the physiological psychology of hunger: a … review 1976, vol. 83, no. 6, 409-431 the physiological...

Psychological Review1976, Vol. 83, No. 6, 409-431

The Physiological Psychology of Hunger:A Physiological Perspective

Mark I. FriedmanUniversity of Massachusetts

Edward M. StriekerUniversity of Pittsburgh

Hunger and satiety are usually discussed from the perspective of the centralnervous system. In this paper we instead find the foundation for an under-standing of hunger in the basic biochemical and physiological processes ofenergy metabolism. Such considerations suggest that the stimulus for hungershould be sought among changes that occur in the supply of metabolic fuelsrather than in the utilization of specific nutrients or in the levels of fuel re-serves. This line of reasoning diverts attention from the brain, which is notusually subject to dramatic fluctuations in its fuel supply, and focuses insteadon the intestines, adipose tissue, and liver, the three peripheral organs that aremost involved in the production or delivery of metabolic fuels. We propose thatthe stimulus for hunger derives from information provided to the brain by theliver in the course of normal hepatic function. More specifically, the stimulus forhunger may be associated with an alteration in oxidative metabolism withinthe liver, with food intake reversing that change. This view of hunger con-forms closely to the fundamental features of caloric homeostasis and makesunnecessary such traditional hypothetical constructs as hunger and satietycenters, glucostat, lipostat, and body weight set point.

Physiological psychologists have tradition-ally viewed hunger from the perspective ofthe central nervous system. The early findingsof Brobeck and his colleagues, that damageto specific hypothalamic areas provokes dra-matic alterations in food intake and bodyweight (Anand & Brobeck, 1951; Brobeck,Tepperman, & Long, 1943), first riveted at-tention to the brain. Their concept of a ven-tromedial hypothalamic satiety center, whichinhibits the activity of a primary feedingcenter in the lateral hypothalamus, providedthe framework for much of the theorizingabout hunger that has occurred in the lastquarter of this century. Multiple physiolog-ical factors are now believed to stimulatefeeding and thus to ensure the constancy ofbody weight, body temperature, and glucose

This work was supported by Postdoctoral Fellow-ship MH-54187 to Mark I. Friedman and GrantMH-25140 to Edward M. Strieker, both awardedby the National Institute of Mental Health.

We thank D. A. Booth, J, F. Marshall, N. Row-land, P. Rozin, R. J. Schimmel, and M. J. Zigmondfor their helpful comments on this manuscript.

Requests for reprints should be sent to Mark I.Friedman, Department of Psychology, University ofMassachusetts, Amherst, Massachusetts 01002.

utilization, each of which has been assumedto exert its influence on the medial or lateralhypothalamic areas or both (e.g., Anand,1961; Epstein & Teitelbaum, 1967; Stellar,19S4; Stevenson, 1969).

We believe that preoccupation with centralcontrols has been premature and has led tomisconceptions about the stimuli for hunger,misconceptions that become apparent whenexperimental findings are viewed from a morecontemporary physiological perspective. Ac-cordingly, rather than accepting the dualhypothalamic model as the starting point, wesought for the foundation of an understand-ing of hunger in the basic biochemical andphysiological processes of energy metabolismin higher mammals. We believe this approachleads to a view of hunger that conforms moreclosely to the fundamental features ofcaloric homeostasis that have been disclosedin recent years. Such a view also makes un-necessary the notion of multiple stimuli forhunger and the need for such traditionalhypothetical constructs as body weight setpoint, lipostat, and glucostat.

The present paper is divided into threesections. First, we briefly describe energymetabolism, with an emphasis on those prin-

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410 MARK I. FRIEDMAN AND EDWARD M. STRICKER

FIGURE 1. Disposal of metabolic fuels in the post-prandial state. (Because the liver plays a pivotalrole in determining the fate and availability of meta-bolic fuels, insert shows the pattern of substrate flowin that organ.)

ciples that seem most relevant to the presentdiscussion. Then, we relate that presentationto our view of hunger, and from that perspec-tive reexamine selected experimental findingsthat have provided the strongest argumentsfor traditional hypotheses. Finally, we re-evaluate the evidence that dual hypothalamiccenters control hunger and satiety and thenconsider the origin of the metabolic stimulusthat signals the animal to feed.

ENERGY METABOLISM

Metabolism in tissues requires continuoussupplies of utilizable fuels. These may be de-rived from carbohydrate, fat, or protein,which are ingested due to hunger or are mobi-lized from bodily energy reserves. The physi-ological and biochemical mechanisms thatmaintain and direct energy metabolism havebeen investigated extensively and are the sub-ject of many excellent reviews (Newsholme

& Start, 1973; see also Cahill, 1970; Felig,1973; Flatt & Blackburn, 1974; Levine &Haft, 1970; Owen & Reichard, 1971a;Tepperman & Tepperman, 1970). Thesemechanisms can be conveniently grouped intothose that provide for the initial disposal ofingested nutrients following a meal and thosethat permit a measured recruitment of storedfuels in the postabsorptive state. They arebriefly summarized as follows.

Disposal of Metabolic Fuels

Food consumption usually delivers meta-bolic fuels to the animal in amounts that farexceed its immediate requirements. Becauseof the large capacity of the gastrointestinaltract to accommodate food, and the relativelyslow absorption of nutrients therefrom, theperiod during which metabolic fuels are pro-vided by feeding extends well beyond themeal itself. During this time, ingested nutri-ents either are utilized directly or are storedfor later use (see Figure 1). Carbohydratesare broken down into utilizable sugars, suchas glucose, and are absorbed from the smallintestine into capillaries going directly to theliver via the hepatic portal system. Glucosefreely enters the liver and is there eitheroxidized to provide energy, stored in limitedquantities as glycogen, or converted to lipids(lipogenesis), which enter the circulation andare transported to adipose tissue for storage.The circulating glucose not removed by theliver is used for energy production in brain,muscle, and other tissues or else is stored inadipose tissue as triglycerides. Wasteful gly-cosuria is always avoided, regardless of howmuch carbohydrate is ingested, except indisease states (e.g., diabetes mellitus).

Protein from the food is degraded to aminoacids which, after absorption, are either re-synthesized into new protein, used for energyproduction (especially when they are in excessand little carbohydrate is available), or me-tabolized in the liver to carbohydrate or lipid.Dietary fat, mainly as triglyceride, passesfrom the intestine and is transported throughthe lymphatic system to the general circula-tion. The bulk of the triglyceride is hydro-lyzed in the capillary beds to liberate glyceroland free fatty acids. The glycerol is convertedin the liver to glucose, which is handled as

PHYSIOLOGICAL PSYCHOLOGY OF HUNGER 411

described above. The free fatty acids canenter tissues rapidly and be utilized, but usu-ally they are esterified to reform triglycerideswithin adipose tissue cells and then are storedthere. The storage capacity of adipose tissueis virtually limitless, and thus, lipids de-rived from carbohydrate, protein, or fat canalways be stored when caloric intake exceedsexpenditures.

Mobilization of Metabolic Fuels

The need for energy production by livingcells is continual. Thus, the animal with nofood to consume must consume itself. Com-pared to the postprandial flood of nutrientsfrom the gastrointestinal tract, the post-absorptive mobilization of metabolic fuelsfrom reserves (see Figure 2) is conservativelyattuned to tissue needs, thereby maximizingthe duration of adequate maintenance duringan indeterminate period of privation. Ofgreatest significance is the lipid depot inadipose tissue, which normally contains atleast 80-90% of the calories stored. Tri-glycerides in adipocytes are hydrolyzed toform glycerol and free fatty acids (lipolysis),which are then released into the blood. Bothare taken up by the liver, in which glycerol istransformed into glucose and the free fattyacids are either used for energy or convertedto ketone bodies (ketogenesis). Glucose isalso synthesized (gluconeogenesis) from aminoacids and other substrates (see below), andthe reduction of liver glycogen (glycogenoly-sis) adds to the glucose supply. The glucosethus produced is released into the blood, andthe major portion of it is used by the brain;the ketone bodies, in contrast, are used asmetabolic fuels by brain as well as othertissues. Free fatty acids not taken up by theliver provide a major fuel for muscle butcannot be used by the brain.

Aside from this ebb and flow of nutrients,there are four additional features of metabo-lism that have important implications for ourview of hunger.

1. Both endocrine and neural events helpto satisfy the organism's needs for metabolicfuels. For example, two antagonistic pancre-atic hormones, insulin and glucagon, providea coordinated control over enzymes in the

FIGURE 2. Mobilization and disposal of metabolicfuels in the postabsorptive state. (Because the liverplays a pivotal role in determining the fate andavailability of metabolic fuels, insert shows thepattern of substrate flow in that organ.)

liver and adipose tissue that direct the depo-sition and mobilization of the different meta-bolic fuels (e.g., Randle et al., 1966; Unger,1974). Thus, the postprandial delivery of glu-cose into the hepatic portal system, togetherwith other meal-related events, stimulates thesecretion of insulin, which promotes the for-mation of lipids and glycogen (while inhibit-ing their mobilization) as well as the uptakeof glucose into muscle and its utilizationthere. In the postabsorptive period, on theother hand, insulin secretion declines andglucagon secretion increases; these changespromote the mobilization of liver glycogen,and fats from storage and the production ofnew glucose from glucogenic precursors(Cahill et al., 1966; Marliss, Aoki, Unger,Soeldner, & Cahill, 1970). Some of thesemetabolic effects are additionally stimulatedby growth hormone and by adrenal gluco-corticoids and catecholamines, secretions ofwhich increase during fasting (e.g., Exton,1972; Jeanrenaud, 1968). Complementing


them still further (and, in part, modulatingall of the endocrine secretions) are the actionsof the autonomic nervous system. Thus, exci-tation of the sympathetic nerves stimulatesglycogenolysis in the liver (Shimazu & Fukuda,1965) and lipolysis in adipose tissues (Havel& Goldfien, 1959), whereas converse effectsin the liver result from activation of theparasympathetic fibers (Shimazu, 1967).

2. The supply of fuels to the brain is elabo-rately defended even during prolonged fast-ing. Insulin is not required for transportingglucose into nerve cells, and thus glucose uti-lization by the brain continues early in thepostabsorptive state despite reduced insulinsecretion. In contrast, utilization of glucoseby muscle is diminished when insulin levelsare reduced, and glucose is thereby sparedfor use by the brain (Cahill et al., 1966).Further conservation of glucose results fromthe utilization of free fatty acids and ketonebodies by muscle, since intermediates in theirmetabolism retard the degradation of glucoseinto pyruvate (glycolysis) and its subsequentoxidation in the tricarboxylic acid cycle(Randle, Garland, Hales, & Newsholme,1963). Moreover, the pyruvate and lactateformed from glucose in nonneural tissues arereturned to the liver for resynthesis intoglucose to be used by the brain (Owen, Felig,Morgan, Wahren, & Cahill, 1969). Becauseliver glycogen stores are relatively small,these processes are important for conservingglucose and thereby minimizing the need forgluconeogenesis from amino acid substrates(principally alanine) produced by musclecatabolism (Felig, Owen, Wahren, & Cahill,1969). Nevertheless, as fasting continues, theproduction of glucose decreases, thus con-serving body protein, and ketone bodies pro-vide increasingly more of the substrate thatis used for metabolic fuel by the brain (Owenet al., 1969; Sherwin, Hendler, & Felig,1975). For example, it is estimated that morethan 60% of brain oxygen consumption inobese human subjects during prolonged star-vation is provided by the oxidation of ketonebodies (Owen et al., 1967). At this time, theutilization of ketone bodies by muscle dimin-ishes, and free fatty acids are preferentiallyoxidized, thus sparing the ketone bodies formetabolism by the central nervous system

(Owen & Reichard, 1971b). Such alterationsin the mixture of glucose and ketone bodiesthat is delivered to the brain permit it tomaintain its function without disruption(see also Krebs, Williamson, Bates, Page, &Hawkins, 1971; Sokoloff, 1973).

3. Lipid deposition and mobilization aredirectly related to the content of triglyceridesalready present in adipose tissue, in additionto being influenced by hormones (especiallyinsulin) and autonomic tone. Thus, decreasesin tissue lipid levels shift equilibrium condi-tions toward fat storage, whereas increases inlipid levels tend to facilitate fat loss. Thisfeature of adipose tissue metabolism underliesobservations that postprandial glucose uptakeand lipogenesis are greater in a previouslyfasted animal, whose adipocytes have beenpartially emptied, than in an animal eatingad libitum (Connor & Newberne, 1974;Tepperman & Tepperman, 1958), whereas thebasal rate of lipolysis is greater in obesesubjects than in lean individuals (Goldrick &McLoughlin, 1970; Hartman, Cohen, Richane,& Hsu, 1971). The intrinsic tendency towardmaintenance of lipid mass in adipose tissuemight also provide the basis for apparentalterations in the sensitivity of adipose tissueto insulin as a function of body weight (DiGirolamo & Rudman, 1968; Salans, Knittle,& Hirsch, 1968), as well as for the long-termstability of body weight at fairly steady levelspresumably set by genetic and early post-natal factors (Johnson, Stern, Greenwood,Zucker, & Hirsch, 1973; Knittle & Hirsch,1968), which is commonly observed in adultanimals.

4. The liver is not entirely dependent onactivity in the tricarboxylic acid cycle forenergy production. In the fed state, glucoseis usually the primary substrate in nonrumi-nants, and its oxidation to COa is the majorsource of energy in the liver, as in all tissues.In contrast, whereas peripheral tissues mainlyoxidize free fatty acids and ketone bodiesrather than glucose during fasting, the liveruniquely lacks the enzyme needed to convertthe ketone bodies synthesized there into asubstrate that can be oxidized in the tri-carboxylic acid cycle (Krebs et al., 1971).Instead, the partial oxidation of free fattyacids that occurs in ketogenesis may provide


a considerable portion of the energy that isproduced (Krebs & Hems, 1970; Mayes &Felts, 1967; Wieland, 1968).

To summarize, energy metabolism is main-tained by alternating tides of nutrients thatsweep in from the intestines or adipose tissueat regular intervals depending on when foodconsumption occurs. Adipose tissue partici-pates actively in metabolism by removingthe excess nutrients that are usually obtainedduring each meal and by releasing them in thesubsequent postabsorptive period. This tissuethus provides a massive energy buffer thatprevents dramatic shifts in nutrient supplydespite the episodic nature and inconstantmagnitude of food ingestion. The liver com-plements the function of adipose tissue andensures that nutrient supplies are sufficientand appropriate to the specific needs of indi-vidual tissues. In satisfying those needs,metabolic fuels are used interchangeably inperipheral cells, while the brain's special re-quirements for glucose and ketone bodies areaccommodated by the economic utilization ofthese fuels by nonneural tissue. This harmonyof tissue metabolisms is orchestrated by neu-ral and endocrine actions, which influence thecourse of bidirectional biochemical reactionsboth by establishing substrate availabilityand by modifying enzyme activities. Theseintegrated physiological events, unaccountablyneglected in most essays on hunger (see dis-cussion of a "bodiless psychology" by LeMagnen, 1971), provide the background forour present formulation.

HUNGER

Traditional interpretations given for theappearance of hunger are that food intakeserves (a) to replete diminished fat reserves(Kennedy, 19S3) and (b) to increase theutilization of glucose (Mayer, 1955). Webelieve that hunger instead occurs wheneverthe immediate availability of utilizable meta-bolic fuels is reduced below some critical level(e.g., as might occur early in the post-absorptive state). In essence, our argumentsrest on two basic observations regardingenergy metabolism. The first is the fact thatthe supply of metabolic fuels to all tissuesalways remains adequate for them to function

during physiological conditions and evenduring prolonged food deprivation (until, ofcourse, the starving animal is in extremis).The second is the fact that, with but a fewexceptions, each of the various metabolicfuels is equally capable of providing energyin all tissues. From the perspective of thesephenomena, it seems reasonable to focus oncaloric homeostasis, rather than the mainte-nance of energy stores, as the goal of feedingbehavior and the complementary biochemicaland physiological mechanisms that serve tomaintain the fuel supply. Moreover, it doesnot seem likely that quantitative changes inthe utilization of specific nutrients would pro-vide a stimulus for hunger, because com-pensatory changes in the utilization of othernutrients would limit their functional signifi-cance. Instead, we propose that the stimulusfor hunger should be sought among changesthat occur in the supply of metabolic fuels.This line of reasoning diverts attention fromthe brain, which is not usually subject todramatic fluctuations in its fuel supply, andfocuses instead on the intestines, adiposetissue, and liver, the three peripheral organsthat are most involved in the production ordelivery of metabolic fuels.

In this section we shall reevaluate familiarresearch from a perspective that focuses onthe availability of utilizable fuels duringvarious experimental conditions and empha-sizes the changes in fuel supply that canresult from variations in diet, in tissue de-mands, and in storage or mobilization ofnutrients. We have organized our discussionaround experiments related to the lipostaticand glucostatic hypothesis, since these haveprovided the focus for most of the research onhunger during the past 25 years.1

1 A third familiar proposal is the "therraostatichypothesis" of Brobeck (1948) which, stated simply,holds that "animals eat to keep warm." At the timeit was formulated, this hypothesis rested largely onthe incontrovertible facts that (a) food intake isadjusted in accordance with changes of energy bal-ance (i.e., it typically increases in cold environmentsand decreases in warm environments), (b) mealsize could be influenced by the heat liberated duringthe assimilation of the ingested nutrients, and (c)the hypothalamus was involved in the controls ofboth food intake and body temperature. Mechanisms


Lipostatic Hypothesis

As animals mature, their progressive in-crease in body weight reflects growth in avariety of tissues, including bone, muscle,and organs. In the adult animal, however,such structures stop growing rapidly, andchanges in body weight result mostly fromchanges in the mass of adipose tissue due toenergy imbalances. Thus, increases in bodyweight that occur when caloric intake exceedsexpenditures can be attributed primarily tostorage of the extra calories as fat (obesity),whereas decreases in body weight when ex-penditures exceed intake reflect the mobiliza-tion and utilization of body fat. As might beexpected, little change in body weight occurs,even when food intake is unusually high, whencaloric expenditures are also elevated, as inexercise, lactation, or the need for thermo-genesis (e.g., Brobeck, 1948; Kennedy, 1953,1961; Mayer, 19SS).

An increased utilization of calories result-ing in the production of heat following over-feeding, and a decreased utilization duringfasting, serve to minimize the consequencesof fluctuating volumes of food intake (e.g.,Adolph, 1947; Lyon, Dowling, & Fenton,19S3; Sims,Horton, & Salans, 1971). Becausethese changes may not be entirely adequateto this task (viz., metabolism does not stopduring food deprivation), changes in foodintake usually provide a major contributionto the maintenance of energy balance. Forexample, when rats are made obese by forcedhyperalimentation or by excessive voluntaryfeeding induced either by injections of insulinor by electrical brain stimulation, they reducetheir consumption of food when the respec-tive treatment is terminated and remain

for thermorcgulation and for the regulation ofcaloric homeostasis are more easily distinguishednow, as are neural controls within the hypothalamus.In addition, subsequent investigations have shownthat food consumption is not correlated with fluctua-tions of temperature in the brain (Rampone &Shirasu, 1964). Furthermore, in a particularly illumi-nating study, Rozin and Mayer (1961) found thatfood intake by fish was depressed reliably by adecrease in ambient temperature. These results wouldbe expected if feeding was responsive to the need formetabolic fuels rather than to changes in bodytemperature per se.

hypophagic until their body weights returnto normal (Cohn & Joseph, 1962; Hoebel &Teitelbaum, 1966; Steffens, 197S). Similarly,rats that have been starved increase theirfood intakes and remain hyperphagic untilbody weight losses have been restored(Kennedy, 1950). According to the lipostatichypothesis, the increased body-fat reservesresulting from the former treatments providethe brain with a blood-borne signal for satietythat results in decreased feeding, whereas thedepleted fat reserves resulting from the lattertreatment lead to a reduction of that stimulusand, in consequence, increased feeding. Inboth cases, it is believed that food intake isadjusted appropriately so as to regulate body-fat reserves around some predetermined "setpoint" (Kennedy, 1953; Mayer, 1955).

As mentioned previously, we believe thatmaintenance of body-fat stores is not the goalof food intake but may instead reflect anintrinsic tendency toward stability of lipidlevels in adipose tissue, and that observedvariations in food intake result from changesin the supply of metabolic fuels. Thus, theanimal made obese may decrease its feedingnot because of some signal for satiety butbecause of the absence of a stimulus forhunger, due to the considerable nourishmentthat is provided by the presumably heightenedavailability of free fatty acids (Bjorntorp,Bergman, & Varnauskas, 1969; Issekutz,Bortz, Miller, & Paul, 1967; see also LeMagnen, Devos, Gaudilliere, Louis-Sylvestre,& Tallon, 1973). Similarly, the previouslyfasted animal may increase its feeding notbecause it receives less of a satiety signal butbecause enhanced lipogenesis after a mealmore rapidly reduces the normal postprandialavailability of nutrients in the circulation (cf.Brobeck, 1975). According to this conceptual-ization, we would expect inhibition of lipoly-sis to prevent the decline in food intake thatoccurs when any of the above treatmentsproducing obesity are terminated, whereasinhibition of lipogenesis should reduce foodintake in previously fasted animals. Evidenceconsistent with both hypotheses has beenreported recently (Le Magnen & Devos,1970; Sullivan & Triscari, 1976).

These same considerations are relevant toan analysis of the periodic meals taken by


rats feeding ad libitum. The patterning ofmeals has been studied extensively by LeMagnen and his colleagues, who discoveredthat meal size is not dependent on the lengthof time since the preceding meal but that itdoes predict the interval until the onset ofthe next meal (Le Magnen & Tallon, 1966).These important findings suggest that feedingis not initiated in order to replace metabolicexpenditures and therefore that meal size maybe strongly influenced by nonmetabolic fac-tors. Ingestion of food thus provides an in-constant quantuum of calories, and hungerseems to recur only after those calories havebeen expended. For example, meal fre-quency is not nearly so great by day, whenfree fatty acids are available due to lipolysis,as at night, when fat is stored (Le Magnenet al., 1973).

Perhaps the strongest arguments in supportof the lipostatic hypothesis have been basedon the hyperphagia and obesity that resultfollowing ventromedial hypothalamic (VMH)lesions. Animals with such lesions usually eatvoraciously for weeks but eventually reducefood intake and stabilize body weight at anew, elevated level (Brobeck, 1946; Hether-ington & Ranson, 1940; Kennedy, 1950).Their obesity seems to be as well defendedas normal body weight is in neurologicallyintact animals, since even after being de-prived of food and thereby forced to loseweight, these brain-damaged rats quickly re-attain their previous level of obesity whengiven ad libitum access to food (Brobeck etal., 1943). Furthermore, VMH lesions do notinduce hyperphagia in rats that have previ-ously been made obese by chronic insulintreatments, but they do prevent the loss ofbody weight that otherwise would occur whenthe injections of insulin are ended (Hoebel& Teitelbaum, 1966).

In interpretations of these findings, thecontrols of feeding have been linked to theregulation of body fat in two ways. First, ithas been proposed that VMH lesions releasea primary "hunger center" from normal in-hibitory influences (Brobeck, 1955; Hervey,1959; Teitelbaum, 1961). According to thishypothesis, VMH lesions induce hyperphagiabecause satiety signals arising from body fatare insufficient to activate the residual VMH

neurons, and thereby to suppress feeding,until the animal becomes obese. Alternatively,it has been proposed that the function of theventromedial hypothalamus is to stabilize fatstores and that VMH lesions raise the "setpoint" at which body fat is regulated (Keesey& Pbwley, 1975; Kennedy, 1953). Accordingto this hypothesis, the hyperphagia seenafter VMH lesions is an appropriate, well-controlled response designed to achieve ahigher level of regulated body fat.

We believe that in neither of these inter-pretations is the VMH syndrome viewed fromthe correct perspective. Rather than adiposetissue passively accommodating the extra foodthat is consumed due to a primary disturb-ance in the hypothalamic controls of feeding,considerable evidence indicates that VMHlesions produce a primary disruption in fatmetabolism in favor of lipogenesis, with sec-ondary consequences for feeding. For example,in vivo and in vitro studies have shown thatrats with VMH lesions incorporate more glu-cose as fat, burn less fatty acids, and mobilizeless fat from adipose tissue than neurologicallyintact control rats (e.g., Frohman, Goldman,& Bernardis, 1972; Goldman, Schnatz, Ber-nardis, & Frohman, 1970, 1972a; Haessler& Crawford, 1967). This increased accumula-tion of fat has been demonstrated to occur asearly as 12 to 48 hours after VMH lesions,2

even when food is withheld or restricted, withthe degree of lipogenesis correlating highlywith the hyperphagia observed when the ani-mals are subsequently allowed to feed adlibitum (Hustvedt & Lj%f, 1973; L0vp? &Hustvedt, 1973; see also Hustvedt & Ljzfvjrf,1972). Thus, an animal with VMH lesionsmay not increase its food intake in order togain weight but because it is gaining weight.That is, animals may become hyperphagicafter VMH lesions because more of the in-gested food is removed from the circulationto be deposited as fat than previously (see

2 Presumably, alterations in metabolism begin im-mediately after VMH lesions, thereby contributingto the ravenous feeding that is often reported as theanesthesia dissipates (see also Rabin, 1968; Reynolds,1963) as well as accounting for the augmented intakesthat occur following local anesthetization of theventromedial hypothalamus (Epstein, 1960).


Han, 1967; Han & Frohman, 1970), andbecause these expanding fat stores are alsoless accessible.

Since lipogenesis is well-developed at nightin the intact rat, the primary metabolic effectof the VMH lesions is to enhance fat deposi-tion by day. Instead, these lesions eliminatedaytime lipolysis in rats despite excessiveeating during the previous dark period, andglucose clearance rises to high rates through-out the 24-hour period (Le Magnen et al.,1973). The diminished availability of freefatty acids by day is presumably responsiblefor the increased food intake that occursthen, and that increase amounts for most ofthe hyperphagia that is observed in rats afterVMH lesions (Balagura & Devenport, 1970;Brooks, Lockwood, & Wiggins, 1946; LeMagnen et al., 1973). Thus, we would expecttreatments that either interfere with fatstorage or promote lipolysis to limit hyper-phagia following VMH lesions (cf. Kennedy,1953).

The physiological changes that followVMH lesions result, in part, from the well-documented increases in circulating insulinlevels; in addition, the normal modulatoryaction of growth hormone on hyperinsulinismis prevented because secretion of that hor-mone is impaired (e.g., Frohman & Bernardis,1968; Steffens, 1970). However, since in-creased lipogenesis occurs despite replace-ment of growth hormone or elimination ofhyperinsulinemia (Goldman et al., 1970,1972b; see also Friedman, 1972; Vilberg andBeatty, 1975), it seems that alterations inthe neural controls of glucose and fat me-tabolisms must parallel the endocrine effects.The net result is an increased deposition offuels that is so pronounced that gluconeo-genesis, normally seen only during fasting, isfound after brain damage despite hyperphagia(Holm, Hustvedt, & L^v0, 1973; see alsoGoldman & Bernardis, 1975). Presumably,these metabolic dysfunctions continue until anew equilibrium between lipogenesis and lipol-ysis is attained that permits some mobiliza-tion of the fat reserves and consequent stabi-lization of body weight (Martin & Lamprey,1974).

Genetic defects in adipose-tissue metabo-lism of neurologically intact animals lead to

alterations in food intake and body weightthat are comparable to those observed afterVMH lesions (although the two conditionsdiffer in some respects; see Haessler & Craw-ford, 1965; Mayer, 1957; Opsahl & Powley,1974). For example, abnormal lipogenesisoccurs in at least two strains of rodents, theobob mouse and the jaja rat, even when foodintake is restricted (Alonso & Maren, 1955;Bates, Mayer, & Nauss, 1955; York & Bray,1973; Zucker, 1975). This primary metabolicdysfunction enhances the postabsorptive re-moval of utilizable fuels from the circulationand presumably is responsible for the increasesin food intake and body fat that develop. Theseasonal obesity of animals prior to migra-tion or hibernation (Farner, Oksche, Kame-moto, King, & Cheyney, 1961; Klain &Rogers, 1970; see also Mrosovsky, 1974),and the daily accumulation of fat in smallbirds that precedes nocturnal inactivity(Kendeigh, Kontogiannis, Mazac, & Roth,1969; Wolf & Hainsworth, in press), maypromote hyperphagia for similar reasons.

In addition to the changes in fat metabo-lism, a more rapid rate of gastrointestinalclearance may reduce the duration of post-prandial satiation in VMH-lesioned rats. Inthis respect, as in the others, rats with VMHlesions would then resemble unlesioned ani-mals given ad libitum access to food after animposed fast (Booth, Toates, & Platt, 1976).Nevertheless, it is well known that rats withVMH lesions do not always behave like hun-gry rats. For example, although rats usuallyare hyperphagic soon after VMH lesions, theymay not work hard for food reinforcements(McGinty, Epstein, & Teitelbaum, 1965;Miller, Bailey, & Stevenson, 1950; Singh,1973; Teitelbaum, 1957), they may becomehypophagic or refuse a less palatable diet thatis accepted readily by intact rats (Kennedy,1950; Singh, 1974; Teitelbaum, 1955), andthey may not eat much following vagotomy(Powley & Opsahl, 1974). We believe thatchanges in sensory reactivity and emotional-ity caused by the brain damage depressed thefeeding behavior and food-directed activitiesin each of the experiments cited above andthereby obscured the increased incidence ofhunger that resulted from concurrent meta-bolic dysfunctions. Indeed, there is consider-


able evidence that after VMH lesions, ratsbecome hyper-reactive and generally unwill-ing to tolerate aversive experiences (e.g.,Grossman, 1966; Lewinska & Romaniuk,1966; Marshall, 1975).

In summary, excessive deposition and se-questration of metabolic fuels appears tounderlie the observed hyperphagia in ratsfollowing a fast or lesions of the ventro-medial hypothalamus. The fact that hungeroccurs in rats with VMH lesions despite thepresence of an internal excess of metabolicfuels suggests that the size of the fat depotsbecomes important to feeding only if the ani-mal has ready access to them. These andother considerations dispute the traditionallipostatic hypothesis by suggesting that body-fat stores influence feeding only indirectly,through an alteration in the immediate supplyof utilizable metabolic fuels that results fromchanges in lipogenesis and lipolysis.

Glucostaiic Hypothesis

When peripheral models of hunger empha-sizing gastric fill were abandoned early inthis century, attention was directed insteadto chemical changes in the blood that mightstimulate feeding behavior. One enduringtheory focused on glucose as the major meta-bolic fuel and initially held that small de-creases in blood sugar increased food intakeand that satiety resulted when blood sugarlevels were restored to normal (Carlson,1916). The simple, negative-feedback controlof hunger inherent in this "glucostatic" hy-pothesis was strongly supported by experi-mental observations that insulin treatmentsproducing hypoglycemia promoted feeding inrats (MacKay, Callaway, & Barnes, 1940)and induced hunger sensations in human sub-jects (Janowitz & Ivy, 1949). Indeed, theingestion of food in response to hypoglycemiawas perceived as another striking example ofthe way in which appetites were appropriatelydirected to relieve specific nutritional defi-ciencies (Richter, 1942a, 1942b).

Because hyperphagia is associated withhyperglycemia during diabetes mellitus,Mayer (1952) later proposed that hunger wasdue to a reduction in the utilization of glucoserather than to a reduction in its concentrationin the blood. He further suggested that the

central receptors monitoring fluctuations inglucose utilization required insulin for glucosetransport (Mayer, 1955; see also Panksepp,1974), like peripheral tissue but unlike therest of the brain. Thus modified, the need forglucostasis has been widely accepted as animportant factor in the control of food intake.This need is believed to arise from the pre-sumed dependence of the brain on glucose forits function and is reflected in intermittentfeeding episodes both because glucose storesare not appreciable and because they aredisproportionately depleted between meals.

Mayer believed that the glucoreceptors werelocated in the ventromedial hypothalamus,since destruction of this area and hyperphagiaresulted in mice that were administeredgoldthioglucose but not other goldthio- com-pounds (Mayer & Marshall, 1956). Morepersuasive evidence in support of this hypothe-sis was provided by Debons and his col-leagues, who showed that goldthioglucose didnot produce brain damage in diabetic miceor in mice pretreated with anti-insulin serumbut that brain damage did occur in theseanimals when insulin was administered di-rectly into the hypothalamus (Debons, Krim-sky, & From, 1970; Debons, Krimsky, Li-kuski, From, & Cloutier, 1968). However,other experiments have revealed that (a) thebrain damage caused by goldthioglucose re-sults from ischemia following the local de-struction of cerebral capillaries (Arees, Velt-man, & Mayer, 1969), (b) similar hypo-thalamic damage, hyperphagia, and obesitycan be produced by vascular poisons not con-taining glucose (Caffyn, 1972; Rutman,Lewis, & Bloomer, 1966), and (c) insulin-induced hypoglycemia promotes feeding evenin animals with lesions of the ventromedialhypothalamus (Epstein & Teitelbaum, 1967).These observations raise serious doubts aboutthe role of cerebral glucoreceptors in the con-trol of food intake (see also Epstein, Nico-laidis, & Miselis, 1975) and reopen the ques-tion of why animals with diabetes mellitus orinsulin-induced hypoglycemia show increasedfeeding,

In many respects, diabetes mellitus resem-bles starvation. That is, the familiar increasein circulating glucose levels results morefrom a marked increase in gluconeogenesis


than from decreased glycolysis, and in-creased lipolysis and ketogenesis are evidentas well (Havel, 1972). While the abundanceof glucose provides the brain with more thanenough fuel, the periphery must depend onfatty acids and ketone bodies for metabo-lism, since neither of these substrates requireinsulin for transport into cells. However,lipid reserves are rapidly diminished in theabsence of insulin (Winegrad, 1965), andconsequently, ingested fats become an increas-ingly important source of fuel to the diabeticanimal. From this perspective, the fat contentof the usual laboratory diet can be viewed as"diluted" with carbohydrate, material of lit-tle metabolic significance during diabetes. Thehyperphagia of diabetic animals thus resem-bles the increased feeding that occurs in intactrats when food is diluted with nonnutritivebulk (Adolph, 1947) and may result becausethe decrease in utilizable metabolic fuels inthe diet reduces the diet's capacity to satiatethe animal (cf. Booth, 1972b, 1972e; deCastro & Balagura, 197S). Consistent withthis interpretation is the finding that diabeticanimals maintained on a high-fat diet do notdisplay hyperphagia despite continued im-pairments in glucose utilization (Friedman,197S; Janes & Prosser, 1947; Richter &Schmidt, 1941).

The hyperphagia induced by insulin maysimilarly be traced to a decrease in all utiliz-able fuels, but here both peripheral tissue andbrain tissue suffer. It should be noted that inaddition to its well known effect on bloodglucose, insulin also tends to suppress fattyacid catabolism, thereby minimizing keto-genesis and the possible substitution of ketonebodies for glucose as a metabolic fuel. Be-cause insulin also retards glycogenolysis andgluconeogenesis, the hormone is particularlyeffective in lowering the circulating levels ofmetabolic fuels. Thus denied ready access toendogenous stores, the insulin-treated animal(not unlike the rat with VMH lesions) canonly support metabolism by feeding andthereby increasing the delivery of fuels fromthe intestines.

The effects of insulin on cerebral glycolysisare usually emphasized (Smith & Epstein,1969; Steffens, 1969a), because hunger doesnot appear unless blood sugar is depressed

well below the level (70 mg/100 ml) at whichglucose transport mechanisms in the brain aresaturated (Crone, 1965; Daniel, Love, &Pratt, 1975). However, together with N.Rowland and C. Sailer, we have recently ob-served that intravenous administration of ke-tone bodies to insulin-treated rats abolishesthe adrenal sympathetic response otherwiseprominent during severe hypoglycemia (seealso Drenick, Alvarez, Tamasi, & Brickman,1972; Flatt, Blackburn, Randers, & Stan-bury, 1974) but does not depress feeding.Although energy metabolism in the brain isevidently restored by this infusion, the feed-ing behavior may have persisted due to de-creased metabolism in the liver, the one organthat cannot utilize ketone bodies (see below).Consistent with this hypothesis are our addi-tional findings that circulating catecholaminesremain elevated but increased feeding be-havior is prevented in insulin-treated hypo-glycemic rats following intravenous infusionsof fructose, a hexose that does not cross theblood-brain barrier but is readily utilized bythe liver (Friedman, Rowland, Sailer, &Strieker, Note 1; see also Hetenyi, 1972;Haddock, Hawkins, & Holmes, 1939). Thus,the hypothesis that insulin-induced feeding isstimulated by cerebral cytoglucopenia appearsto mistakenly identify both the critical stim-ulus and its source.

Administration of 2-deoxy-D-glucose (2-DG) is frequently used as an alternativemeans of producing cytoglucopenia and hunger.This sugar inhibits glycolysis by competingwith glucose as a substrate both for transportinto cells and for subsequent phosphorylationbut is not itself further metabolized (Hor-ton, Meldrum, & Bachelard, 1973; Wick,Drury, Nakada, & Wolfe, 1957). In addition,2-DG inhibits the secretion of insulin (Froh-man, Muller, & Cocchi, 1973; Smith, Gibbs,Strohmayer, Root, & Stokes, 1973), whichfurther retards peripheral utilization of glu-cose. As a result of these inhibitory actions,glucose utilization is decreased both in periph-eral and brain tissue (Meldrum & Horton,1973; Wick, Drury, & Morita, 1955), asoccurs in insulin-treated rats; furthermore, asin diabetics, hyperglycemia and hunger co-exist (Smith & Epstein, 1969). However, incontrast to either of these conditions, in-


creased food intake can do little to overcomethe cytoglucopenia caused by 2-DG. In thisregard, note that oxygen consumption de-creases markedly after 2-DG treatment (Nico-laidis, Epstein, & Le Magnen, 1972) despitethe increased production of glucose in theliver (Brodows, Pi-Sunyer, & Campbell, 1975;Hbkfelt & Bydgeman, 1961).

The basis for hunger following systemic2-DG treatment has not yet been specified.Intraportal injections of 2-DG have beenshown to increase feeding (Hernandez, Mac-Kenzie, & Hoebel, 1976; Novin, VanderWeele,& Rezek, 1973; Rowland & Nicolaidis, 1974),thus suggesting that a decrease in hepaticmetabolism may provide the stimulus for hun-ger (see below). However, because admini-stration of 2-DG into the cerebral ventriclesalso elicits feeding behavior in rats (Miselis& Epstein, 197S), central receptors may ad-ditionally participate in mediating the feedingresponse to systemic 2-DG treatment. If so,other studies demonstrating that alternativemetabolic fuels can suppress the physiologicalresponses that occur during cerebral cyto-glucopenia (Fiorentini & Miiller, 1975; Flattet al., 1974; Hetenyi, 1972; Friedman et al.,Note 1) suggest that feeding probably doesnot result from a decrease in glucose utiliza-tion per se.

The stimulation of hunger following treat-ment with substantial doses of insulin or2-DG is disrupted by lateral hypothalamic(LH) lesions (Epstein & Teitelbaum, 1967;Wayner, Cott, Millner, & Tartaglione, 1971),even though rats with such brain damagemaintain body weight by ad libitum feeding.It is also known that rats with LH lesionsincrease their food intake when placed in acold environment (Epstein & Teitelbaum,1967; see also Marshall & Teitelbaum, 1973;Zigmond & Strieker, 1972). These two find-ings have had an important influence on the-ories of hunger by suggesting that separateglucoregulatory and thermoregulatory con-trols of feeding exist. However, in collabora-tion with M. Zigmond, we have recentlyfound that rats with LH lesions, whose foodintake did not increase in response to 2-DGor large doses of insulin, did become hyper-phagic when given repeated low doses of long-acting protamine zinc insulin. Furthermore,

although these rats increased their food in-takes when exposed to an ambient tempera-ture of 5 °C, they failed to eat when the coldstress was made more severe by shaving offtheir fur prior to testing (Strieker, Friedman,& Zigmond, 1975). These results do not sup-port the concept of multiple stimuli for hun-ger ; instead, they suggest that the permanentfeeding deficits of rats with LH lesions sim-ply reflect their inability to behave appropri-ately when the homeostatic imbalance ismarked and abrupt (see also Strieker, 1976).

To summarize, we believe that glucostasisis not the specific goal of feeding behavior.While it is true that several different condi-tions of cytoglucopenia can lead to increasedfeeding, it does not seem to be the decreasein glucose utilization per se that elicits hun-ger but, rather, a general decrease in the uti-lization of all metabolic fuels for energy pro-duction. Thus, food intake can be decreasedin cytoglucopenic rats following the restora-tion of metabolism by substrates other thanglucose. Recent studies of rats with goldthio-glucose-induced lesions of the VMH area orelectrolytic lesions of the LH area have re-moved the other major props for the gluco-static hypothesis, and consequently, it appearsthat there is now little basis for maintainingthat fluctuations in glucose utilization in thebrain provide the signal for the short-termcontrol of food intake.

IMPLICATIONS OF THE PHYSIOLOGICALPERSPECTIVE

Thus far, we have reexamined a numberof experimental findings from a perspectivethat takes into account well-known physio-logical mechanisms that maintain the supplyof metabolic fuels. In each case we believe thedata can be interpreted readily if one as-sumes that an alteration in the supply ofutilizable fuels provides the stimulus forhunger. This theory is much more simplethan contemporary notions of hunger, whichwe believe have been overburdened by suchunsubstantiated hypothetical constructs aslipostat, glucostat, body weight set point, andthe like. However, in abandoning these tradi-tional concepts in favor of a more tangiblephysiological model, we recognize that two


basic questions still remain to be answered.First, given our perspective, what is thestatus of the dual hypothalamic model forthe control of feeding? And second, in theabsence of lipostatic and glucostatic recep-tors, what is the origin of the stimulus thatsignals the animal to feed? We shall now con-sider each of these general issues in turn.

Central Controls oj Hunger

The ventromedial hypothalamus was firstviewed as a satiety center whose function wasto suppress the activity of a primary feedingcenter in the adjacent lateral hypothalamicarea. Thus, VMH lesions were believed to in-crease food intake by attenuating the satiety-inducing effects of feeding (Brobeck, 1955;Miller et al., 1950), whereas LH lesions werethought to abolish ingestive behaviors byeliminating the signal for hunger (Anand &Brobeck, 1951; Stellar, 1954). A more recentview of these dual control mechanisms hasthem interacting to determine body weightset point. According to this model, VMH le-sions raise the body weight set point, andhyperphagia results so that the animal willreestablish weight regulation, albeit at a newand elevated level; conversely, LH lesions arebelieved to lower the set point, and aphagiaresults so that the animal, perceiving its sud-den "obesity," will reduce its weight to thenew desired level (Keesey & Powley, 1975).

It is difficult to reconcile the proposal thatVMH lesions disrupt satiety mechanismswith subsequent findings that when brain-damaged rats feed ad libitum, the intermealinterval is decreased but remains proportionalto the size of the preceding meal (Le Mag-nen et al., 1973; Thomas & Mayer, 1968).It is also difficult to accept the hypothe-sis that hyperphagia occurs after VMHlesions in order to elevate fat reserves, sinceas discussed previously, the change in fatmetabolism toward lipogenesis may precedethe increase in food intake and even predictits magnitude (Hustvedt & L0v0, 1973). Todescribe the complex changes that increase thedeposition and storage of metabolic fuels asan increase in body weight set point seems toobscure the details of the phenomenon un-necessarily, to attribute set point properties

prematurely to the maintenance of fat re-serves, and to mistakenly identify the causeof the hyperphagia as its consequence.

Damage in several brain areas other thanthe ventromedial hypothalamus has recentlybeen reported to induce hyperphagia, but aswith VMH lesions, in no instance is it clearthat the increased food intake is the primaryeffect. Thus, feeding is increased (a) follow-ing parasagittal knife cuts lateral to theventromedial hypothalamus (Albert & Stor-lien, 1969; Gold, 1970; Sclafani & Grossman,1969)—but hyperinsulinemia results in theseanimals even when food is restricted (Tan-nenbaum, Paxinos, & Bindra, 1974); (b)following lesions of the ventral diencephalonpresumed to specifically interrupt noradre-nergic fibers ascending to the hypothalamus(Ahlskog & Hoebel, 1973; Ahlskog, Randall,& Hoebel, 1975)—but this hyperphagia isabolished by hypophysectomy (Ahlskog, Hoe-bel, & Breisch, 1974); and (c) following de-struction of central serotonin-containing neu-rons (Sailer & Strieker, 1976; see alsoBreisch, Zemlan, & Hoebel, 1976)—but ratslesioned when juvenile continue to grow insize as adults and show no remarkable ac-cumulation of abdominal fat despite their ele-vated body weights. Thus, it seems likely thatin each of these preparations hyperphagia isassociated with, and possibly secondary to,some disruption in peripheral metabolism.

In the absence of data demonstrating theexistence of a central system that specificallymediates satiety, the possibility arises thatsatiation originates in the periphery. For ex-ample, it has recently been proposed thatintestinal glucoreceptors or hormones providesignals forecasting satiation (Davis, Camp-bell, Gallagher, & Zurakov, 1971; Novin,Sanderson, & VanderWeele, 1974). However,the involvement of pancreatic hormones inmediating these effects has not yet been ex-cluded (see Footnote 3, below). More re-cently, cholecystokinin has been reported tosuppress feeding in hungry rats (Smith &Gibbs, 1976), but it is still uncertain whetherthe doses used fall within the physiologicalrange. Alternatively, satiation may resultfrom removal of a peripheral metabolic stimu-lus that activates feeding, both due to condi-tioned effects of food consumption (Booth,


1972a; Louis-Sylveslre, 1976; Stunkard,197S) and to unconditioned physiologicalchanges that result from the ingestion andrapid absorption of carbohydrates (Pilcher,Jarman, & Booth, 1974; Steffens, 1969b;Strubbe & Steffens, 1975; Wiepkema, AlinghPrins, & Steffens, 1972; see below). Indeed,Booth and his colleagues have successfullysimulated meal patterns of intact and brain-damaged rats with a computer model thatconsists essentially of a single-loop, negative-feedback system, with a diminished fuel sup-ply from the intestines and adipose tissue inthe face of ongoing energy consumption as thesole stimulus for hunger (Booth & Toates,1974; Booth et al., 1976; Toates & Booth,1974). Those remarkable findings obviouslyare in accord both with the possibility ofperipheral controls for hunger and satiety andwith the theoretical approach we have takenin this paper.

The role of the lateral hypothalamus as afeeding center also must be reexamined inlight of repeated findings that aphagia andstarvation can be obtained with lesions orknife cuts that spare the lateral hypothalamus(e.g., Albert, Storlien, Wood, & Ehman, 1970;Gold, 1967; Grossman & Grossman, 1971;Morgane, 196la). These findings are con-sistent with the fact that the most effectiveplacements for the production of feedingdeficits have been localized in the far-lateralaspects of the tuberal hypothalamus (Anand& Brobeck, 19S1; Morgane, 1961b; Oltmans& Harvey, 1972), a region consisting largelyof ascending and descending fibers of passagerather than compact cellular masses (Mor-gane, 1969). Destruction of one particularpathway, the dopamine-containing neurons ofthe nigrostriatal bundle, has been emphasizedby Ungerstedt (1971), since that pathway isdamaged by effective LH lesions as well as byextrahypothalamic lesions that result in simi-lar behavioral impairments (see also Fibiger,Zis, & McGeer, 1973; Marshall, Richardson,& Teitelbaum, 1974; Zigmond & Strieker,1972).

The seminal experiments by Teitelbaumand his colleagues, which showed that volun-tary feeding behavior would ultimately reap-pear if rats with LH lesions were initiallymaintained by intragastric intubations of

liquid nutrients (Teitelbaum & Epstein, 1962;Teitelbaum & Stellar, 1954), have been repli-cated using rats with extrahypothalamic,dopamine-depleting lesions (e.g., Marshall etal., 1974; Zigmond & Strieker, 1973). A re-cent neurochemical model of the "lateralhypothalamic syndrome," proposed by Striekerand Zigmond (1976), suggests that destruc-tion of central dopaminergic fibers disruptsnot the differentiating aspects of specific mo-tivated behaviors but a nonspecific activa-tional component that is common to all moti-vation. This hypothesis accounts for the broadrange of motivated activities that are dis-rupted by LH or other dopamine-depletingbrain lesions, such as feeding, drinking, ma-ternal, and thermoregulatory behaviors (e.g.,Avar & Monos, 1969; Satinoff & Shan, 1971;Strieker, 1976; Strieker & Zigmond, 1974) aswell as for the reversal of these deficits bysuch nonspecific activators as amphetamine,caffeine, tail pinch, and environmental stress(Antelman & Rowland, 1975; Marshall, Levi-tan, & Strieker, 1976; Strieker & Zigmond,1976; Teitelbaum & Wolgin, 1975). Non-catecholaminergic pathways, as yet unidenti-fied, presumably mediate the specific signalsfor hunger and other drives (Strieker & Zig-mond, 1976).

The broad disruption of behavior followingLH lesions apparently accounts for the alter-ations in food intake and body weight thatare observed following combined VMH andLH lesions. The effects of combined lesionsdo not cancel one another as might be pre-dicted by the set point hypothesis of Keeseyand Powley (1975). Instead, rats becomeaphagic and lose weight initially (Anand &Brobeck, 1951), but later, after they resumefeeding behavior, they become hyperphagicand obese (Williams & Teitelbaum, 1959).While the ventromedial and lateral hypothala-mus thus do not simply determine a bodyweight set point, or serve as satiety and feed-ing centers, they may nevertheless contributeto the control of peripheral metabolism(Frohman, 1971). Indeed, following consump-tion of a meal, electrophysiological activity inthe ventromedial hypothalamus is known toincrease, while that in the lateral hypothala-mus decreases or does not change (Anand,Chhina, Sharma, Dua, & Singh, 1964; Anand


& Pillai, 1967; Oomura et al., 1964). Further-more, electrical stimulation of loci in the hy-pothalamus has been shown to alter carbo-hydrate metabolism in the liver, with sympa-thetic nerves being activated by stimulationin medial areas and parasympathetic fibersactivated by more lateral placements (Shim-azu, Fukuda, & Ban, 1966). It thereforeseems possible that LH lesions alter fat me-tabolism toward increased lipolysis, mirroringthe effects of VMH lesions (see also Steffens,Mogenson, & Stevenson, 1972). This hypothe-sis, which resembles a central feature of therecent proposal by Keesey and Powley (1975)without subscribing to their notions aboutbody weight set point, awaits experimentalinvestigation.

Origin of the Stimulus for Hunger

Receptors that monitor changes in theavailability of utilizable nutrients may be lo-cated in the brain. Indeed, central receptorsare well known to trigger a massive sympa-thetic discharge when stimulated during in-sulin-induced hypoglycemia (Cannon, Mclver,& Bliss, 1924). Such receptors are presuma-bly involved in mediating the hyperglycemiaand associated feeding responses that areseen in rats after intracranial injections of2-DG (Miselis & Epstein, 1975; Muller,Cocchi, & Forni, 1971), although, as notedearlier, the specific stimulus that activatesthem may not be a decrease in the utiliza-tion of glucose per se (Fiorentini & Muller,1975; Flatt et al., 1974; Hetenyi, 1972;Friedman et al., Note 1). However, it is notlikely that pronounced decreases in cerebralglycolysis ever occur except under nonphysio-logical experimental conditions, because thebrain is normally protected from such emer-gencies. Thus, the usual stimulus for hungershould be sought elsewhere.

Our recent findings that insulin-inducedfeeding is abolished by infusions of fructose,but not ketone bodies, strongly implicate theliver as the origin of the hunger signal (Fried-man et al., Note 1). The liver appears to bea likely site for peripheral receptors becauseof its strategic location and critical involve-ment in the traffic of metabolic fuels fromboth exogenous and endogenous sources. In the

postabsorptive state, when hunger normallyoccurs, glucogenic precursors are divertedfrom energy production to the service of glu-coneogenesis. The liver then becomes increas-ingly dependent on the supply of free fattyacids from adipose tissue, but free fatty acidsare converted to ketone bodies in proportionto their availability (Van Harken, Dixon, &Heimberg, 1969). Although total hepatic en-ergy production may not be compromised(Mayes & Felts, 1967), it is tempting tospeculate that the shift in substrate flow awayfrom the tricarboxylic acid cycle somehowprovides the signal for hunger.

A decrease in oxidative metabolism in theliver would be expected when there is adecline in the supply of utilizable fuels to thatorgan, as following large doses of insulin or2-DG, and that change may contribute to theobserved feeding response. Alterations in oxi-dative metabolism also may account for theappearance of hunger in the postabsorptivestate, when the flood of nutrients to the liverabates and fuels are diverted from tricarbox-ylic-acid-cycle activity toward gluconeogenesisand ketogenesis. In this regard, note that he-patic glucose production in rats is increasedboth after VMH lesions (Holm et al., 1973)and during alloxan diabetes (Friedmann,Goodman, & Weinhouse, 1967), the two con-ditions in which chronic hyperphagia is mostprominent. Glucose output also is increasedafter 2 hours of fasting (Schimmel & Knobil,1970), at which time feeding may be expected(Snowdon, 1970). On the other hand, notethat hunger is not associated with enhancedglucose output when the supply of utilizablefuels for the liver is abundant, as occurs whenrats are fed high-protein or high-fat diets(Eisenstein, Strack, & Steiner, 1974).

An important role for the liver in stimulat-ing hunger has been advocated previously,most notably by Russek (1963, 1971). Insupport of his position, Russek (1970) hasdemonstrated that infusions of glucose di-rectly into the portal vein can depress foodintake in hungry animals (see also Booth &Jarman, in press; Campbell & Davis, 1974;Novin, Sanderson, & VanderWeele, 1974). Inaddition, feeding by fasted animals results ina prompt reversal of hepatic metabolismtoward glycogen formation (Foster, 1967;


Mayes, 1962 ).3 While these results clearly areconsistent with Russek's (1975) notion of ahepatic glucoreceptor participating in the"glycogenostatic" control of hunger, theyneither specify the critical event nor do theydemand that it is a change in the metabolismof glucose per se. Indeed, intragastric injec-tions of fatty acids and intermediary metabo-lites similarly reduce feeding in mildly hungryanimals, after a delay suitable for absorption,in proportion to the estimated energy yield ofthe load (Booth, 1972c, 1972d; Booth & Jar-man, in press). Moreover, a model based onchanges in liver glycogen levels or glycolysisrates cannot explain recent findings that de-spite pronounced depletions of liver glycogen,overeating did not occur in diabetic rats feda high-fat diet (Friedman, 1975). Collec-tively, these observations are instead consis-tent with our suggestion that alterations inhepatic oxidative metabolism provide thestimuli for hunger and satiety.

In order for hepatic events to have behav-ioral repercussions they must influence thebrain. Both blood-borne and neural signalsshould be considered, but unfortunately,there are few unambiguous data at presentthat bear on this point. Nevertheless, it isinteresting to note that electrical stimulationof the vagus has been found to elicit feedingin satiated cats (Penaloza-Rojas, Barrera-Mera, & Kubli-Garfias, 1969), while DCblockade of the vagus decreases feeding inhungry cats (Penaloza-Rojas & Russek,1963). Furthermore, portal infusions of glu-cose have been shown to affect the firing ratesof afferent fibers from the liver (Niijima,1969) as well as single neurons in the hypo-thalamus (Schmitt, 1973). Taken together

3 According to our proposal, this shift in metabo-lism would tend to remove hunger as a stimulus forfeeding rather early in the meal, and the increasingdependence of ingestion on nonmetabolic factors(e.g., palatability of the diet) might explain whymeal sizes are so unpredictable (Le Magnen &Tallon, 1966). Because metabolic shifts within theliver are strongly influenced by fluctuations in insulinlevel, or in insulin/glucagon ratios (Cahill et al.,1966; Exton & Park, 1967; Friedman et al., 1967;Menahan & Wieland, 1969; Seyffert & Madison, 1967),such endocrine changes might have a considerableindirect effect on satiety (cf. de Castro & Balagura,197S; Steffens, 1975).

with the apparent centrifugal influence onliver function (Ban, 1967; Frohman, 1971),these observations raise the admittedly spec-ulative but exciting possibility of an interac-tion between the brain and the liver in thecontrol of food intake and energy metabolism.

SUMMARY AND CONCLUSIONS

Many physiological changes occur with thedevelopment of hunger. As we have seen,insulin secretion diminishes as the gastroin-testinal tract empties, and the utilization ofglucose in cells that are dependent on insulinfor its entry decreases too. Conversely, thereis an increase in the secretions of glucagon,growth hormone, and epinephrine, all of whichprovide for the mobilization of glucose andlipid from body stores. Almost every one ofthese correlated events has provided a basisfor a single-factor theory concerning thephysiological stimulus for hunger (e.g., Ken-nedy, 1953; Mayer, 1953; Snowdon, 1970;Woods, Decke, & Vasselli, 1974). However,we believe these theories have focused onsecondary issues and have missed the phe-nomenon at the core—-namely, the continuedavailability of diverse metabolic fuels to main-tain the energy supply (Adolph, 1947; Booth,1972c, 1972d; Ugolev & Kassil, 1961).

Hunger usually is associated with a de-creased supply of fuels from the intestines.Elaborate physiological and biochemicalmechanisms can maintain energy productionin the postabsorptive state, and the internalreserves they draw on are adaptively doledout in response to tissue needs. The principlestorage reserve is fat. When the lipid supplyfrom adipose tissue is unusually abundant,this surplus is utilized and hunger is fore-stalled. However, when the availability of fatis relatively low, the need for exogenous fuelsincreases. The liver is the organ that is mostresponsive to differences of this kind in thesupply of metabolic fuels from both endoge-nous and exogenous sources. We propose thatthe stimulus for hunger arises in the liver,when fuel delivery from the intestines andadipose tissue is inadequate for the mainte-nance of bodily functions without significanthepatic contributions. The stimulus for hun-ger may be associated with some shift inhepatic metabolism, and food intake may


reverse that change. In other words, it is theliver that may integrate information aboutcaloric homeostasis and provide the specificstimulus for hunger to the brain, and it is theliver whose function seems to be most af-fected by feeding and thus allow rapid feed-back for the termination of hunger.

This discussion has been directed solelytoward deducing the metabolic factors thatmight underlie the urge to eat. However, werecognize that animals with nutritional needsmay not choose to eat, and that animals withno such needs may eat anyway. Although wehave neglected these issues, we do not wish tominimize their importance or the significanceof additional questions regarding the recogni-tion, detection, and selection of food, theeffects on feeding of individual experience,learning, affective state, competing drives, andthe like. Indeed, these psychological variablesultimately will have to be integrated with thephysiological factors to obtain a balancedappreciation of feeding behavior. From thisbroad context we have selected hunger as asingle issue for consideration and have em-phasized the following two points.

First, we do not find it useful to divide thesignals for hunger into glucostatic and lipo-static, subserving short-term and long-termcontrols of food intake. Instead, we believethat hunger appears and disappears accord-ing to normally occurring fluctuations in theavailability of utilizable metabolic fuels, re-gardless of which fuels they are and how fullthe storage reserves.

Second, we believe that the traditional de-scription of central control mechanisms interms of feeding and satiety centers or sys-tems cannot be maintained in light of recentevidence. Instead, lateral hypothalamic lesionsappear to interrupt all motivated behaviors,not just feeding, while ventromedial hypo-thalamic lesions primarily disrupt nutrientprocessing so that animals cannot readily ob-tain fuel from bodily stores.

These conclusions have been reached bytaking a physiological approach in consideringthe physiological basis of hunger. This mayseem ironic, but physiological psychology hastraditionally contained little classical physi-ology and instead has found its evolutionaryroots in neurology. Thus, while the Sherring-

tonian metaphor of reciprocal excitatory andinhibitory controls is evident in the populartheories of dual hypothalamic centers andbody weight set points, we believe that hungerand satiety are more appropriately analogousto the coordinated mechanisms that normallycontrol gluconeogenesis and lipogenesis (cf.Tepperman & Tepperman, 1970). We hopethat future work on the physiological basis ofhunger will focus on these pathways of me-tabolism instead of so exclusively pursuingpathways in the brain.

REFERENCE NOTE1. Friedman, M. I., Rowland, N., Sailer, C. F., &

Strieker, E. M. Homeostasis dttring hypoglycemia:Central control 0} adrenal secretion and peripheralcontrol of feeding. Manuscript submitted for pub-lication, 1976.

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