Download (2004). Oxidative fuel selection: adjusting mix and flux to stay alive

International Congress Series 1275 (2004) 22 – 31
www.ics-elsevier.com
Oxidative fuel selection: adjusting mix and flux to
stay alive
Jean-Michel Weber*, François Haman
Biology Department, University of Ottawa, 30 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Abstract. To be able to match ATP supply with demand, animals must ensure adequate delivery of
metabolic fuels and oxygen to tissue mitochondria. Therefore, the mixture of fuels provided and their
individual flux must be tightly orchestrated to cope with changing physiological needs. In exercising
mammals, metabolic rate—expressed relatively to the aerobic maximum: %VO2 max—determines
what mixture of oxidative fuels is being used. This simple model of fuel selection accurately predicts
the relative contributions of lipids and carbohydrates to total metabolism, and it applies widely across
body sizes, aerobic capacities, and even to exercise in hypoxic environments. However, it is also
becoming obvious that significant exceptions to this pattern exist in other vertebrates that rely more
heavily on lipids (e.g., migrating birds) or proteins (e.g., migrating salmonids), or for stresses other
than exercise (e.g., cold exposure in mammals). Instantaneous fuel use is determined by multiple
interacting mechanisms involving fuel availability, storage location, muscle recruitment, fiber
recruitment within each muscle, and metabolic pathway selection within each fiber. These various
mechanisms are being characterized in more detail to try designing a general model of fuel selection
applicable to a wider range of animals and physiological stresses. D 2004 Elsevier B.V. All rights
reserved.
Keywords: Animal energetics; Energy metabolism; Metabolic substrate; Exercise; Shivering thermogenesis;
Migration; Hibernation; Metabolic depression; Lipid; Carbohydrate; Protein
1. Introduction
The ability to adjust energy expenditure to cope with changing physiological
circumstances is a key feature of organismal survival, and a lot of research has
focused on understanding the fundamental mechanisms involved in the upregulation
* Corresponding author. Tel.: +1 613 562 5800 6007; fax: +1 613 562 5486.
E-mail address: [email protected] (J.-M. Weber).
0531-5131/ D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.ics.2004.09.043
J.-M. Weber, F. Haman / International Congress Series 1275 (2004) 22–31
23
(exercise, cold exposure, lactation) or depression of metabolism (fasting, hypoxia,
torpor, hibernation, estivation). However, merely changing total flux of O2 and
substrates to mitochondria is not sufficient to ensure long-term survival because
internal fuel sources are extremely diverse in size, chemical properties, and storage
locations. Therefore, the capacity to select an adequate mixture of metabolic fuels
(change in mix) and to modulate this blend (change in flux) is another essential
requirement for survival. This paper examines the strategies used by animals to alter
their pattern of fuel selection together with the supply rate of each individual
substrate to mitochondria. The tight regulation of mix and flux is necessary to balance
rates of ATP production with prevailing rates of ATP utilization. Locomotion,
thermogenesis, and metabolic depression are perhaps the most striking examples of
functional needs that critically depend on modulating the quality and quantity of
oxidative fuel supply.
2. Oxidative fuel diversity
To produce ATP for long-term activities, animals must rely on the oxidation of lipids,
carbohydrates, and proteins stored within their tissues. These metabolic fuel reserves are
obtained from the diet and are usually replenished during periods of rest, recovery from
exercise, or seasonal preparation for prolonged fasting associated with long-distance
migration or hibernation. The oxidation of each fuel presents clear advantages and
disadvantages for any particular physiological situation. To illustrate the convenience and
constraints afforded by such diversity, different criteria can be used for comparing the
various sources of energy, and, in this context, key characteristics of the fuels available are
summarized in Table 1.
Lipids represent the most concentrated source of energy in living organisms for two
important reasons: (i) they are the most chemically reduced of all fuels and (ii) they can
be stored without water. Therefore, animals favour lipids for energy storage, and most
land species could simply not afford to transport the additional weight associated with
alternative fuels. Despite their enormous bweight handicapQ, carbohydrates are essential
when ATP must be produced at high rates, without delay, or, possibly, when O2
availability is compromised. For many aquatic animals, weight is not an issue because
fuel reserves do not have to be carried against gravity. Unlike lipids, carbohydrates and
Table 1
Comparison of the different oxidative fuels available for ATP synthesis
Isocaloric weight
Percent total energy reserves
Maximal rate of ATP production
Time to reach maximal rates
Energy per volume O2
Unit
Lipids
Carbohydrates
Proteins
g fuel MJ 1
%
Amol ATP g
min
kJ l O2 1
26
85
20
N30
19.8
239
1
30
b2
21.1
55
14
1
min
1
18.7
Adapted from Refs. [1–4]. Lipid values are based on triacylglycerol with an average mammalian fatty acid
composition. Carbohydrate values were calculated for natural glycogen with an average level of hydration. For
proteins, values were calculated for ureotelic animals and only for the mobilizable fraction of total proteins.
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J.-M. Weber, F. Haman / International Congress Series 1275 (2004) 22–31
proteins are soluble in aqueous biological fluids and do not depend on carrier molecules
like serum albumin and fatty acid-binding proteins (FABP) for circulatory and
cytoplasmic transport. The complete oxidation of all fuels produces CO2 and H2O,
two end-products that can usually be managed without problems. However, protein
oxidation presents a unique metabolic limitation because it also yields noxious ammonia
that must be eliminated or detoxified.
The size of fuel reserves may be altered drastically in preparation for specific
physiological challenges. As an extreme example, lipid stores can be increased to reach
up to 50% of total body mass before hibernation in small mammals [5] or longdistance migration in birds [6]. To a lesser extent, fuel storage is also affected by
endurance training [7,8] or large shifts in diet composition [9]. In turn, these changes in
internal substrate availability can influence the pattern of fuel selection during exercise,
cold exposure, or metabolic depression. In addition to inflating or decreasing the size
of specific energy reserves, animals can also change the distribution of each type of
fuel among storage sites. During sustained exercise, ATP production of locomotory
muscles depends on the oxidation of both, intramuscular fuels (muscle glycogen and
muscle triacylglycerol), and circulatory fuels brought to working muscles from remote
storage sites (hepatic glucose and adipose tissue lipids) [10]. To be able to reach high
rates of oxidative fuel supply to muscle mitochondria, very aerobic mammals (high
VO2 max) rely relatively more on intramuscular fuels, and relatively less on circulatory
fuels than sedentary species (low VO2 max) [11,12]. This strategy is necessary to
circumvent significant constraints associated with the multiple trans-membrane crossings required to bring fuels from distant storage locations [13–15]. Nowhere is this
adaptation made more obvious than in the way intramuscular lipid reserves are
organized: all muscle lipid droplets are actually in direct contact with mitochondria
[16,17]. With such a spatial arrangement, lipid transport from storage to the enzymatic
Fig. 1. (A) Transmission electron micrograph of dog triceps muscle illustrating the close association between
intramuscular lipid droplets loaded with triacylglycerol (li) and mitochondria (mt). Adapted from Ref. [17]. (B)
Fuel selection pattern for mammalian exercise. Changes in the relative contribution of carbohydrate oxidation
(CHO; open symbols) and lipid oxidation (closed symbols) to total oxygen consumption of the whole organism
(VO2) as a function of exercise intensity (%VO2 max). Values are for dogs (o, ) [18], goats (q, z) [18],
humans (5, n) [19] and rats (D, E) [20,21]. Results include values for trained and untrained rats acclimated to
normoxia or to hypoxia.
!
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25
machinery of energy metabolism is reduced to its simplest form: one single membrane
to cross (see Fig. 1A).
3. Exercising mammals: a robust model of fuel selection
Almost all the information available on fuel selection comes from one
experimental model: mammalian exercise. For this group of animals, the observed
pattern is surprisingly simple. Total ATP production can be attributed exclusively to
lipid and carbohydrate oxidation because the contribution from proteins is minimal
[17,22]. More importantly, exercise intensity, expressed in relation to the aerobic
maximum (%VO2 max), determines the relative importance of lipids and carbohydrates according to the relationship presented in Fig. 1B. The contribution of
carbohydrates increases progressively, and that of lipids decreases progressively as
exercise intensifies. Therefore, the oxidation of each one of these two fuels is
responsible for half the metabolic rate of the whole organism at a work intensity of
about 50% VO2 max (or the work intensity sometimes referred to as the bcrossover
pointQ; Ref. [22]).
Different approaches have been used to build this model and to ensure that it could be
generalized to all mammals. Because the balance between lipids and carbohydrates
originally seemed to depend on %VO2 max, the robustness of the model was assessed by
exploiting various ways to manipulate aerobic capacity. Large adaptive differences in VO2
max (i.e., genetic differences) exist in nature between very sedentary and highly aerobic
species. Dogs and goats of the same size were used in this context because their aerobic
capacities differ by more than twofold [18]. Although highly aerobic dogs (geared for
endurance exercise) were anticipated to favor the use of the ample lipid reserves available
to all animals (see Table 1), results show that both species oxidize the same mixture of
fuels when they exercise at the same relative intensity (Fig. 1B) [18]. Because massspecific VO2 max varies greatly with body mass, measurements were extended to smaller
species (0.3 kg rats) and larger ones (70 kg humans), but without finding significant
deviation from the dog-goat pattern (Fig. 1B). Finally, experiments were carried out under
low oxygen availability because aerobic capacity is reduced by acclimation to hypoxia. In
addition, there is a convincing theoretical reason to think that animals should favor
carbohydrates when exercising in hypoxia because this fuel yields 11% more ATP per unit
volume of oxygen than lipids (Table 1, but see Ref. [23] for arguments supporting an even
greater difference). Again, results show that, individuals acclimated to hypoxia, running
under normoxic or hypoxic conditions, follow the same pattern of fuel selection previously
observed in all other mammals (Table 1) [20,24,25]. Therefore, the theoretical O2-saving
advantage provided by carbohydrates seems to be outweighed by the potential danger of
depleting this small, but critical energy reserve [25]. Although the relative partitioning
between lipids and carbohydrates is the same for different mammals, it is important to
realize that, for each relative exercise intensity, absolute rates of lipid and carbohydrate
oxidation are scaled directly with VO2 max (i.e., they are more than two times higher in
dogs than in goats). From these observations, we can conclude that the fuel selection
model proposed for exercising mammals (Fig. 1B) is extremely robust because it is
independent of aerobic capacity when tested for: adaptive variation (dog vs. goat),
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allometric variation (0.3 kg rat vs. 70 kg human), and environmental variation in O2
availability (normoxia vs. hypoxia).
4. Alternative fuel selection patterns: swimming fish, flying birds, and shivering
humans
Multiplying measurements in more examples of exercising mammals is unlikely to
yield further useful insights. Instead, developing a theoretical framework explaining the
reasons for the observed pattern appear more promising. To achieve this goal, two
interrelated strategies come to mind: uncover clear exceptions to this seemingly general
pattern (this section) and characterize the mechanisms available for altering fuel selection
(next section). In the last few years, several examples of divergent patterns have emerged,
and these exceptions could prove very useful for future research. As more information is
accumulating for various animals, it is obvious that the mammalian pattern is far from
universal; major differences in fuel metabolism can be found, even among vertebrates. In
fish, ignoring the contribution from proteins, as it was done for mammals, could lead to
enormous errors because some species are probably able to rely almost exclusively on this
source of energy for sustained swimming (e.g., during the late stages of migration in
sockeye salmon [3]). In addition, the three to fourfold increments in glucose flux (rate of
hepatic glucose production) and fatty acid flux (rates of lypolysis and fatty acid supply)
classically reported for all exercising mammals, are completely absent in rainbow trout,
even during prolonged swimming [26,27]. Salmonids clearly fail to follow the mammalian
model, but more research is needed to determine whether their fuel selection pattern is
typical of teleosts in general.
Long-distance migrant birds are another example at variance with mammals because
their relative use of lipids is much higher than that predicted in Fig. 1B. They have been
able to push conventional energy metabolism well beyond the limits set by the best
mammalian athletes. Many bird species migrate at 10–15 times their basal metabolic rate,
or twice the VO2 max of same-size mammals [28]. More importantly, most of the energy
used to power long-distance flights is provided by the circulation from adipose lipid
reserves [29]. These characteristics are incompatible with the mammalian model,
stipulating that, at intensities approaching VO2 max, over 80% of the energy comes from
carbohydrates (mainly muscle glycogen) [15], and that the oxidation of circulating lipids
accounts maximally for 10–20% of VO2 [11,12]. Although limited quantitative
information is available on the fuel metabolism of migrant birds, we can deduce from
first principles that using glycogen at such high rates is impossible; glycogen reserves of
the necessary magnitude do not exist in nature because their weight would prevent
movement (see Table 1). During migration flights, rates of circulatory lipid oxidation are
therefore at least 10, possibly 20 times higher than the maximal rates ever measured in
exercising mammals. Therefore, we can conclude that the mammalian crossover curves
presented in Fig. 1B must be strongly shifted to the right for long-distance migrant birds.
Artificially modifying the size of energy reserves can also lead to significant
adjustments in substrate use. In humans [30–32] and sled dogs [8], important changes
in fuel selection have been elicited by dietary manipulations (high-fat diet or glycogen
loading). Therefore, bon-boardQ availability of each fuel type influences the mixture of
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27
metabolic substrates oxidized. Although the exact signals relaying information about the
size of energy stores are still poorly understood, major advances have been made in this
area. For example, leptin levels signal the size of lipid stores [33], and, on its own, this
hormone has significant effects on fuel selection [34,35]. Finally, recent experiments on
the effects of cold exposure in humans suggest that the fuel selection patterns of shivering
and exercise are different [36]. Detailed measurements of fuel oxidation for thermogenesis
show that carbohydrates play a much more important role during shivering than exercise,
when these activities are compared at the same metabolic rate [32,36–38]. Therefore, the
fuel selection pattern of shivering humans can probably be obtained by shifting the
exercise curves of Fig. 1B to the left. The fact that the same muscles use different mixtures
of fuels during shivering and exercise when they function at the same metabolic rate is
very intriguing. The quest for an explanation of this fascinating difference could provide
novel insights on the fundamental mechanisms of fuel selection.
5. Mechanisms for selection
Fuel selection can occur by changing the supply rate or the utilization rate of the
different substrates available. Most of the well-characterized mechanisms of selection
operate directly at the level of fuel utilization, but a simple (and often overlooked)
mechanism acting at the level of fuel supply can also play an important role. Experiments
on thoroughbred horses have allowed showing that the supply of circulatory fuels to
working muscles is regulated in two ways [39,40]. First, the animal can change the supply
rate of all the fuels provided through the circulation by adjusting cardiac output and blood
flow to target tissues (coarse control of substrate flux acting indiscriminately on all
circulatory fuels). Second, the supply rate of individual fuels can be modulated separately
by changing their concentration in the blood (fine control of flux acting specifically on
each fuel). Together, these two mechanisms allow adjusting the flux of each blood-borne
substrate, thereby setting a fuel mixture adequate for present conditions.
The last part of this review deals with the best-characterized selection mechanisms that
act at the level of fuel utilization in skeletal muscle. These mechanisms can be divided in
three categories based on the level of organization where they exert their effects. Changing
the mixture of fuels can be done by selective recruitment of: (i) different muscles, (ii)
different fibers within the same muscle, or (iii) different metabolic pathways within the
same fiber. The selective recruitment of different muscles was first demonstrated in fish
where red muscle (made of slow fibers specialized for lipid oxidation) and white muscle
(made of fast fibers specialized for carbohydrate oxidation) are spatially separated (e.g.,
see Refs. [41,42]). The same mechanism can also regulate fuel selection in exercising
mammals and birds, although their muscles are made of mixed fibers. Using blood flow as
an index of recruitment, it has been possible to show that muscles with predominantly
slow fibers (specialized for fat oxidation) are already active at low work intensities,
whereas muscles with predominantly fast fibers (oxidizing carbohydrates) are only
recruited at high exercise intensities [43,44].
Similarly, it has been accepted for a long time that fuel metabolism can be regulated
within individual muscles through the selective recruitment of different fiber populations
specialized for different substrates [18]. Direct proof of this mechanism has only been
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provided very recently by making simultaneous measurements of fiber recruitment and
fuel utilization. Clear enough electromyographic (EMG) signals cannot be obtained during
exercise because of the large background noise created by limb movements. Therefore, the
problem was eliminated by using an alternative experimental model: shivering muscles of
humans exposed to cold. During high-intensity shivering, large differences in fuel
selection between individuals (i.e., carbohydrates accounting for 33% to 78% of metabolic
rate) are explained by differences in the recruitment of fast (type II) fibers, specialized for
carbohydrate oxidation [36]. Interestingly, the alternative mechanism of selection—the
recruitment of different metabolic pathways within the same muscle fibers—is used during
low-intensity shivering. Detailed EMG analyses reveal that glycogen-depleted and
glycogen-loaded individuals can have the same (low) thermogenic rate, but by using
widely different fuel mixtures within the same (type I) muscle fibers [32,38]. Biochemical
mechanisms of fuel selection have been investigated in mammalian muscles and they
continue to be the subject of intense research [19]. Numerous extra- and intracellular
signal molecules have been implicated. Since the early sixties, the bglucose–fatty acid
cycleQ of Randle et al. [45] has often been invoked to explain how the balance between
lipids and carbohydrates can be achieved. When fatty acid availability is high,
carbohydrate oxidation is reduced and lipid oxidation is stimulated. Randle et al. [45]
proposed that high plasma fatty acid concentration caused these changes by suppressing
the activation of the pyruvate dehydrogenase complex (PDC; through a rise in the
mitochondrial acetyl-CoA/CoA ratio) and by decreasing glycolysis (through inhibition of
phosphofructokinase via elevated citrate levels). Although PDC is still considered a
significant element in the regulation of fuel selection [46], it has become clear that other
mechanisms such as the direct inhibition of glucose transporters (GLUT-4) and of glucose
phosphorylation can also play important roles [47].
Over the last few years, malonyl-CoA has also attracted some attention as a possible
regulator of fuel selection [48]. The high glycolytic flux associated with intense exercise
causes the accumulation of acetyl-CoA, and it has been proposed that this would increase
cytosolic malonyl-CoA, thereby causing the inhibition of carnitine palmitoyltransferase I
(CPT I) and limiting fatty acid entry into mitochondria. However, direct measurements of
malonyl-CoA levels suggest that this probable intramuscular signal does not increase
during heavy exercise (at least in rats and humans). Therefore, this mechanism remains
doubtful [49]. Ongoing research suggests the involvement of free carnitine levels and
intracellular pH that would both inhibit CPT I when low [19,50]. Finally, it has been
suggested that fatty acid-binding proteins could play a significant role in fuel selection
through their direct regulation of glycolytic enzymes [51].
6. Conclusions
An array of fuels with different properties is available for energy metabolism, and each
one (or each mix) is advantageous for a particular physiological situation. Fuel selection
strategies are geared to manage energy reserves in a way to avoid the complete depletion
of any individual fuel to preserve the capacity to respond adequately to all life challenges.
Exercising mammals follow a simple pattern of fuel utilization whereby the balance
between lipids and carbohydrates is determined by relative work intensity (%VO2 max).
J.-M. Weber, F. Haman / International Congress Series 1275 (2004) 22–31
29
This model is very robust because it is independent of aerobic capacity across adaptive,
allometric, and environmental variation. In contrast, swimming fish, long-distance migrant
birds, and shivering humans follow different patterns of fuel selection whose study will
provide important novel insights on fundamental aspects of energy metabolism. The
mechanisms responsible for the regulation of fuel selection in working muscles include the
selective recruitment of different muscles, of different fibers within the same muscle, and
of different metabolic pathways within the same fiber. Reconciling detailed mechanistic
information with the fuel selection patterns observed in the whole organism remains a
major challenge for future research.
Acknowledgements
This research program is supported by NSERC grants (Canada) to J.-M. Weber.
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