dehydrogenase activity (24). plasma fatty acid uptake rose linearly with increasing (non-
protein bound) plasma fatty acid concentrations in trained
Malonyl-CoA and fat utilization after training subjects, the uptake followed saturation kinetics (i.e. leveled
off) in untrained subjects above plasma concentrations of
As discussed above malonyl-CoA may be an important regula- - 700 mmol .1- '.The observation that the uptake of fatty acids
tor of fatty acid oxidation in slteletal muscle during exercise is a saturable process was previously shown in a rat model
(124.125). Decreased malonyl-CoA levels during exercise may (116). Training may provoke changes in the transport across
allow more long chain fatty acids to be transported into the the membrane (117). It has been suggested that FABP. FATand
mitochondrial matrix, since CAT I is less inhibited. The de- FATP may play an important role in the transport across the
creased muscle malonyl-CoA concentrations during exercise membrane and inside the cytosol (44,119). In rats, however.
parallel a decreased carbohydrate flux. Recently evidence was training increased FABP content of heart muscle, but not in

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provided that carbohydrate flux directly regulated fatty acid the EDL and soleus (118). However, as discussed by Coggan
oxidation during exercise at 50%\i02max (25,112). It is there- (21), the results of studies using knee extension exercise as ap-
fore tempting to speculate that training may result in a greater plied by Turcotte et al. (117) cannot be easily extrapolated to
fall in muscle malonyl-CoA concentration during exercise. whole body exercise since with this knee extension exercise
thereby relieving inhibition of CAT 1, and enhancing fatty acid hormonal changes are much smaller compared to whole body
oxidation. However, these mechanisms are rather speculative exercise. Since the extraction of fatty acids does not seem to be
and additional research is required to test these challenging increased after training during whole body exercise (68.81).
hypotheses. the reduction of plasma fatty acid oxidation must be due to re-
duced lipolysis. The most likely explanation for an effect of
Training also decreases glucose uptake during exercise at the training on adipose tissue lipolysis is probably a decrease in
same absolute exercise intensity (18.20) even though the the sympathoadrenal response to exercise of the same abso-
number of glucose transporters (GLUT4)in the muscle may in- lute intensity. The level of sympathoadrenal activity, which is
crease (52).This lowering of plasma glucose uptake, in combi- a major determinant of adipose tissue lipolysis in humans. is
nation with an increased fat oxidation after training has been markedly blunted even after a few weeks of training (127).
suggested to be regulated through the classic glucose fatty acid Winder et al. (127) observed a 55% reduction in the plasma
cycle. However, Coggan et al. (20) reported that citrate andglu- catecholamine concentrations durjng prolonged exercise (de-
cose-6-phosphate concentrations were lower at the same ex- creased heart rate may be an indicator of decreased sympa-
ercise intensity in the trained than in the untrained state, thoadrenal activity after training). Endurance training also at-
which is in contrast to the concept of the glucose fatty acid cy- tenuates the exercise-induced increase in plasma concentra-
cle. tions of other lipolytic hormones such as glucagon and growth
hormone (127).In addition, Lavoie et al. (78) showed that after
Effect of training on plosmo fatty acid utilizorion endurance training the inhibiting effect of insulin on lipolysis
is increased, which leads to reduced release (Ra) of fatty acid
Wjth fatty acid uptake and oxidation being dependent on their (78,81) and reduced plasma fatty acid concentrations (18.78,
vascular concentration and from the increased oxidative 81,127). However, although the reduction of the release of fatty
potential of endurance-trained skeletal muscle (2,53,65.73, acids after training may mainly be explained by the decreased
116), it might be expected that an enhanced rate of Iipolysis rate of lipolysis, it cannot be excluded that trained subjects
would accompany training. This could be envisaged as a mech- have higher rates of triacylglycerol-fatty acid cycling. De-
anism to provide more fatty acids to the working muscle to creased lipolysis (measured as Ra glycerol) at the same abso-
support the increased potential to oxidize fatty acids. How- lute exercise intensity has been reported to be the same (75)
ever. lower plasma fatty acid concentrations after training or slightly decreased (93) after training while whole body lipo-
(26,64,81,127) suggest that the effect of training on plasma lyds at the same relative exercise intensity may be increased
fatty acid oxidation during exercise is either a diminished mo- (76).
bilization from adipose tissue or an increased extraction of fat-
ty acids by the muscle. Interestingly, lipolysis in adipose tissue seems to be decreased
after training whereas at the same time lipolysis in skeletal
A study of Martin et al. (81) using isotopic labeling of palmitate muscle seems to be increased (see "Effect of training on IMTG
shows that both the rate of appearance(Ra) and the rate of dis- utilisation"). The mechanism behind these disparate effects of
appearance (Rd) of fatty acids are diminished as a result of training is unclear. There are, however, a few differences in li-
training. Henriksson (54) found similar rates of fatty acid up- polysis in skeletal muscle and adipose tissue that may at least
take between a trained and an untrained leg during 50min partly explain the different responses to training. First of all.
moderate-intensity two-legged exercise and Jansson and Kaij- skeletal muscle lipolysis appears to be more sensitive to P-
ser (68) found no effect of training on leg extraction of plasma adrenergic blockade than adipose tissue lipolysis (16), impli-
Fat Metabolism During Exercise: A Review Int.]. Sports Med. 19 (1998)

cating that, at lower levels of sympathoadrenal stimulation Conclusion

(such as after training [127]), lipolysis will be stimulated rela-
tive more in skeletal muscle. Secondly it has been suggested In conclusion, the increased mitochondrial density after train-
that there is a tissue specific upregulation of lipolysis in the ing and increased oxidative enzymes may partly explain the
trained state (81) as evidenced by increased adenylate cyclase increased fatty acid oxidation during exercise as observed after
activity in skeletal muscle of trained rats compared to un- training, However. also supply of fatty acids to the mitochon-
trained rats (10).It also cannot be excluded that exercise leads dria may be important. The available evidence suggests that
to allosteric activation of HSL especially in trained muscles or the additional fatty acids oxidized after training are primarily
that training leads to an increase in t h e HSL enzyme concen- derived from intramuscular triacylglycerols and not from adi-
tration in muscle. However, w e can only speculate on this in- pose tissue derived fatty acids o r circulating triacylglycerols.
teresting difference between trained and untrained individ-
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