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10.1146/annurev.physiol.68.040104.105739

Annu. Rev. Physiol. 2006. 68:223–51doi: 10.1146/annurev.physiol.68.040104.105739

Copyright c© 2006 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on October 19, 2005

THE COMPARATIVE PHYSIOLOGY OF FOOD

DEPRIVATION: From Feast to Famine

Tobias Wang,1 Carrie C.Y. Hung,2 and David J. Randall21Department of Zoophysiology, Aarhus University, 8000 Aarhus C, Denmark;email: [email protected] of Biology and Chemistry, City University of Hong Kong, Kowloon Tong,Hong Kong PRC; email: [email protected], [email protected]

Key Words feeding, fasting, starvation, metabolism, atrophy, digestion,gastrointestinal organs, specific dynamic action, phenotypic plasticity

■ Abstract The ability of animals to survive food deprivation is clearly of consider-able survival value. Unsurprisingly, therefore, all animals exhibit adaptive biochemicaland physiological responses to the lack of food. Many animals inhabit environmentsin which food availability fluctuates or encounters with appropriate food items are rareand unpredictable; these species offer interesting opportunities to study physiologicaladaptations to fasting and starvation. When deprived of food, animals employ vari-ous behavioral, physiological, and structural responses to reduce metabolism, whichprolongs the period in which energy reserves can cover metabolism. Such behavioralresponses can include a reduction in spontaneous activity and a lowering in body tem-perature, although in later stages of food deprivation in which starvation commences,activity may increase as food-searching is activated. In most animals, the gastrointesti-nal tract undergoes marked atrophy when digestive processes are curtailed; this struc-tural response and others seem particularly pronounced in species that normally feedat intermittent intervals. Such animals, however, must be able to restore digestive func-tions soon after feeding, and these transitions appear to occur at low metabolic costs.

INTRODUCTION

All animals supply the energy required for basal metabolism, physical activity,growth, and reproduction from their food. When food is not available, animalsmust use internal energy stores to fuel these activities. Starvation resistance re-flects an animal’s ability to store energy and control its allocation during extremeresource limitation. Many animals live in environments in which food abundanceand quality vary drastically over time, and periods of starvation are common.Bacteria can lead a feast-or-famine existence (1, 2), many planktonic species livein a resource-limited world (3), and many fish overwinter with little or no food.Sommer (4) suggested organisms can be grouped according to their responsesto variations in food supplies. “Velocity specialists” are those species with high,

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224 WANG � HUNG � RANDALL

maximum population-growth rates that respond to sudden increases in resourceabundance with rapid increases in population density; many bacteria fall into thiscategory. “Affinity specialists” can maintain growth at low-food-intake levels; thismay describe many tropical fish. Lastly, “storage specialists” such as hibernatingmammals create large internal stores that increase the chances of survival whenresource abundance is extremely low.

Many of the animals that inhabit environments with fluctuating food availabilityare adapted to consume very large meals when prey is available. Classic examplesare sit-and-wait predators, such as snakes; such species feed only once or a fewtimes a year. Very large meals followed by low rates of energy expenditure, typicalof crocodiles as well as a number of other reptiles and various fish, allow fordays or weeks between feeding. When the lack of food is due to seasonal changesin temperature or water availability, animals may enter into dormancy, duringwhich digestive processes are curtailed. With the exception of birds and somelarge mammals, which migrate to more desirable areas, dormancy is common invertebrates living in temperate or arctic environments that hibernate during coldperiods of the year. In tropical areas, many vertebrates, with the notable exception ofbirds, enter into a dormant estivating state during dry, and typically warm, periods.Fasting may also occur when animals engage in activities that compete with oreven preclude feeding or the search for food. Such activities include migration,moulting, or the care of eggs or young (e.g., 5–7). Examples of voluntary anorexiaexist in all major groups of vertebrates and may be very prolonged. Some speciesof penguins, for example, do not eat for several months when tending to eggs (8,9); Pacific salmon do not feed during their upstream migration, which can be morethan 1000 km in length (10); and eels do not feed during their migration across theAtlantic to spawn.

The ability of animals to survive food deprivation is clearly of considerablesurvival value. Unsurprisingly, therefore, all animals exhibit adaptive biochemicaland physiological responses to the lack of food. These responses prolong survivalwhen food is not available. Equally important, however, these responses also helpanimals to (a) preserve physiological functions so that behaviors, such as physicalactivity to avoid predators or to seek food, can be maintained and (b) ensure thatthe animals can resume digestive and metabolic processes when food becomesavailable again.

OVERALL FASTING TOLERANCE IS DETERMINED BYENERGY STORES RELATIVE TO USAGE

When animals experience food deprivation, they must derive the energetic costsfor basal metabolism, physical activity, growth, and reproduction from the inter-nal energy available at the onset of fasting. Large energy stores at the onset offasting, therefore, obviously aid in prolonging starvation tolerance; animals com-monly gain weight before dormancy. A reduction in metabolism also prolongsstarvation tolerance, and various biochemical and physiological responses to food

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PHYSIOLOGY OF FOOD DEPRIVATION 225

deprivation contribute to the efficient use of resources. Animals reduce metabolismin diverse ways. Many animals inhibit reproduction and reduce both activity andbody temperature. In fact, many animals breed only when food supplies are read-ily available, for example, in the springtime in temperate regions, and they do notbreed during the winter, when food supplies are limited. The response to starvationis integrated at all levels of organization and is directed toward the survival of thespecies.

Starvation has been more extensively studied in birds and mammals than ininvertebrates and other vertebrates. Birds and mammals are special among ver-tebrates because they normally must eat at regular intervals owing to their highmetabolic rates relative to their body stores. Most definitions and ideas of fastingcome from the human literature. The extent to which our knowledge of fasting andstarvation in birds and mammals can be transferred to other animals is not clear,as we discuss below.

The Phases of Fasting and Starvation in Mammals and Birds

The responses to absolute food deprivation in birds and mammals proceed instages, culminating in death. The initial period involves fasting, and the laterstages starvation. The demarcation between these two states is rarely appreciated,perhaps owing to lack of definition. In humans, fasting often refers to abstinencefrom food, whereas starvation is used for a state of extreme hunger resulting froma prolonged lack of essential nutrients. In other words, starving is a state in whichan animal, having depleted energy stores, normally would feed to continue normalphysiological processes. The metabolic transitions of food deprivation in birdsand mammals have been divided into three phases. Most investigators probablywould agree that the transition from fasting to starvation occurs by the end ofphase II or the start of phase III. Alternatively, and not in conflict with this view,others have argued that the transition between fasting and starvation may occurwhenever animals opt to abort voluntary anorexia (sensu Reference 5). In ourview, fasting should denote voluntary anorexia. Thus, salmon moving upstreamand eels crossing the Atlantic to spawn are fasting rather than starving. The stagesof starvation, if they exist in fish, amphibians, and reptiles, span a much moreextended time frame, and the distinction between fasting and starvation becomessomewhat esoteric. In any event, the severity of the food deprivation and timerequired before an animal enters actual starvation vary among species, and thetransition to starvation will depend on individual responses and nutritional status aswell as a number of environmental conditions. Thus, whereas a small endothermicanimal may be starving within a day of lacking food, it would take much longer forlarge ectothermic animals to undergo the same transition. Future studies shouldaddress questions such as whether large predatory ectotherms, such as sharks, thathave not fed for a few days, are starving or fasting while waiting for the next meal.Similarly, is a hibernating ground squirrel starving or fasting?

The different phases of response to food deprivation, which are defined accord-ing to the progressive metabolic changes that occur, were initially characterized

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for humans and other mammals (e.g., 11–14). These stages have been successfullyapplied to birds (8, 9, 15), and although not thoroughly investigated in ectother-mic vertebrates, the overall progression in metabolic adaptation appears similar formost vertebrates. As a major difference, however, resting and maximal metabolismare much lower in ectothermic vertebrates than in endotherms (e.g., 16). For a givenbody composition and amount of energy stores, ectothermic vertebrates thereforecan maintain normal metabolic functions for much longer than can endother-mic animals, thereby deferring the detrimental consequences of food deprivation.Thus many ectothermic vertebrates can tolerate more lengthy starvation than canendotherms. Eels, for example, can migrate many thousands of kilometers overalmost a year without feeding and may survive lack of food for many years (17,18), whereas a similar-sized mammal would die from starvation within a few daysor a week. Likewise, small animals are much more susceptible to food deprivationthan are larger animals.

In mammals, the three metabolic phases during food deprivation are character-ized as follows on the bases of the primary fuel available for use and the associatedchanges in overall body mass:

Phase I. The postabsorptive phase is the initial phase of fasting immediatelyafter the last meal has been absorbed from the gastrointestinal tract. During thisperiod, which normally lasts for hours, metabolism is largely fueled by glycogenol-ysis, or glycogen depletion of liver stores, which maintain constant blood sugarlevels. In addition, fatty acids are liberated from adipose depots, and the availabil-ity of plasma fatty acids allows for some tissues, such as skeletal muscle, to sparethe overall use of glucose.

Phase II. When liver glycogen stores are depleted, gluconeogenesis becomesnecessary to supply the requirements of glucose-requiring organs such as the brain.In humans, the initial fuel for gluconeogenesis is amino acids from proteolysisof muscle protein, but this contribution falls markedly as increased amounts ofglycerol, another substrate for gluconeogenesis, is liberated from adipose tissues.Increased oxidation of fatty acids leads to an elevated production of ketone bodies,which can be used as an oxidative fuel in many tissues including the brain. As phaseII progresses, protein degradation is rather slow, and degradation of adipose tissuefuels most bodily metabolism. In owls, lipid contributes more than 90% of the en-ergy consumption in phase II, and approximately 2.5% of the energy consumptionis derived from protein (19). In humans, this state can be maintained for severalweeks and has often been referred to as a period of adapted starvation. Because ofthe high energy content of lipid, weight loss is rather slow during this state.

Phase III. If starvation continues until the adipose stores are depleted, muscleis rapidly degraded for gluconeogenesis. The rapid loss in muscle mass cannot besustained for long and eventually kills the animal.

Figure 1 presents these three phases in rats. It shows how, as rats enter phaseIII, the rate of body mass loss along with nitrogenous waste production and itsexcretion increase as a result of protein degradation.

Although similar metabolic changes and the transitions between fasting andstarvation remain to be studied in detail for ectothermic vertebrates, numerous

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Figure 1 Changes in body mass, daily loss of body mass, and excretion of nitrogenous

waste in rats during the three phases of starvation (modified from Reference 48).

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studies have reported on the gradual but slow decrease in body weight and somaticindices as food is withheld. Most species studied utilize fat before protein is de-graded (e.g., 10, 20–24). Other reports suggest that in ectotherms, as in mammals,glycogen is utilized even before lipid or protein (25, 26). Table 1 shows expressionprofiles of the main energy-generating pathways that are related to the three phasesof the mammalian response to starvation. Mammals have to utilize energy reservesmuch earlier than fish in response to starvation. Genes that encode protein productsin lipolysis and protein turnover were induced after 24 and 48 h of starvation inmice and rats. Figure 2 shows that starvation did not trigger significant changes ingene expression in carp until after at least 16 days of food deprivation. Lipolysisgenes, such as β-oxidation, remained unchanged in carp liver throughout the sixweeks of food deprivation, reflecting the fact that, unlike in mice and rats, hep-atic lipid utilization was not enhanced in carp. Carp hepatic ubiquitin-proteasomegenes were upregulated by approximately 1.3-fold after 28 days of starvation butdid not trigger a significant decline in total hepatic protein content. In fact, hepaticprotein appears to be well conserved during starvation in carp (27–30). Of course,before mobilizing hepatic reserves, carp use other lipid sources such as viscerallipid, as do rainbow trout (31). Carp contained a large amount of visceral lipids,although they were not quantified in the experiment. Carp hepatic glycogen, onthe other hand, was mobilized during the first four days of starvation and then de-clined again after six weeks, which coincided with an increase in glycolytic geneexpression. Hepatic glycogen was not exhausted completely in carp after 100 daysof starvation (32). Early mobilization of hepatic glycogen in carp may be relatedto glucagon release during the initial phase of starvation; this has been observed inteleosts and may be a response to stress rather than starvation (24, 33). Migratingsalmon utilize lipid and spare protein until later in the migration phase, when lipidstores are almost completely depleted (10).

REDUCTIONS IN ENERGY EXPENDITURE DURINGFOOD DEPRIVATION

Responses to starvation occur at the behavioral, physiological, biochemical, andmolecular levels. In general, the time to reach starvation-induced death increaseswith body mass (34–37), reflecting larger animals’ greater abilities to lower specificmetabolic rate and increase stores of energy. Reductions in energy expenditurecan also occur via a reduction in body temperature, which reduces metabolicrate (the Q10 or Arrhenius effect). Animals also can decrease energy expenditureduring starvation by reducing locomotor activity as well as other behavioral andphysiological functions such as reproduction and care for young. Many of theseactivities, although interconnected, are often studied in isolation. Protein synthesisis decreased, and expression of many metabolic genes is also reduced. Whethergene expression is reduced in response to decreased energy expenditure or viceversa is not clear.

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Basal and Resting Metabolic Rates

Humans and other mammals decrease resting metabolism during fasting and star-vation (38). A very pronounced example is that of the golden spiny mouse, Acomysrussatus, which inhabits dry deserts in the Middle East. Within one day, this smallrodent apparently reduces oxygen uptake to half of the normal value and main-tains this low metabolism when kept on restricted food availability for two weeks(39). This reduction takes places without changes in body temperature and mayrepresent sympathetic control of energy-requiring processes (39). However, a re-cent study on the same species showed that food restriction elicits a reduction inboth body temperature and metabolism that resembles torpor in other mammalianspecies (40). Nevertheless, although most animals do seem to lower body tempera-ture when food is limited, substantial reductions in basal metabolic rate may occur.In salmon, for example, oxygen uptake decreased gradually over approximatelytwo months when food was withheld (22).

A reduction in basal metabolic rate, with no attendant decline in body tempera-ture, requires that some energy-requiring processes be reduced at the cellular level.The changes in cellular metabolism responsible for a reduction in basal metabolismin fasting or food-restricted animals have not been studied, but the response mayinvolve some of the same mechanisms as those occurring during the metabolicreduction observed during hypoxia. Many vertebrates respond to lack of oxygenby lowering protein synthesis, and a lower membrane permeability decreases thedemand for active ion transport. Cell cycle may arrest, and cell proliferation maydecrease, leading to the observed reduction in growth (41). Certainly food restric-tion and therefore the lower rate of intestinal nutrient uptake should also decreaseprotein synthesis, cell proliferation, and growth. It is difficult to envision, however,that changes in membrane properties would occur without an associated loss offunction.

Measuring basal metabolic rate while controlling for changes in spontaneousactivity or alertness and sleep is difficult. Also, as described in more detail below,digestion also involves specific dynamic action and a rise in metabolism of animalsseemingly at basal conditions. Fasting or starvation may therefore be associatedwith an apparent decline in basal metabolism that actually should be ascribed to agradual cessation of digestive processes. The mammalian digestive tract displaysgreat morphological and functional changes in response to starvation. Epithelialcell renewal and cell migration from crypt to villi tips were both reduced in starvedmice (42) and rats (43). Total intestinal and jejunal mucosal mass was decreasedby a factor of two in fasting rats, accompanied by reductions in jejunal crypt sizeand villi size and numbers as well as increases in villi tip cell apoptosis (44). An-other recent study on rats, however, reports only minor changes in intestinal villusapoptosis (45). In any event, these studies concur that during phase III, apoptosisdecreases and cell proliferation and migration increase (44, 45). Altogether, thisupregulation of cellular events and presumably of absorptive capacity may reflectpreparation for future feeding (45). The restoration of the intestine during phase III

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of starvation may be related to a “refeeding signal,” which has been described inpenguins (46), and/or to behavioral changes in food hunting that mammals displayduring this phase (47). Intestinal restoration may also be related to increased expres-sion of genes encoding orexigenic, hypothalamic peptides such as neuropeptide Y,agouti-related protein, and pro-opiomelanocortin (48). Rapid restoration of intesti-nal structures was observed during refeeding in mammals (49). This restorationtook place as quickly as 30 minutes after refeeding following phase II starvation(43). By contrast, starvation had no significant effect on the intestinal tract of thecommon carp. After 42 days of starvation, intestinal mucosal thickness of carpwas not affected, and cellular events (e.g., apoptosis and cell proliferation) of thegut remained active. The expression of many digestive genes—including thosefor chemotrypsin A and B, elastases, trypsins, carboxypeptidase A and B, propro-teinase E, and amylase 3—were suppressed greatly during starvation in carp, withmost of the downregulation occurring after 16 days of starvation.

The acquisition and processing of food are expensive processes; their cessationis manifested as a reduction in basal metabolic rate. The large reduction in gutmucosal surface area during starvation probably results from a large reduction inenergy expenditure in maintaining the gut. This reduction in gut energy expenditureconstitutes a part of the overall bodily reduction in energy expenditure duringstarvation. Several studies reporting on metabolic depression of fasting animalsdid not report body temperature, and some of the decline in metabolism may stemfrom hypothermia. Thus, part of the alleged reduction in standard metabolic rateduring food deprivation may be ascribed to factors that lead to a reduction incellular metabolism.

Body Temperature

In both birds and mammals, fasting and the associated depletion of energy reservesare important physiological cues to initiate torpor, which is a reduction in bodytemperature during inactive parts of the diurnal cycle (50). Thus, in some species,torpor occurs only when energy stores have reached a certain threshold and can beprevented by artificial administration of nutrients such as glucose (e.g., 36, 40, 51–53). The gradual depletion of energy stores may also explain why the hypothermicresponse is enhanced as fasting is prolonged (e.g., 54). Torpor reduces energy us-age by the direct effect of temperature on metabolism and because the metabolismof activity is negligible. Hypothermia is more pronounced in small as comparedto large mammals and birds (e.g., 55–57). Some hummingbirds, for example, maydecrease body temperature by as much as 30◦C. Small animals may benefit fromthis body-size effect because of their higher mass-specific metabolism and greaterease for heat transfer due to their large surface area relative to body mass. However,body mass alone does not explain the occurrence and patterns of torpor. Many smallbirds, such as passerines, rarely reduce body temperature by more than 3–5◦C,whereas some larger birds can undergo much larger changes (e.g., 57–59). Tor-por appears to be more pronounced in animals that inhabit areas in which large

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fluctuations in temperature and food availability are common, such as deserts.However, torpor also occurs in laboratory rats (e.g., 60) and may therefore be arather common and widespread response.

An entrance into torpor in response to food deprivation has been described invarious animals. Nocturnal reductions in peripheral temperatures, associated withlower heart rate and presumably reduced metabolism, occur in large mammalssuch as red deer and reindeer (e.g., 61, 62). Torpor also occurs in primates; forexample, torpor in response to food deprivation has recently been documented inthe gray mouse lemur, Microcebus murinu (63). Also, barnacle geese and PuertoRican todies undergoing long-term migration without feeding reduce body temper-ature by several degrees (64, 65). However, as Schleucher (57) points out, neitherfood supply nor energetic stress per se appear to be the ultimate factor determiningthe hypothermic response in these species, as the response is more pronounced infatter premigratory birds. Torpor, therefore, may be a strategy to reduce energyexpenditure during accumulation of fat stores. Thus, in addition to fasting and en-ergy status of the individual, diverse ecological, morphological, and physiologicalvariables, breeding, or migration periods, as well as physical parameters such asweather and annual cycles, are likely to influence the extent to which differentendotherms utilize torpor (e.g., 57).

Ectothermic animals rely on external heat sources and appropriate behaviorto regulate body temperature, and when provided with these opportunities, theymaintain remarkably constant and well-regulated body temperatures. The effectsof food deprivation have been studied in a few species freely selecting body temper-ature in laboratory settings. Several of these studies on fish and lizards have shownreductions in the preferred body temperature by a few degrees, which developsprogressively as food is withheld (e.g., 66, 67).

Physical Activity

Decreasing physical activity and allowing body temperature to decline are likely tocontribute more to energy sparing, and thereby to tolerance of starvation, than doreductions in basal metabolic rate, which are comparatively small. When food is notavailable, however, animals may search more actively for food, at the expense ofincreased energy usage, or decrease activity so as to reduce energy expenditure. Ananimal’s use of these alternatives depends on its foraging mode, the causes of fooddeprivation, and many other aspects of the animal’s natural history. In general, sit-and-wait predators are likely to reduce activity when food is not available, whereasactive hunters and grazers are more likely to increase activity as they search forfood. Furthermore, although many animals reduce physical activity during theinitial phases of fasting, many other animals exhibit a marked stimulation of activityduring the later and more critical phases of starvation.

In captive rats, food deprivation leads to reduced physical activity during theinitial phases of food deprivation (68), followed by a marked hyperactivity whenthe animals enter phase III of starvation (47; see also Reference 69). Similar events

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ensue in captive emperor penguins, in which the transition from phase II to III andthe associated depletion of fat stores coincide with increased activity and escapebehaviors. Teleonomically, these responses appear beneficial, as the transition tophase III of starvation signifies that existing resources are limited and that needfor food is acute.

Some [but not all (23, 66)] fasting fish and amphibians reduce activity. Mendez& Wieser (21) proposed that the behavioral response of fish to starvation consistsof three phases, which has some resemblance to the biochemical changes outlinedabove. The first phase is short lasting (approximately 24 h) and involves the in-creased activity of food searching. A transition phase, in which the fish graduallyreduce swimming activity and thereby lower energy expenditure, then follows. Thethird and final phase, adaptation, is characterized by low activity and metabolism,which persist until the fish are presented with the possibility of food. Van Dijket al. (66) did not observe the stress phase in fasting roach (Rutilus rutilus), andit is quite likely that the specific responses will vary among fish with differentbehaviors and with the experimental setting.

Reproduction

Reproduction is energy expensive and requires either large energy stores in themother or a ready source of food for both parents and offspring. Reproduction inmany animals coincides with a high probability of food. Starvation is an inhibitorof reproduction in vertebrates; for example, most anorexic human females do notmenstruate and cannot conceive (38). Female hamsters generally fail to ovulate andshow little interest in sex if deprived of food for one or two estrous cycles. Ovulatoryfailure in these animals is related to an absence of an ovulatory gonadotropinsurge and a set of immature follicles (70). Starvation for three days suppressessexual receptivity in female rats, and this is associated with a reduction in theestrogenic response in the ventromedial nuclei of the hyopothalamus, critical forsome reproductive behaviors (71). Sexually mature zebrafish spawn daily, but whenthey are starved, the number of eggs they produce per day drops rapidly (Figure 3)(26). The prompt decline in egg production is associated with decreased expressionof CYP19a, an enzyme that converts testosterone into estrogen in female zebrafish(Figure 4).

Not all animals exhibit inhibition of reproduction during starvation. Tessieret al. (72) suggested that reproduction during starvation may be advantageous forshort-lived species. Some rotifer species maintain or even increase egg productionduring starvation (73), whereas other rotifer species reduce reproduction and sur-vive starvation for longer than the reproducing rotifer species. Those rotifers thatincrease reproduction when energy supplies are limited invest resources in theiroffspring, which presumably have a better chance of surviving starvation. Thisis at the expense of the parent’s survival, possibly because of the accompanyingbenefits of predator avoidance, reduced energy requirements of the young, and/orincreased chance of moving to a resource-rich environment.

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Figure 3 Daily egg production of zebrafish when fed continuously for 10 days and after

11 days of food deprivation (fasting). A parallel experiment on continuously fed fish, which

served as a control group, is shown on the right side of the figure. Each group represents results

from 26 pairs of zebrafish, sex ratio 1:1, and presented as mean ± S.E. Food-deprived fish

produced significantly lower numbers of eggs produced than did fed fish (modified from

Reference 26).

Some vertebrates starve during reproduction; the Pacific salmon and eel areclassic examples. Yellow eels feed and grow in freshwater, but they stop feedingwhen they become silver and start their migration across the Atlantic to spawn inthe Sargasso Sea. Eels that have been starved in both seawater (74) and freshwater(75) for up to three to four years have survived. During this time, these eels lost

Figure 4 RT-PCR analysis of CYP19a mRNA expression in female gonad of control and

zebrafish starved for 11 days.

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between 70 and 80% of their body weight. Interestingly, starvation was associatedwith an increase in growth hormone (GH) brain-cell hypertrophy and plasma GHlevels (75). GH binds predominately to liver cell membrane receptors, but theincrease in plasma GH during starvation is not associated with an increase in livergrowth, as these liver GH receptors are downregulated.

Atlantic salmon and trout species spawn repeatedly, whereas Pacific salmon dieafter their first spawning. The lifestyles of Pacific salmon vary between species.Sockeye salmon, Oncorhynchus nerka, are born in freshwater and enter the oceanas one- or two-year olds, weighing between 4 and 15 g. They return to their natalstream to spawn after two or three years at sea, weighing between 1.6 and 3 kg (76).These animals do not feed once they have entered the river. The upstream migrationmay be more than 1000 km, depending on the river. Not only do these animalsswim such large distances but they also produce numerous eggs. The gonad of thefemale reaches 14% of the pre-spawning total body mass. The starving migratingPacific salmon use fat to fuel both their upstream migration and egg production;at death, both sexes will have expended more than 95% of their fat reserves (10).The fat reserves when the fish enters the river are, in general, proportional tothe distance to be traveled. Female pink salmon spend less energy on migrationthan do males but more on gonad production such that, in the end, total energyexpenditure is approximately the same for both sexes. When fat reserves start toexhaust, first protein (from white muscle, but not heart or red muscle) and thencarbohydrates are utilized (77). When the fish reaches the spawning ground, thecalorific content of the fish is reduced to less than half of that which existed whenthe fish entered the river (10). There is increased interrenal activity and cortisolproduction, presumably directing some of the metabolic changes. The fish spawnand are usually in a moribund condition associated with energy depletion. All ofthe fish die, but they are not all moribund, and the cause of death is not clear,although the depletion of energy reserves must be an important component. Othersalmonids, such as trout and Atlantic salmon, are repeat spawners.

Immediately after reproduction, survival of the parent rather than the offspringis usually favored; this is particularly true for vertebrates. In penguins that faston the ice during incubation of their eggs, the transition to phase III also leads toincreased activity, and parents will abandon their eggs to secure their own survivalat the expense of successful reproduction (46). There are, however, exceptions.Some species of octopus continually ventilate their developing embryos; feedingbehavior is inhibited during this time, and these octopi can starve to death in theprocess. Adult cuttlefish, Sepia officinalis, migrate toward coastal waters to spawnand then die a month later. They also stop feeding and age rapidly during thisperiod, with a marked deterioration in long-term memory. The cessation of feedingis associated with defects in visuomotor coordination as a result of degenerativechanges in the central nervous system (78). There may be selection for genesthat cause the rapid death of the postreproductive, or even just older and larger-sized, individuals within the population. This may be the case in spawning salmonand lampreys. Nothing is known of such death genes, but if they exist, they may

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be functionally similar to genes observed in Sepia (78), in which degenerativechanges in the central nervous system lead to a loss in prey capture ability and, asa consequence, death by starvation.

PHENOTYPIC PLASTICITY OF THE VISCERAL ORGANSIN RESPONSE TO DIGESTIVE STATE

The size and functional capacity of most visceral organs and muscle change inresponse to the physiological demands that are placed upon them (e.g., 79, 80). Thisphenotypic plasticity is pronounced for the gastrointestinal organs, which undergoa marked structural and functional reduction during fasting. The gastrointestinalorgans are very metabolically active and have been estimated to account for asmuch as 40% of basal metabolic rate (e.g., 81). Thus, a reduction in organ sizeduring fasting may confer a significant energetic savings, which may contribute toa marked reduction in the basal metabolic rate of fasting animals.

Within nonmammalian vertebrates, the effects of food deprivation on gastroin-testinal organs have predominantly been studied in snakes. This group of rep-tiles has attracted particular interest because they tolerate very prolonged fastingperiods—in some cases up to several years—and because they can ingest verylarge meals. Thus, under natural conditions, some snakes may eat only a few timesa year, but when they do eat, they can consume prey items of 50% of their ownbody mass or more (e.g., 82, 83). When snakes such as pythons or rattlesnakeseat these large meals after fasting for a few weeks or longer, the mass of the smallintestine increases drastically within the first 12–24 h after ingestion (84–86). Thegut wall of reptiles, like that of other vertebrates, consists of an outer muscularcoat and an inner mucosal layer with an epithelial lining toward the gut lumen(80, 87, 88). The mucosa in particular increases in mass upon feeding (Figure 5)(85, 89), and is attended by a many-fold increase in the transport capacities forvarious amino acids and glucose (85). This rise in nutrient transport capacity likelyreflects that the length of the intestinal microvilli increases almost fivefold within24 h (Figure 6) (90).

In ectothermic vertebrates, whether the nutrient transport proteins are beingsynthesized de novo as the enterocytes expand and microvilli lengthen, or whetherthe increased nutrient transport capacity merely reflects the increased surface areaand that more transport proteins are exposed to the lumen, is unknown. Whenexpressed relative to the mass of the intestine, nutrient transport capacity actuallyincreases in mammals during hibernation (91–93). Thus, although the mucosaatrophies, the intestinal transport proteins are well preserved, and the mRNA levelsof the transporter protein SGLT1 does not change during hibernation in groundsquirrels (94). This is also the case for the activity and mRNA levels of Na+,K+ ATPase (94). The membrane potential of the enterocytes actually increasesslightly during hibernation, which enhances the Na+ gradient that drives many ofthe intestinal nutrient transporters (92). It is not clear how this hyperpolarization

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Figure 5 Effects of feeding on the mass of the small intestine of the snake Python molurusbefore and after ingestion of a meal equalling 25% of the snake’s body mass. Intestinal mass

is shown for fasting snakes (time 0). Each bar represents the total mass of the intestine and is

divided into three parts representing the three parts of the intestine: proximal (black), middle

(gray), and distal (white). The data are modified from Reference 90.

of the enterocytes affects cellular metabolism, and it certainly would be of interestto perform similar studies in ectothermic vertebrates in which cellular functionscould be compared at similar temperatures in fasting and digesting animals.

In contrast to that of the mucosa, the thickness of the intestinal muscle layerappears unchanged (85, 89). Furthermore, digestive status does not affect the totalnumber of gut neurons in the intestinal muscle layer, spontaneous activity of themuscle layer in vitro, or the motility responses of isolated intestinal preparationswhen exposed to various excitatory neuropeptides (87). The mass and nutrienttransport capacity of the gastrointestinal system undergo progressive reductionsduring subsequent food deprivation. Although other species of nonmammalian ver-tebrates have received much less attention than have snakes, phenotypic plasticity,both in terms of mass of the organs and their functional correlates, is seeminglyuniversal, albeit less pronounced, in species with a more continuous feeding pat-tern, where prolonged periods of food deprivation are less common (e.g., 95).Thus, a progressive reduction in the intestinal epithelium during fasting, whichis rapidly reversed after feeding, occurs in all other major groups of ectothermicvertebrates (e.g., 95–98, 150, 151).

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Figure 6 Electron micrographs of proximal intestinal microvilli of Python molurus during

fasting (a) and at 0.25 (b), 0.5 (c), 1 (d ), 3 (e), 6 ( f ), and 14 (g) days after ingestion of a meal

equalling 25% of the snake’s body mass. Note the immediate lengthening of the microvilli

and the subsequent regression (bar = 1 μm). Modified from Reference 90.

Organ growth can occur by increased cell size (hypertrophy) or cell proliferation(hyperplasia). A two- or threefold increase in mucosal mass through hyperplasiawould require extremely high rates of cell division and mitotic activities and pre-sumably would be energetically expensive. Several recent studies on snakes andother ectothermic vertebrates have shown that the feeding-induced rise in intestinalmass is due predominantly to increased size of the individual enterocytes (84, 89,90, 99–101), suggesting that hypertrophy is the major mechanism. Thus, althoughcell proliferation may start early in the digestive phase, cell division reaches itsmaximal rate rather late in the digestive process. Therefore, the cells that have been“worn down” during digestion may be replaced. In this manner, the fully func-tional gut can be rapidly restored when food becomes available again (89). In allectothermic vertebrates, the epithelium—which in fasting animals is pseudostrat-ified, with folded cell membranes of neighboring cells—may be rapidly unfoldedafter feeding and converted to a single layer of cells with stretched membranesas the enterocytes expand (reviewed in Reference 80). Each enterocyte appears toswell owing to a very rapid incorporation of lipid droplets (89, 90, 100), and thereis also a small increase in fluid content as relative wet mass of the intestine in-creases (87). Although evidence is still inconclusive, the lipid droplets likely comefrom the ingested food; alternatively, some of the lipids may stem from fat bodiesin the body of the predator. Although incorporation of the lipid droplets certainlymust account for a major part of enterocytic expansion, Starck & Beese (89) alsohave suggested that increased lymphatic pressure contributes. The increased watercontent of the enterocytes, however, cannot be caused by lymph pressure per sebut would require movements of osmolytes such that osmotically obliged water isdragged along. Clearly, this aspect needs further experimental clarification.

The structure and function of the intestines of birds and mammals are alsoflexible. However, mammals and birds normally feed on a much more regularbasis than do ectothermic vertebrates, and the former generally have a constantrenewal of the gut epithelium. Structural and functional changes occur rapidly

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after food deprivation in small mammals, whose high metabolism places extrapremium on energy-saving mechanisms. For frequent feeders that are not adjustedto long periods of fasting, prolonged food deprivation or actual starvation maybe more destructive to the gut, as compared to animals that normally experiencelong periods of fasting. The reduction in intestinal mass is due to atrophy, and therestoration of the gut upon subsequent feeding is accomplished by hyperplasia,although hypertrophy also contributes (e.g., 49, 102–105). This is also the case inhibernating mammals, although lower body temperature and metabolism greatlyextend starvation tolerance (91–93, 106). The evolution of endothermy, whichoccurred independently in birds and mammals and has required much higher ratesof nutrient uptake across the gut because of the high metabolism requirements(107), seemingly has led to a structure for which gastrointestinal and digestiveplasticity is energetically more expensive.

The signals that elicit the growth of the gastrointestinal organs are not wellunderstood in nonmammalian vertebrates. In mammals, gastrointestinal growthcan be elicited through luminal, hormonal, neural, and secretory pathways (e.g.,108). Although these regulatory pathways appear phylogenetically old and con-served (e.g., 88), few studies have experimentally investigated the respective rolesof the individual mechanisms. Secor et al. (109) performed systematic infusionsof nutrients into the intestine of fasting animals. Infusion of amino acids or proteindirectly into the intestine increased intestinal mass and transport capacity, whereasinfusion of glucose, lipid, or bile had no effect (109). However, only infusion ofhomogenized rats caused a structural and functional response equivalent to thatelicited by a normal meal (109). Cephalic responses, investigated by allowing thesnake to constrict a prey item, followed by its removal, did not affect the intestine(109). Luminal signals predominantly from protein, therefore, appear sufficient forintestinal expansion and rise in transport capacity during digestion. However, themucosal mass and transport capacity of surgically isolated portions of the intestine(Thiry-Vella loops) increase in voluntarily eating snakes (101), so hormonal and/orneural pathways also seem to contribute to gut expansion. Circulating levels of anumber of regulatory peptides, some released from various gastrointestinal organs,increase dramatically during digestion (110); some of these peptides may serve astrophic factors.

THE METABOLIC RESPONSE TO DIGESTION:SPECIFIC DYNAMIC ACTION

Lavoisier first showed that metabolism increases in response to digestion, andthis metabolic response, documented in all animals investigated, now representsa general phenomenon. The postprandial rise in metabolism, normally referred toas the specific dynamic action of food (SDA), includes the energetic costs associ-ated with the ingestion, digestion, absorption, and assimilation of the food. Thus,the physiological mechanisms that underlie the SDA response may vary among

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different animals depending on feeding habits, food composition, temperature, andother factors. In the past ten years, SDA in carnivorous reptiles has received muchattention, owing both to its magnitude and its potential to elucidate the large struc-tural and functional changes in the gut. Also, in the animals that exhibit a largeSDA response, the costs of digestion may account for a large proportion of thetotal energy budget, and the metabolic response to feeding becomes ecologicallyrelevant (e.g., 111, 112).

The SDA response is normally characterized as the factorial rise in oxygenuptake and by its duration. Another useful manner of expressing the response isvia the SDA coefficient, which is the integrated metabolic response, calculated incaloric equivalents, relative to the energy consumed. Although some have criticizedthis parameter (113), it provides information on the energetic costs of digestionand allows therefore for a quantitative comparison between digestive responsesunder different environmental parameters or among different types or amountsof food ingested. There does not appear to be an anaerobic contribution to theSDA response, and the entire response therefore is reflected in the rate of oxygenuptake (114–117). The causes and determinants of the SDA response in vertebratesis beyond the scope of the present review, and this area has been summarizedelsewhere (95, 118–120). Also, the respiratory and cardiovascular correlates ofthe high metabolic rate during digestion have been reviewed recently (121, 122).

The effects of fasting duration on the SDA response can be a particularly in-sightful example of the phenotypic plasticity of the gastrointestinal organs. Thus,Overgaard et al. (123) studied the effects of the previous fasting duration on SDAresponse. Upon feeding, animals exhibit elevated intestinal mass and function formany days, suggesting that if the expansion of the gut is energetically expensive,then a second meal, ingested while intestinal function is still elevated, should elicita SDA response smaller than the first response. Overgaard et al. (123) showed thatthe SDA coefficient does not change with a fasting duration between 3–60 days(Figure 7) and that intestinal growth does not constitute a major contributor toSDA response. Fasting duration does not affect the SDA coefficient in skinks orrattlesnakes either (124, 125). A small contribution of intestinal growth was alsosuggested for turtles (126). Collectively, these findings are consistent with the pro-posal that intestinal expansion is structurally simple and energetically cheap (89).Secor (127) subsequently estimated that gastrointestinal upregulation contributesonly 5% of the SDA response in pythons. A recent study of frogs, nevertheless,shows that the rate of digestion of the first meal following three months of esti-vation is slower than for subsequent meals and that reconstitution of the gut mayaccount for this delay (98). The efficiencies of accumulation of various nutrients,however, were not affected (98).

A recent study on snakes has implied that the stomach and the secretion of acidand digestive enzymes are the main contributors to the SDA response (97). In thisstudy, the SDA response to a meal of 25% of the snake’s body weight was reducedby more than half when digesting a liquid meal. The study further showed thatthe response was a third of its normal value when the liquid meal was infused

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Figure 7 The SDA coefficient in the snake Python molurus following fasting periods of

various duration. The SDA coefficient does not change with the duration of the previous

fasting duration, indicating that structural and functional upregulation of the intestine occurs

at a low energetic cost (modified from Reference 123).

directly into the small intestine. It was estimated therefore that gastric functionscontribute 55% of the SDA response and that the stomach operates on a “pay-before-pumping” principle, in which the snakes must spend endogenous energysources to initiate acid production and other digestive processes before ingestednutrients can be absorbed and used for metabolic pathways. To investigate thispossibility further, we recently used another strategy: tying off of the pylorus,which is the anatomical connection between the stomach and the intestine, sothat the chyme was unable to enter the intestine from the stomach. In the thus-operated animals, the SDA response was completely abolished, whereas sham-operated animals had a normal response (Figure 8). Visual inspection of the preyitems clearly indicated that gastric functions had started digestion, and these datatherefore suggest that secretion of acid and digestive enzymes can proceed at arelatively low energetic cost. That gastric acid secretion has a low energetic costis further supported by the observation that treatment with omeprazole, a specificinhibitor of the H+, K+ ATPase that drives gastric acid secretion, does not affectthe SDA response in another snake species, Boa constrictor (128).

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Figure 8 The metabolic response to digestion in snakes (Python molurus) in which the

pylorus has been ligated to prevent chime from entering the intestine from the stomach (M.

Andersen, H. Cueto, & T. Wang, unpublished data).

In most animals studied, the SDA response elicited by a given food type in-creases proportionally with meal size, and both the maximal oxygen uptake duringdigestion and the duration of the response increase as meal size increases (e.g.,129–133). In most cases, the SDA coefficient is unaffected by meal size, indicat-ing that the costs of digestion are proportional to the amount of food ingested.Although these data are often interpreted to reflect that it is merely the caloriccontent of the food that determines the SDA, numerous studies have documentedthat protein-rich meals elicit larger metabolic changes than do diets composed offat or carbohydrates. Thus, force-feeding reptiles with fat or carbohydrates elicitsalmost no metabolic response (e.g., 134–138). This would indicate that stimulationof protein synthesis in response to high circulating levels of amino acids (139) isa major contributor to the SDA response (140). The role of protein metabolismin the SDA response (140, 141) is pivotal in fasting catfish, toads, alligators, andpythons in which either systemic infusion of amino acids, or infusion of proteinor amino acids directly into the stomach, leads to a rise in metabolism that iscomparable to that observed during normal feeding (138, 141–144). In catfish andpythons, inhibition of protein synthesis with cyclohexamide completely abolishesthe SDA response (138, 142, 143). If increased protein synthesis is indeed the

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major contributor to the SDA response, metabolism of all organs should increaseduring the postprandial period, a reasonable suggestion in light of the very highgrowth efficiency of snakes in which some 40–60% of ingested food is directedto growth (123, 145, 146). Obviously, the resulting rates of growth must requireprotein synthesis in all organs.

SUMMARY AND FUTURE DIRECTIONS

Digestive status affects virtually all physiological and behavioral responses, andselective pressure to enhance feeding strategies and digestive processes must besignificant. The ectothermic vertebrates, with their lower metabolic rates, can en-dure prolonged periods of fasting, and many of these species exhibit much morepronounced changes in gastrointestinal organs than are normal in healthy mammals(see also Reference 147). The extreme structural and functional changes in theirdynamic guts make ectothermic vertebrates useful models to explore largely unre-solved issues regarding the interaction and prioritization of physiological functionsamong organ systems. These issues are of basic physiological importance. Suchstudies may contribute to our understanding of the mechanisms that enable organsto adapt to physiological demands. They also may help us to understand the factorsthat in humans can promote intestinal repair following either intestinal resectionsor diseases such as colitis and Crohn’s disease in which there is inflammatorydestruction.

ACKNOWLEDGMENTS

The authors are supported by the Danish Research Council as well as the ResearchGrants Council of Hong Kong Special Administrative Region, People’s Republicof China (project number: CityU RGC1224/02M).

The Annual Review of Physiology is online athttp://physiol.annualreviews.org

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P1: JRX

January 18, 2006 10:52 Annual Reviews AR265-FM

Annual Review of PhysiologyVolume 68, 2006

CONTENTS

Frontispiece—Watt W. Webb xiv

PERSPECTIVES, David L. Garbers, Editor

Commentary on the Pleasures of Solving Impossible Problems

of Experimental Physiology, Watt W. Webb 1

CARDIOVASCULAR PHYSIOLOGY, Jeffrey Robbins, Section Editor

Cardiac Regeneration: Repopulating the Heart, Michael Rubartand Loren J. Field 29

Endothelial-Cardiomyocyte Interactions in Cardiac Development

and Repair, Patrick C.H. Hsieh, Michael E. Davis,Laura K. Lisowski, and Richard T. Lee 51

Protecting the Pump: Controlling Myocardial Inflammatory Responses,

Viviany R. Taqueti, Richard N. Mitchell, and Andrew H. Lichtman 67

Transcription Factors and Congenital Heart Defects, Krista L. Clark,Katherine E. Yutzey, and D. Woodrow Benson 97

CELL PHYSIOLOGY, David L. Garbers, Section Editor

From Mice to Men: Insights into the Insulin Resistance Syndromes,

Sudha B. Biddinger and C. Ronald Kahn 123

LXRs and FXR: The Yin and Yang of Cholesterol and Fat Metabolism,

Nada Y. Kalaany and David J. Mangelsdorf 159

ECOLOGICAL, EVOLUTIONARY, AND COMPARATIVE PHYSIOLOGY,Martin E. Feder, Section Editor

Design and Function of Superfast Muscles: New Insights into the

Physiology of Skeletal Muscle, Lawrence C. Rome 193

The Comparative Physiology of Food Deprivation: From Feast to Famine,

Tobias Wang, Carrie C.Y. Hung, and David J. Randall 223

Oxidative Stress in Marine Environments: Biochemistry and

Physiological Ecology, Michael P. Lesser 253

GASTROINTESTINAL PHYSIOLOGY, John Williams, Section Editor

Brainstem Circuits Regulating Gastric Function, R. Alberto Travagli,Gerlinda E. Hermann, Kirsteen N. Browning, and Richard C. Rogers 279

vii

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P1: JRX

January 18, 2006 10:52 Annual Reviews AR265-FM

viii CONTENTS

Interstitial Cells of Cajal as Pacemakers in the Gastrointestinal Tract,

Kenton M. Sanders, Sang Don Koh, and Sean M. Ward 307

Signaling for Contraction and Relaxation in Smooth Muscle of the Gut,

Karnam S. Murthy 345

NEUROPHYSIOLOGY, Richard Aldrich, Section Editor

CNG and HCN Channels: Two Peas, One Pod, Kimberley B. Cravenand William N. Zagotta 375

RENAL AND ELECTROLYTE PHYSIOLOGY, Gerhard H. Giebisch, Section Editor

Claudins and Epithelial Paracellular Transport, Christina M. Van Itallieand James M. Anderson 403

Role of FXYD Proteins in Ion Transport, Haim Gartyand Steven J.D. Karlish 431

Sgk Kinases and Their Role in Epithelial Transport, Johannes Loffing,Sandra Y. Flores, and Olivier Staub 461

The Association of NHERF Adaptor Proteins with G Protein–Coupled

Receptors and Receptor Tyrosine Kinases, Edward J. Weinman,Randy A. Hall, Peter A. Friedman, Lee-Yuan Liu-Chen,and Shirish Shenolikar 491

RESPIRATORY PHYSIOLOGY, Richard C. Boucher, Jr., Section Editor

Stress Transmission in the Lung: Pathways from Organ to Molecule,

Jeffrey J. Fredberg and Roger D. Kamm 507

Regulation of Normal and Cystic Fibrosis Airway Surface Liquid Volume

by Phasic Shear Stress, Robert Tarran, Brian Button,and Richard C. Boucher 543

Chronic Effects of Mechanical Force on Airways, Daniel J. Tschumperlinand Jeffrey M. Drazen 563

The Contribution of Biophysical Lung Injury to the Development

of Biotrauma, Claudia C. dos Santos and Arthur S. Slutsky 585

SPECIAL TOPIC, TRP CHANNELS, David E. Clapham, Special Topic Editor

An Introduction to TRP Channels, I. Scott Ramsey, Markus Delling,and David E. Clapham 619

Insights on TRP Channels from In Vivo Studies in Drosophila,

Baruch Minke and Moshe Parnas 649

Permeation and Selectivity of TRP Channels, Grzegorz Owsianik,Karel Talavera, Thomas Voets, and Bernd Nilius 685

TRP Channels in C. elegans, Amanda H. Kahn-Kirbyand Cornelia I. Bargmann 719

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