elsevier fuel selection review

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Oxidative fuel selection: adjusting mix and flux to

stay alive

Jean-Michel Weber*, Francois 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 rateexpressed relatively to the aerobic maximum: %VO2 maxdetermines

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 moreheavily 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

0531-5131/D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.ics.2004.09.043

* Corresponding author. Tel.: +1 613 562 5800 6007; fax: +1 613 562 5486.

E-mail address: [email protected] (J.-M. Weber).

International Congress Series 1275 (2004) 2231

www.ics-elsevier.com


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(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 O2availability 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

Unit Lipids Carbohydrates Proteins

Isocaloric weight g fuel MJ1 26 239 55

Percent total energy reserves % 85 1 14

Maximal rate of ATP production Amol ATP g1 min1 20 30

Time to reach maximal rates min N30 b2

Energy per volume O2 kJ l O21

19.8 21.1 18.7Adapted from Refs. [14]. 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.

J.-M. Weber, F. Haman / International Congress Series 1275 (2004) 2231 23


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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 long-

distance 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 sizeof 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 cross-

ings required to bring fuels from distant storage locations [1315]. Nowhere is thisadaptation 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.

J.-M. Weber, F. Haman / International Congress Series 1275 (2004) 223124


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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 carbohy-

drates according to the relationship presented in Fig. 1B. The contribution of

carbohydrates increases progressively, and that of lipids decreases progressively asexercise 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 VO2max (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 aerobiccapacities 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 mass-

specific 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 unitvolume 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 O2availability (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 isaccumulating 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 istypical 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 1015 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 lipidsaccounts maximally for 1020% 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 [3032] 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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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 [32,3638]. Therefore, the

fuel selection pattern of shivering humans can probably be obtained by shifting the

exercise curves ofFig. 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 bloodflow 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 thesame 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 selectionthe

recruitment of different metabolic pathways within the same muscle fibersis 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 theycontinue to be the subject of intense research [19]. Numerous extra- and intracellular

signal molecules have been implicated. Since the early sixties, the bglucosefatty 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 othermechanisms 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 andintracellular 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).



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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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