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CONTROL OF FOOD INTAKE
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CONTROL OF FOOD INTAKE A Physiologically Complex, Motivated Behavioral System Paula J. Geiselman, PhD
Psychologists have used the term motivation, derived from the Latin movere meaning to move, in reference to internal processes involved in initiating, directing, maintaining, and terminating a behavioral response.Iz3Feeding is a motivated behavior that is objective and readily quantifiable. Hence, eating behavior has been studied extensively, having traditionally been treated by psychologists as a model for the physiologic study of other motivated behaviors. Eating is an important system of motivated behavior necessary for survival and certainly merits study in its own right. To understand eating as a physiologically complex, motivated behavioral system, one must understand the underlying mechanisms allowing an organism to (Fig. 1) (1) detect hunger signals indicating a biologic deficit and the need for food, (2) seek food and initiate eating behavior in response to hunger signals, (3) monitor kilocalories and specific nutrients ingested, and (4) detect signals to terminate eating when sufficient kilocalories and nutrients have been ingested. Based on this model, physiologic psychologists have long been concerned with the study of the physiologic signals that motivate an organism to initiate a meal and those that motivate an organism to terminate a meal. HOMEOSTATIC FEEDBACK THEORIES OF INGESTIVE BEHAVIOR Historically, conceptual models of the physiologic control of eating behavior have been based on homeostatic feedback. According to the homeostatic models, the body has mechanisms allowing it to monitor and regulate physiologic variables within a narrow range of limits. This tendency for the body to selfFrom the Pennington Biomedical Research Center; and the Department of Psychology,
Louisiana State University, Baton Rouge, Louisiana ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA
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Hunger
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Food-seeking behavior
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Eating and monitoring total kilocalories and specific nutrients ingested
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depletion of regulated variable@)
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Critical level of repletion of regulated variable(s)
Satiety Satiation
Figure 1. The control of food intake as a physiologically complex, motivated behavioral system. Satiation refers to the processes involved in terminating a meal, and satiety refers to postprandial inhibition of food intake. That is, satiety refers to the proccesses occurring after satiation to a meal and before hunger signals occur again.*.i'6
regulate, or self-stabilize, is achieved by a system of both physiologic and behavioral control mechanisms activated by negative feedback, which is, of course, a motivational concept. Therefore, the homeostatic feedback model is essentially a restatement of the study of eating as a system of physiologically complex, motivated behaviors (Fig. 1).According to this model, an organism initiates feeding in response to the detection of hunger sensations. Eating behavior continues while the total quantity and specific nourishment of the ingested food is being monitored. With repletion, the organism becomes satiated and responds to signals to terminate the meal. During the subsequent intermeal interval, endogenous fuel is depleted as satiety wanes, and, eventually, the organism will detect hunger signals to initiate another meal. Several homeostatic feedback theories have been proposed to explain the control of food intake! Some of these theories are based on the regulation of a specific nutrient. According to the glucostatic theory:', 69, 70, 71 specialized cells regulate glucose utilization. During the intermeal interval as glucose utilization in these cells becomes lower, hunger signals will be generated. In response, the organism will begin to eat and will continue to eat until satiation signals terminate food intake when glucose utilization in these cells has become high. The aminostatic theory maintains that eating behavior regulates blood levels of amino acids. The lipostatic proposes that body fat, especially triglyceride stores in adipose tissue, is the regulated variable. According to the lipostatic theory, an organism has a set point for body fat, and any deviation from the set point will produce changes in feeding behavior that will correct the body fat deviation. In this way, a lipostatic mechanism may account for long-term regulation and the difficulty that frequently is seen in individuals who are trying to lose weight with a weight-reduction diet or who are trying to maintain such a weight loss.
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Other homeostatic feedback theories proposed that metabolic processes (rather than specific nutrients) are regulated. The thermostatic theory proposes that metabolic heat production is being regulated in the control of food intake. Obesity has been associated with reduced activity of the thermogenic component of the sympathetic nervous system.loNicolaidis and Even’s ischymetric theory7h maintains that hunger is produced by a decrease in metabolic rate and thus is focused on heat production but takes other factors such as the cost of movement into account as we1L8The energostatic theory encompasses the other homeostatic feedback theories in postulating that the regulated variable is the energy yielded by the liver from the oxidative metabolism of all nutrient^.^, 38 All of the homeostatic feedback models make the following assumptions: (1)detector cells in the brain monitor the body’s level of the regulated variable; (2) activation of a system of physiologic and behavioral controls subserves meal initiation, meal continuation, transport, digestion, absorption, metabolism, and the storage of nourishment; and (3) negative feedback mechanism(s) signal correction of the deficient variable and lead to meal termination. This article discusses putative signals for hunger (meal initiation), satiation (meal termination), and satiety (continuing inhibition of food intake during the intermeal interval until signals are detected to initiate another meal). It does not focus on the brain structures and their neurotransmitters involved in the control of food intake (for a review, see the articles by Bray? Leibowitz,61and Plata-Salamans8). PUTATIVE SIGNALS FOR HUNGER, SATIATION, AND SATIETY
Physiologic psychologists and other investigators have been strongly interested in hunger signals since at least the 1950s, but it has proven difficult to identify the physiologic mechanisms that signal meal initiation. Moreover, it is generally agreed that feeding stops in most cases before the initiating cause has been corrected. It has been a relatively easier task to identify physiologic factors associated with meal termination. As a result, we know much more about satiation and satiety than we do about hunger.
Sensory Feedback Positive Sensory Feedback
Sensory information on the appearance, odor, taste, texture, and temperature of food is conveyed to the central nervous system (CNS) via cranial nerves I, 11, V, VII, IX, and X. The senses of sight and smell can provide important cues for locating food sources and initiating a meal. Once the oral receptors have made contact with food, the taste and tactile (texture) sensory input combined with the sight and smell of the food can provide positive sensory feedback in stimulating further hunger motivation and ingestive behavior.118“Positive alliesthesia,” which is an increased positive response to taste, is well-documented as being associated with hunger motivation5*It is assumed that the cephalic-phase responses are related to the palatability or hedonic value of the f00d.l~When meal-fed rats are presented with a diet that has been made more palatable with sucaryl, they have a significantly greater preabsorptive insulin response and ingest a significantly larger meal in comparison with their responses when given a control dietffi, 66 Furthermore, the
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amplitude of the cephalic-phase insulin response to the taste of saccharin in normal-weight rats is a predictor of susceptibility to dietary-induced obesity: These data suggest that the cephalic-phase insulin response is involved in the mediation of the hunger-stimulating effects of palatable, sweet-tasting substances. Negative Sensory Feedback E p ~ t e i nhas ~ ~suggested that total caloric intake monitored by oropharyngeal receptors may contribute to signals for meal termination. Oropharyngeal signals are important in providing meal termination cues to a novel food for which there has been no opportunity to learn gastrointestinal signals for satiation. Cues from the sight, smell, taste, and tactile sensations of food can also provide negative feedback signals for terminating a meal (see the article by G e i ~ e l m a nfor ~ ~ a discussion of specific tastants and other food stimuli that are mo$ associated with either positive sensory feedback or negative sensory feedback.) Scott and Mark'"* have demonstrated that taste sensitivity is dependent on what has been ingested, and it is well-known that palatability is a major factor in determining meal size.25These results are consistent with the foodspecific satiation and satiety effects that have been extensively documented by Rolls and colleagues,g6showing that a food that has been ingested continuously becomes less palatable and is eaten in smaller amounts than a previously nonconsumed food. Bedard and Weingarten3 have provided data demonstrating that postabsorptive increases in plasma glucose levels can decrease the excitatory effects of taste that drive ingestive behavior. This attenuation of motivation from positive tastes may contribute to spontaneous meal termination. Bedard and Weingarten's3 behavioral data are consistent with electrophysiologic data showing that firing rates in the nucleus tractus solitarius in response to tastants administered to the tongue are reduced by both increased levels of blood glucose5"and gastric distension.51The data provide an animal model of Cabanac's extensive studies of negative alliesthesiaIsin which human subjects reported a decrease in the pleasantness of a taste cue from before a meal to after or with a gastrointestinal load.16, Distension in the Gastrointestinal Tract
Stretch receptors in the gastrointestinal tract can monitor the volume of ingested food; and pharyngeal, esophageal, gastric, and intestinal distension may provide signals for meal termination through negative feedback. Evidence suggests a role of gastric distension in response to a large volume in the ratz8 and the monkeyh7as a meal-termination signal relayed to the brain by the vagus nerve.28,46 However, these vagal signals seem to operate only when gastric volume is high, because vagotomy does not block the satiating effect produced by a small gastric load.57Gibbs and c o - ~ o r k e r shave ~ ~ additionally provided evidence that duodenal distension, in the absence of gastric distension, can produce satiation, and that this effect can be inhibited by vagotomy. Effects of Nutrients, Nutrient Reserves, and Metabolism in Producing Signals to the Liver or Brain Carbohydrate, fat, and protein metabolites may act on central and peripheral structures to control food intake. Centrally, it has been shown that glucose
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and free-fatty acids can act directly on hypothalamic sites involved in the control of food intake and can influence their firing rates.84 In 1970 R ~ s s e kproposed ~~ that the liver also has an important role in the control of food intake. Certainly, the liver is in a position to serve as an early warning signal for hunger, because it is the first organ to encounter most absorbed nutrients including glucose. In addition, the liver oxidizes most metabolic fuels, including glucose, amino acids, glycerol, and fatty acids, and can store glucose as glycogen.1uuChemoreceptors in the gastrointestinal tract may provide satiation signals to the liver or brain. Deutsch and Jang AhnZ8have shown that the nutrient content of the stomach may act as a satiation signal relayed by the splanchnic nerve, whereas satiation signals elicited by nutrients in the intestines are mediated by the vagus nerve.47Nutrients infused into the intestine can inhibit gastric emptying67 and thus enhance gastric distension satiation signals as well. Debate continues as to whether the various chemical stimuli act on different chernoreceptors with nutrient-specific sensitivities or on a single chemoreceptor responsive to energy in general. Data reported by Deutsch and colleagues support the argument for chemoreceptors with nutrient-specific sensitivity. Deutsch and Tabuenaz9have tested for satiation and demonstrated that rats can distinguish intragastric infusions of amino acids from infusions of breakdown products of oil emulsion (see the article by Novin and VanderWeele*l for data in support of nutrient-specific sensitivity). Other data support the existence of chemoreceptors with nutrient specificity.
Glucostafic Theory According to the glucostatic theory, glucose (together with insulin’”) and the size of glycogen reserves9*are monitored and regulated in the control of food intake. Glucose is the primary metabolic fuel in the CNS, thus it seems reasonable to assume that glucose can act directly on the brain. Centrally, there is support for the concept of glucoreceptor mechanismsToo operating in the shortterm control of feeding by producing hunger signals when glucose utilization is low in the ventromedial hypothalamus (VMH)54.83 and the caudal especially the nucleus tractus solitarius” (see study by OomuraMfor additional evidence that glucose directly affects the activity of hypothalamic sites involved in the control of food intake; also see study by Scharrer and LanghanslUofor further discussion of CNS glucoreceptors) and the caudal especially the nucleus tractus s ~ l i t a r i u s . ~ ~ Chafetz and co-workersZ2have reported an association between decreased glucose availability and increased norepinephrine turnover in the hypothalamus. Activity of the alpha-2 noradrenergic system in the paraventricular nucleus (PVN) is positively correlated with an animal’s total daily food intake.6’Injection of norepinephrine or the alpha-2 agonist clonidine into the PVN stimulates food intake, especially carbohydrate intake, and restores circulating levels of glucose. This effect, which is accompanied by decreased energy expenditure, is dependent on and potentiated by corticosterone.lO, 61 There is also support for the existence of hepatic glucoreceptors.8z,yR Infusion of 2-deoxy-D-glucose (2-DG), an inhibitor of glucose metabolism, into the hepatic-portal system of the intact rabbit stimulates feeding to a greater extent and with a shorter latency to meal initiation than do comparable injections into either the jugular vein of intact rabbits or into the hepatic-portal vein of vagotomized rabbits.82Conversely, intraportal infusion of glucose has been shown to suppress food intake in food-deprived rabbits, and this effect can be blocked by vagotomy.8’ Hepatic receptors are able to distinguish among energy-yielding fuels, and this suggests a special role for glucose because the effect of intraportal
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glucose in suppressing food intake in the deprived rabbit was greater than were the effects of glycerol or amino acids.8l Electrophysiologic data also indicate that hepatic signals for hunger and satiation are relayed to the brain by vagal afferents. Niijima78has shown that the infusion of glucose or its metabolite pyruvate into the hepatic-portal circulation of the guinea pig decreases hepatic vagal afferent firing rates, whereas intraportal infusion of 2-DG increases hepatic vagal afferent firing. Considerable data suggest a causal relationship between spontaneous transient declines in blood glucose and meal initiation. Louis-Sylvestre and LeMagnen=,66 first reported that blood glucose decreased prior to spontaneous meals in rats, and this effect has been replicated by Campfield and colleague^.^^ When glucose is infused intravenously to block partially the premeal decline in blood glucose, meal initiation is significantly delayed,ls but meal size is not affected.'Ol Campfield and SmithI9have concluded that blood glucose dynamics per se provide the signal for meal initiation because intravenous infusions of other substrates (amino acids, ketone bodies, hexoses) after the premeal glucose decline has begun do not affect latency to meal initiation. Normal transient declines in blood glucose occur following total subdiaphragmatic or hepatic vagotomy, indicating that this signal is not dependent on the efferent vagus.19 However, meal initiation did not occur following a decline in blood glucose in approximately 45% of the trials in both vagotomized groups, indicating that detection of the transient decline by vagally innervated peripheral glucoreceptors is important in coupling meal initiation to the blood glucose dynamics. A transient spike in insulin levels has been observed immediately prior to the transient decline in blood glucose that precedes meal initiati~n.'~ Insulin can act either to stimulate hunger or to suppress food intake.42, 90 When the transient spike in insulin was induced experimentally by an acetylcholine analog, it was followed by a transient decline in blood glucose that mimicked the pattern of blood glucose before spontaneous meals, and this manipulation also resulted in meal initiati~n.'~ Consistent with these results, Vasselli and Sclafani115 have reported that tolbutamide, which stimulates endogenous insulin release, produces hyperphagia in rats. However, Vasselli (personal communication) has found that the hyperphagic effect does not occur until the rat has become hypoglycemic. Similarly, Woo and co-w~rkers"~ have reported data in humans indicating that increased insulin levels that do not produce hypoglycemia also do not stimulate appetite or hunger. Additional studies have been performed by Rodin and colleagues95and Friedman and G ~ a n n e m a nData . ~ ~ reported in the rabbit have shown that a spike in acute endogenous insulin levels that is sufficient to produce a precipitous decline in glycemic levels but not absolute hypoglycemia is associated with increased food intake following fast intraduodenal glucose infusion." On the other hand, moderate elevations in acute endogenous insulin levels that are insufficient to produce a significant reduction in glycemic levels below baseline produce a suppression of food intake following intraduodenal infusions of glucose at a slow rate in the rabbitj4 Lipostatic Theory
The lipostatic theory makes the assumption that receptors in the CNS monitor and regulate circulating levels of fat metabolites (e.g., fatty acids, glycerol, and 3-hydroxybutyrate)which signal the size of body fat depots. Consistent with this theory, Oomuras4has reported that free-fatty acids directly affect the firing rates of hypothalamic sites involved in the control of food intake. In
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addition, several investigators have shown that manipulations that either increase or decrease the size of fat depots result in compensatory hypophagia or hyperphagia, respectively.88,loo It has been proposed that this change in food intake together with a change in metabolic rate functions to return body fat depots to normal size, thereby integrating the control of body fat with the control of food intake. Although it has been demonstrated that the compensatory decrease in food intake observed in rats recovering from insulin-induced obesity is associated with an increase in blood levels of fatty acids, glycerol, 3-hydroxybutyrate, and glucose,4O,92 it has further been shown that the hypophagic effect cannot be blocked by either antilipolytic drugsgZor hepatic vag~tomy.~’ In addition, Egli and co-worker~~~ have shown that the compensatory hyperphagic response to a manipulation that has decreased the size of fat depots also cannot be inhibited by hepatic vagotomy. Considered together, these results lead to the conclusion that hepatic receptors as well as their afferents may not be necessary in the lipostatic control of food intake?’, I w Evidence suggests that insulin may be an important humoral factor by which the periphery communicates with central body weight control mechanisms. Woods and have proposed that insulin informs the brain about body fat depot size and links the control of food intake with long-term control of body fat reserves. A.considerable body of evidence has demonstrated that plasma insulin levels co-vary with the degree of adiposity,’21including data in humans showing that blood insulin is elevated in individuals with hypertrophic 0 b e ~ i t y .Woods l ~ ~ and co-workers121have demonstrated that very low doses of insulin infused into the lateral ventricles of rats and baboons produce a decrease in food intake. A nutrient-specific satiety effect of insulin has also been demonstrated by Arase and colleagues,2 who reported that intraventricular insulin infusion suppressed food intake in animals maintained on a high-carbohydrate diet but not in animals fed a high-fat diet. It has been suggested that insulin may leak from the ventricles to the VMH, which contains specific receptors for binding insulin, or, alternatively, that insulin may be actively taken up from the cerebrospinal fluid by cells located in the ventricle wall and having connections with the VMH.Io7Insulin binding in the VMH can be reduced by food and Plata-Salaman and Oomuras9 have demonstrated that intraventricular insulin infusion suppresses food intake in free-feeding rats but has no effect in food-deprived rats. Strubbe and Meinlo$have shown that specific insulin antibodies infused into the VMH stimulate feeding behavior during the rat’s active feeding period (dark phase) but not during the light phase. The data described previously have led to the conclusion that insulin may be an important factor integrating the control of food intake with the control of adiposity. Strubbe107has concluded that this lipostatic control mechanism sets the “motivational background for feeding behavior,” and that superimposed on this long-term mechanism are short-term signals in the control of food intake operating on a meal-to-meal basis. The gene product of the recently cloned mouse obese (oh) gene has an important role as part of the signaling pathway in the regulation of adipose tissue mass.62~68,*22 The 0 8 protein, which has been termed le~tin,5~ is a hormone secreted by adipocytes. Both central and peripheral injection of microgram doses of leptin produce a reduction in food intake and body weight in oh/ob and dietary-induced obese mice but not in db/db obese mice.*O The behavioral effects following the central administration of leptin led Campfield and colleagues to conclude that the OB protein can act directly on neural circuitry that controls feeding and energy balance.zoLike insulin, leptin co-varies with the degree of
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adiposity.24,33 This correlation would be expected because the level of secreted leptin is apparently regulated by insulin.62 Other Homeostatic Theories
Historically, most of the emphasis in the control of food intake has been placed on the study of (1) glucose utilization according to the glucostatic theory in the short-term control of food intake and (2) on the metabolism and storage of body fat according to the lipostatic theory in the long-term control of body weight. It has always been assumed that these two mechanisms are coordinated and complementary, and it is of interest that the brain's adrenergic system has been implicated in both the glucostatic and the lipostatic controls of food intake and body weight.IooHowever, as far back as 1961, work by Ugolev and Kassil"* suggested that a common metabolic pathway for fuels may be important in the control of food intake.36More recently, a considerable body of research has focused on oxidative phosphorylation and electron transport, and the data suggest that the liver integrates control of food intake across metabolic fuels. Several investigators have reported that, independent of fuel type, decreases in oxidation are associated with hunger, and increases in oxidation are associated with ~ a t i e t y . ~77,1M) ~ , These ~ ~ , ~data ~ , are consistent with the energostatic theory first proposed by Booth7in 1972. Moreover, the heat generated by the metabolism of nutrients would increase body temperature, which, in turn, would suppress food intake according to the thermostatic theory.lo7 G e i ~ e l m a nhas ~ ~ previously reported seemingly paradoxical hyperphagic effects following fast infusions of hexoses into either the duodenum or hepaticportal vein. Novin and c o - ~ o r k e r shave ~ ~ more recently reported that fast infusion of either glucose or fructose into the hepatic-portal vein of rabbits increases lipid formation, reducing mitochondrial uptake and glycogen formation, and replicates the hunger-enhancement effect. Slow hexose infusion, which has consistently produced a feeding suppression effect, is associated with substrate uptake into mitochondria and glycogen with reduced uptake into fat. These findings all are consistent with the positive correlation reported between mitochondrial oxidation and satietyImand can be incorporated into the energostatic theory as well. Peptides and Hormones Released in Response to Nutrients in the Gastrointestinal Tract
Putative Satiation Signals. A number of peptides that are released during or after a meal (Table 1)have been implicated in providing signals for satiation and satiety, often for specific nutrients. These peptides can be released to act locally in the periphery in a paracrine fashion, or they can be released into the vasculature to act in an endocrine manner.8RAdditionally, these peptides may be released in the brain to act centrally. Among the gastrointestinal peptides, cholecystokinin (CCK) has been the most extensively studied. In 1973 Gibbs and c o - ~ o r k e r sfirst ~ ~ reported that intraperitoneal administration of CCK suppressed food intake in rats. This group subsequently reported that rats exhibit the entire normal behavioral sequence of satiety following peripheral injection of CCK.' More recently, the satiation and satiety effects of CCK have been shown in a number of species including and it has been shown that CCK especially inhibits carbohydrate intake. The satiating effects of CCK seem to be physiologic because antibodies to CCK and CCK receptor antagonists produce an increase in food intake.x5,88,93
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Table 1. PEPTIDES AND HORMONES IMPLICATED IN THE CONTROL OF FOOD INTAKE Stimulation of Food Intake
Suppression of Food Intake
Aldosterone Dynorphin Beta-endorphin Beta-casomorphin Corticosterone Galanin Growth hormone-releasing hormone Insulin Neuropeptide Y Peptide YY
Anorectin Bornbesin Calcitonin Calcitonin gene-related peptide Cholecystokinin Corticotropin-releasing factor Enterostatin Gastrin-releasing peptide Glucagon Insulin Neurotensin Oxytocin Somatostatin Thyrotropin-releasing hormone Vasopressin
During a meal, CCK is released from the duodenal mucosa in response to food and acts on CCK-A receptors in the gut. Peripheral CCK decreases the rate of gastric emptying and thus contributes to gastric d i ~ t e n s i o n An . ~ ~important effect of peripheral CCK in producing satiation and satiety may be that it is acting on CCK-A receptors to produce pyloric constriction to inhibit gastric emptying. Feeding also stimulates the release of CCK in the brain where it can act on CCK-B receptors. Although some studies have suggested that central CCK-B receptors are less important than peripheral CCK-A receptors in meal termination, it has been demonstrated that CCK administered into the third ventricle or the VMH suppresses food intake.26,35 In addition, it has been reported in the baboon that CCK given centrally is more effective than intravenous administration in decreasing meal ~ i z e . 3 ~ The effects of peripherally administered CCK can be abolished by vagotorny,Z7,Io4 indicating that CCK acts on afferent vagal pathways. However, destruction of the nucleus tractus solitarius also disrupts the satiating effects of CCK. Because CCK-releasing neurons and CCK receptors are found along the entire chain from the intestines via the afferent vagal pathway to the nucleus tractus solitarius and from there via the parabrachial nucleus to the VMH, it has been suggested that CCK influences ingestive behavior at all of these levels.1o7 Interestingly, the injection of CCK into the VMH (which has a well-documented role in satiety13,91, 103, 116) suppresses food intake and increases sympathetic activity. Although not so well-studied as CCK, other peptides also may provide signals for satiation and satiety. Bombesin, neurotensin, anorectin, calcitonin, enterostatin, and corticotropin-releasing hormone have all been shown to suppress food intake when injected into the third ventricle or VMH. Bombesin has received considerable attention as a potential satiety signal, having been found to act as a potent suppressor of food intake across a number of species including Bombesin does not affect meal initiation but, rather, specifically acts to decrease meal size, suggesting that this peptide contributes to satiation and satiet~.~~ gear^^^ has demonstrated that glucagon suppresses food intake when given
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in low doses and seems to have some specificity for protein. The satiating effect of glucagon has been reported across species including humans,39,58,74 and it has been shown that this effect is vagally mediated.Io4Furthermore, following the suppression of food intake in response to glucagon, animals exhibit the normal behavioral satiety 49 The satiation produced by glucagon seems to be a physiologic effect because intraportal infusion of glucagon antibodies produces the expected increase in food intake.39 Another peptide that may be involved in satiation and satiety is enterostatin. Lin and c o - w ~ r k e r reported s~~ that intraperitoneal injection of this peptide before meal presentation did not affect meal initiation but specifically shortened the duration of the meal which was then followed by the normal behavioral satiety sequence. Enterostatin, along with corticotropin-releasing hormone and vasopressin have each been demonstrated specifically to inhibit fat intake. Somatostatin, also has been reported to suppress food intake across species,@ but M ~ r l e has y~~ reported that it can produce nausea in humans. Additional peptides and hormones that have been shown to suppress food intake are listed in Table 1. The reader is referred to reports by Bray9 and Plata-Salamana8for further discussion of putative satiation and satiety peptides and of the nutrient-specific satiety effects of peptides and hormones. Plata-Salaman has reviewed putative satiety growth factorsa6and putative satiety immunomodulators.87Several investigators have studied the combined effects of two or more putative satiety peptides and hormones, and the data suggest that these putative satiety factors are interacting to suppress food intake." Putative Hunger Signals. Although less is known about the role of peptides in hunger (as compared with the role of peptides in satiation and satiety), several peptides seem to act as hunger stimulants. Opioids (beta-endorphin and dynorphin) stimulate food intake by acting directly on CNS structures that are known to be involved in the control of food intake (VMH, PVN, nucleus accumbens, and a m ~ g d a l a ~whereas ~), opioid antagonists inhibit eating. Betaendorphin, dynorphin, and beta-casomorphin have hunger-stimulating effects for highly palatable foods with some specificity for Neuropeptide Y stimulates food intake when delivered into the VMH, PVN, or lateral hypothalamus but does not act peripherally.60This peptide specifically stimulates carbohydrate intake, is most potent at the beginning of the rat's active feeding period, and is dependent on circulating levels of corticosterone.61 Leibowitz6I has discussed the role of corticosterone in stimulating a specific carbohydrate appetite. Galanin can stimulate a specific appetite for fat or carbohydrate. The carbohydrate-stimulating effect is short-term and occurs at the beginning of the active feeding period in the rat.61This effect is dependent on circulating corticosterone and the rapid release of norepinephrine in the PVN.61The role of galanin in stimulating fat appetite in rats is the more potent and long-term effect. Galanin stimulates fat appetite independent of either corticosterone or norepinephrine. However, the fat appetite stimulated by galanin may be associated with aldosteAldosterone strongly enhances fat intake in rats and, to a lesser extent, potentiates carbohydrate intake.3o, SUMMARY
This article has examined the control of food intake as a physiologically complex, motivated behavioral system. During the past four decades, considerable progress has been made in understanding putative signals for hunger,
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satiation, and satiety, although hunger signals have proven to be more difficult to identify. The putative physiologic controls of food intake include positive and negative sensory feedback; gastric a n d intestinal distension; the effects of nutrients, nutrient reserves, a n d metabolism i n producing signals t o the liver or brain; and peptides a n d hormones released in the gastrointestinal tract or the brain. However, food intake is not influenced solely b y physiologic signals for hunger, satiation, and satiety. To comprehend feeding behavior more thoroughly, current physiologic models must be extended to include modulating factors such as feeding-associated responses adapted through learning processesZ7and the influence of circadian rhythms,'05 which can be dominating over hunger, satiation, and satiety signals.
References 1. Antin J, Gibbs J, Holt J, et a1 Cholecystokinin elicits the complete behavioral sequence of satiety in rats. J Comp Physiol Psycho1 89:784-790, 1975 2. Arase K, Fisler J, Shargill N, et a1 Intracerebroventricular infusions of 3-hydroxybutyrate and insulin in a rat model of dietary obesity. Am J Physiol 255:R974, 1988 3. Bedard M, Weingarten H: Postabsorptive glucose decreases excitatory effects of taste on ingestion. Am J Physiol256:R1142-R1147,1989 4. Berthoud H-R, Bereiter DA, Trimble ER, et al: Cephalic phase, reflex insulin secretion. Diabetologia 20:393-401, 1981 5. Blundell J, Rogers P: Hunger, hedonics, and the control of satiation and satiety. In Friedman MI, Tordoff MG, Kare MR (eds): Chemical Senses, vol 4. Appetite and Nutrition. New York, Marcel Dekker, 1991 6. Booth DA: The behavioral and neural sciences of ingestion. In Stricker EM (ed): Neurobiology of Food and Fluid Jntake (Handbook of Behavioral Neurobiology, vol 10). New York, Plenum Press, 1990 7. Booth DA: Postabsorptively induced suppression of appetite and the energostatic control of feeding. Physiol Behav 9:199-292, 1972 8. Booth D, Weststrate J: Concepts and methods in the psychobiology of ingestion. In Westerterp-Plantenga MS, Fredrix E, Steffens AB (eds): Food Intake and Energy Expenditure. Boca Raton, CRC Press, 1994 9. Bray GA: Appetite control in adults. In Fernstrom JD, Miller GD (eds): Appetite and Body Weight Regulation. Boca Raton, CRC Press, 1994 10. Bray GA The Mona Lisa hypothesis: Most obesities known are low in sympathetic activity. In Oomura Y, Seiichiro T, Inoue S, Shimazu T (eds): Progress in Obesity Research. London, John Libbey, 1991 11. Bray GA: Nutrient balance and obesity: An approach to control of food intake in humans. Med Clin North Am 73:2945, 1989 12. Bray GA: Obesity-a disease of nutrient or energy balance? Nutr Rev 45:33, 1987 13. Bray GA, York D, Fisler J: Experimental obesity: A homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam Horm 45:1, 1989 14. Bruce DG, Storlien LH, Furler SM, et al: Cephalic phase metabolic responses in normal weight adults. Metabolism 36:721-728, 1987 15. Cabanac M: Sensory pleasure. Q Rev Biol54:1-29, 1979 16. Cabanac M, Duclaux R: Specificity of internal signals in producing satiety for taste stimuli. Nature 227966-967, 1970 17. Cabanac M, Duclaux R, Spector N H Sensory feedback in regulation of body weight: Is there a ponderstat? Nature 229:125-127, 1971 18. Campfield LA, Brandon I?, Smith F: On-line continuous measurement of blood glucose and meal pattern in free-feeding rats: The role of glucose in meal initiation. Brain Res Bull 14:605416, 1985 19. Campfield LA, Smith FJ: Systemic factors in the control of food intake: Evidence for patterns as signals. In Stricker EM (ed): Neurobiology of Food and Fluid Intake (Handbook of Behavioral Neurobiology, vol 10). New York, Plenum Press, 1990
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20. Campfield LA, Smith FJ, Guisez Y, et al: Recombinant mouse OB protein Evidence for a peripheral signal linking adiposity and central neural networks. Science 269(5223):546-549, 1995 21. Carlson AJ: The Control of Hunger in Health and Disease. Chicago, University of Chicago Press, 1916 22. Chafetz MD, Parko K, Diaz S, et al: Relationships between medial hypothalamic alpha 2-receptor binding, norepinephrine, and circulating glucose. Brain Res 384:404408, 1986 23. Chey WY, Hitanaut S, Hendricks J, et al: Effect of secretin and cholecystokinin on gastric emptying and gastric secretion in man. Gastroenterology 58:820-827, 1970 24. Considine RV, Sinha MK, Heiman ML, et al: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292-295, 1996 25. Davis JD, Levine MW: A model for the control of ingestion. Psychol Rev 84:379412, 1977 26. Della-Ferra MA, Baile CA: Cholecystokinin octapeptide: Continuous picomole injections into the cerebral ventricles of sheep suppress feeding. Science 206:471473, 1986 27. Deutsch JA: Food intake: Gastric factors. In Stricker EM (ed): Neurobiology of Food and Fluid Intake (Handbook of Behavioral Neurobiology, vol 10). New York, Plenum Press, 1990 28. Deutsch J, Jang A h S: The splanchnic nerve and food intake regulation. Behav Neural Biol 45:4347, 1986 29. Deutsch J, Tabuena 0 Learning of gastrointestinal satiety signals. Behav Neural Biol 45:282-299, 1986 30. Develport L, Knehans K, Thomas T, et al: Macronutrient intake and utilization by rats: Interactions with type I adrenocorticoid receptor stimulation. Am J Physiol 260 (Regul Integrative Comp Physiol 29):R73-R81, 1991 31. Egli G, Langhans W, Scharrer E: Selective hepatic vagotomy does not prevent compensatory feeding in response to body weight changes. J Auton Nerv Syst 15:45-53, 1986 32. Epstein A: Oropharyngeal factors in feeding and drinking. I n Handbook of Physiology, section 6 (Alimentary Canal, vol 1). Washington, DC, American Physiology Society, 1967 33. Frederich RC, Hamann A, Anderson S, et al: Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nature Med 1:13111314, 1995 34. Figlewicz DP, Sipols AJ, Green P, et al: Satiation due to CCK-8 derivative infusion into VMH is related to a specific macronutrient selection. Physiol Behav 47:911-915, 1990 35. Figlewicz DP, Sipols AJ, Porte D Jr, et al: Intraventricular CCK inhibits food intake and gastric emptying in baboons. Am J Physiol 256:R1313-R1317, 1989 36. Friedman M: Making sense out of calories. In Stricker EM (ed): Neurobiology of Food and Fluid Intake (Handbook of Behavioral Neurobiology, vol 10). New York, Plenum Press, 1990 37. Friedman MI, Granneman J: Food intake and peripheral factors after recovery from insulin-induced hypoglycemia. Am J Physiol231:1790-1793, 1983 38. Friedman M, Stricker M: The physiological psychology of hunger: A physiological perspective. Psychol Rev 83:409431, 1976 39. Geary N Pancreatic glucagon signals postprandial satiety. Neurosci Biobehav Rev 14:323-338, 1990 40. Geary N, Grotschel H, Scharrer E: Blood metabolites and feeding during postinsulin hypophagia. Am J Physio1243:R304-R311,1982 41. Geary N, Smith GP: Pancreatic glucagon and postprandial satiety in the rat. Physiol Behav 28:313-322, 1982 42. Geiselman PJ: Appetite, hunger and obesity as a function of dietary sugar intake: Can these effects be medicated by insulin-induced hypoglycemia? A reply to commentaries. Appetite 6:6479, 1985 43. Geiselman PJ: Carbohydrates do not always produce satiety: An explanation of the appetite- and hunger-stimulating effects of hexoses. In Epstein AN, Morrison A (eds):
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Progress in Psychobiology and Physiological Psychology, vol 12. Orlando, Academic Press, 1987 44. Geiselman PJ: Sugar-induced hyperphagia: Is hyperinsulinemia, hypoglycemia, or any other factor a "necessary" condition? Appetite ll(suppl):26-34, 1988 45. Geiselman PJ, Novin D: Sugar infusion can enhance feeding. Science 218:490491,1982 46. Geliebter A, Westreich S, Hasim SA, et al: Gastric balloon reduces food intake and body weight in obese rats. Physiol Behav 39:399402, 1987 47. Gibbs J, Maddison SP, Rolls E T Satiety role of the small intestine examined in shamfeeding rhesus monkeys. J Comp Physiol Psychol 95:1003-1015, 1981 48. Gibbs J, Smith GP: Satiety: The roles of peptides from the stomach and the intestine. Fed Proc 45:1391-1395, 1986 49. Gibbs J, Young RC, Smith GP: Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 84:488495, 1973 50. Giza BK, Scott TR: Blood glucose selectively affects taste-evoked activity in rat nucleus tractus solitarius. Physiol Behav 31:643-650, 1983 51. Glenn JF, Erickson RP: Gastric modulation of gustatory afferent activity. Physiol Behav 16:561-568, 1976 52. Grill HJ, Norgren R Chronically decerebrate rats demonstrate satiation but not bait shyness. Science 201267-269, 1978 53. Halaas JL, Gajiwala KS, Maffel M, et al: Weight reducing effects of leptin, the 16-kD plasma protein encoded by the obese gene. Obes Res 3(suppl3):32Os,1995 54. Hauger R, Hulihan-Giblin B, Angel A, et al: Glucose regulates (3H)(+)-amphetamine binding and Na + K + ATPase activity in the hypothalamus: A proposed mechanism for the glucostatic control of feeding and satiety. Brain Res Bull 16:281, 1986 55. Kennedy GC: The role of depot fat in the hypothalamic control of food intake in the rat. Proc R SOCLond 140:578-592, 1953 56. Kissileff HR, Pi-Sunyer FX, Thornton J, et al: C-terminal octapeptide of cholecystokinin decreases food intake in man. Am J Clin Nutr 34:154-160, 1981 57. Kraly FS, Gibbs J: Vagotomy fails to block the satiating effect of food in the stomach. Physiol Behav 24:1007-1010,1980 58. Langhans W, Pantel K, Muller-Schell W, et a1 Hepatic handling of pancreatic glucagon and glucose during meals in rats. Am J Physiol 247:R827-R832, 1984 59. Langhans W, Scharrer E: Evidence for the role of sodium pump of hepatocytes in the control of food intake. J Auton Nerv Syst 20:199-205, 1987 60. Leibowitz SF: Hypothalamic neuropeptide Y, galanin, and amines: Concepts of coexistence in relation to feeding behavior. Ann NY Acad Sci 575:221-233, 1989 61. Leibowitz SF: Neurochemical control of macronutrient intake. In Oomura Y, Seiichiro T, Inoue S, Shimazu T (eds): Progress in Obesity Research. London, John Libbey, 1991 62. Leroy P, Dessolin S, Villageois P, et al: Expression of ob gene in adipose cells: Regulation by insulin. J Biol Chem 271:2365-2368, 1996 63. Lin L, McClanahan S, York DA, et al: The peptide enterostatin may produce early satiety. Physiol Behav 53:789-794, 1993 64. Lotter EC, Krinsky R, McKay JM, et al: Somatostatin decreases food intake in rats and baboons. J Comp Physiol Psychol 95:278-287, 1981 65. Louis-Sylvestre J, LeMagnen J: A fall in blood glucose level precedes meal onset in free-feeding rats. Neurosci Biobehav 413-15, 1980 66. Louis-SylvestreJ, LeMagnen J: Palatability and preabsorptive insulin release. Neurosci Biobehav Rev 4(suppl 1):4346, 1980 67. McHugh PR, Moran TH: The stomach A conception of its dynamic role in satiety. In Sprague JM, Epstein AN (eds): Progress in Psychobiology and Physiological Psychology, vol 11. Orlando, Academic Press, 1985 68. Maffei M, Fei H, Lee GH, et al: Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations of the db locus. Proc Natl Acad Sci USA 92:6957-6960, 1995 69. Mayer J: Glucostatic mechanism of regulation of food intake. N Engl J Med 249:1316,1953 70. Mayer J: The glucostatic theory of regulation of food intake and the problem of obesity. Bull New Engl Med Center 14:43-49, 1952
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71. Mayer J: Regulation of energy intake and body weight: The glucostatic theory and the lipostatic hypothesis. Proc Natl Acad Sci USA 63:1543, 1955 72. Melnyk RB, Martin JM: Starvation-induced changes in insulin binding to hypothalamic receptors in the rat. Acta Endocrinol 10778-85, 1984 73. Mizuno Y, Oomura Y: Glucose responding neurons in the nucleus tractus solitarius of the r a t In vitro study. Brain Res 307 109-116, 1984 74. Morley JE: Neuropeptide regulation of appetite and body weight. Endocr Rev 8:256287, 1987 75. Morley JE: Appetite regulation: The role of peptides and hormones. J Endocrinol Invest 12:135-147, 1989 76. Nicolaidis S, Even P: Metabolic rate and feeding behavior. Ann NY Acad Sci 575:86104, 1989 77. Nicolaidis S, Even P: Physiological determinant of hunger, satiation, and satiety. Am J Clin Nutr 42:1083-1092, 1985 78. Niijima A: Glucose-sensitive afferent nerve fibers in the liver and their role in food intake and blood glucose regulation. J Auton Nerv Syst 9:207-220, 1983 79. Novin D, OFarrell L, Acevedo-Cruz A, et al: The metabolic bases for "paradoxical" and normal feeding. Brain Res Bull 27435438, 1991 80. Novin D, Sanderson JD, VanderWeele D A The effect of isotonic glucose on eating as a function of feeding condition and infusion site. Physiol Behav 13:>7, 1974 81. Novin D, VanderWeele D: Visceral involvement in feeding: There is more to regulation than the hypothalamus. In Morrison A, Epstein A (eds): Progress in Psychobiology and Physiological Psychology, vol 7. New York, Academic Press, 1977 82. Novin D, VanderWeele D, Rezek M Infusion of 2-deoxv-~-glucoseinto the hepaticportal system causes eating: Evidence for peripheral glucoreceptors. Science 18i:858860, 1973 83. Oomura Y, Yoshimatsu H: Neural network of glucose monitoring system. J Auton Nerv Syst 10:359-372, 1984 84. Oomura Y: Glucose as a regulator of neuronal activity. Adv Metab Disord 102:319324, 1989 85. Peikin SR Role of cholecystokinin in the control of food intake. Gastrointest Endocrino1 18:757-775,1989 86. Plata-Salaman C R Growth factors, feeding regulation and the nervous system. Life Sci 45:1207-1217, 1989 87. Plata-Salaman C R Immunomodulators and feeding regulation: A humoral link between the immune and nervous systems. Brain Behav Immun 3:193-213, 1989 88. Plata-Salaman C R Regulation of hunger and satiety in man. Dig Dis Sci 9:253-268, 1991 89. Plata-Salaman CR, Oomura Y Effect of intra-third ventricular administration of insulin on food intake after food deprivation. Physiol Behav 37:735-739, 1986 90. Plata-Salaman CR, Oomura Y, Shimizu N: Dependence of food intake on acute and chronic ventricular administration of insulin. Physiol Behav 37717-734, 1986 91. Powley TL: The ventromedial hypothalamic syndrome, satiety, and a cephalic phase hypothesis. Psycho1 Rev 8489-126, 1977 92. Ramirez I, Friedman MI: Metabolic concomitants of hypophagia during recovery from insulin-induced obesity in rats. Am J Physiol 245:E211-E219, 1983 93. Reidelberger RD, ORourke M F Potent cholecystokinin antagonist L 364718 stimulates food intake in rats. Am J Physio1257R1512-Rl518, 1989 94. Ritter RC, Slusser PG, Stone S Glucoreceptors controlling feeding and blood glucose: Location in the hindbrain. Science 213:451, 1981 95. Rodin J, Wack J, Ferrannini E, et al: Effect of insulin and glucose on feeding behavior. Metabolism 34:826-883, 1985 96. Rolls BJ, Rolls ET, Rowe EA, et al: Sensory-specific satiety in man. Physiol Behav 27137-142, 1981 97. Romsos DR, Gosnell BA, Morley JE, et al: Effects of kappa opiate agonists cholecystokinin and bombesin on intake of diets varying carbohydrate-to-fat ratio in rats. J Nutr 117976-985,1987
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98. Russek M: Demonstration of the influence of a hepatic glucosensitive mechanism on food intake. Physiol Behav 5:1207-1209, 1970 99. Scharrer E, Langhans W: Control of food intake by fatty acid oxidation. Am J Physiol 250:R1003, 1986 100. Scharrer E, Langhans W Metabolic and hormonal factors controlling food intake. Int J Vitam Nutr Res 58:249-261, 1988 101. Scharrer E, Thomas DW, Mayer J: Absence of effect of intraaortal infusions upon spontaneous meals of rats. Pflugers Arch 351:315-322, 1974 102. Scott TR, Mark GP: Feeding and taste. Prog Neurobiol 27293-317, 1986 103. Shimizu N, Oomura Y, Plata-Salaman CR, et al: Hyperphagia and obesity in rats with bilateral ibotenic acid-induced lesions of the ventromedial hypothalamic nucleus. Brain Res 416:153-156, 1987 104. Smith GP, Jerome C, Norgren R Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin in rats. Am J Physiol 249:R638-R641, 1985 105. Strominger JL, Brobeck JR. A mechanism of regulation of food intake. Yale J Biol Med 25:383-390, 1953 106. Strubbe JH: Circadian rhythms of food intake. In Westerterp-Plantenga MS, Fredrix E, Steffens AB (eds): Food Intake and Energy Expenditure. Boca Raton, CRC Press, 1994 107. Strubbe JH: Regulation of food intake. In Westerterp-Plantenga MS, Fredrix E, Steffens AB (eds): Food Intake and Energy Expenditure. Boca Raton, CRC Press, 1994 108. Strubbe JH, Mein CG: Increased feeding in response to bilateral injections of insulin antibodies in the VMH. Physiol Behav 19:309-313, 1977 109. Strubbe JH, Steffens AB, deRuiter L: Plasma insulin and the time pattern of feeding. Physiol Behav 18:81-86, 1977 110. Strubbe JH, Wolsink JG, et al: Hepatic-portal and cardiac infusion of CCK-8 and glucagon induce different effects on feeding. Physiol Behav 46:643-646, 1989 111. Temple DL, Kim T, Leibowitz SF Gluco- and mineralocorticoid receptor modulation of food intake. Soc Neurosci Abstr 17495, 1991 112. Ugolev AM, Kassil VG: [Physiology of appetite]. Uspekhi Sovremennoi Biologii 51:352-368, 1961 113. Van Italie TB, Kissileff H R Human obesity: A problem in body energy economics. In Stricker EM (ed): Neurobiology of Food and Fluid Intake (Handbook of Behavioral Neurobiology, vol 10). New York, Plenum Press, 1990 114. VanderWeele DA, Novin D, Rezek M, et al: Duodenal or hepatic-portal glucose perfusion: Evidence for duodenally-based satiety. Physiol Behav 12467473, 1974 115. Vasselli JR, Sclafani A: Hyperreactivity to aversive diets in rats produced by injection of insulin or tolbutamide, but not by food deprivation. Physiol Behav 23:557-567, 1979 116. Weingarten HP, Chang P, McDonald TJ: Comparison of the metabolic and behavioral disturbances following paraventricular- and ventromedial-hypothalamic lesions. Brain Res Bull 14:551-559, 1985 117. Westerterp-Plantenga MS, Fredrix E, Steffens AB: Food Intake and Energy Expenditure. Boca Raton, CRC Press, 1994 118. Wiepkema PR Positive feedbacks at work during feeding. Behavior 39:266-273, 1971 119. Woo R, Kissileff HR, Pi-Sunyer FX. Elevated post-prandial insulin levels do not induce satiety in normal-weight humans. Am J Physiol 247R745R749, 1984 120. Woods SC, totter EC, McKay LD, et al: Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503-505, 1979 121. Woods SC, Porte D, Strubbe JH, et al: The relationships among body fat, feeding, and insulin. In Ritter R, Ritter S, Barnes CD (eds): Neural and Humoral Control of Food Intake. Orlando, Academic Press, 1986 122. Zhang Y, Proenca R, Maffei M, et al: Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425432,1994 123. Zimbardo PG, Weber AL: Motivation and emotion. In Psychology. New York, Harper Collins College Publishers, 1994, p 301
Address reprint yequests to Paula J. Geiselman, PhD Pennington Biomedical Research Center 6400 Perkins Road Baton Rouge, LA 70808-4124
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CONTROL OF FOOD INTAKE A Physiologically Complex, Motivated Behavioral System Paula J. Geiselman, PhD
Psychologists have used the term motivation, derived from the Latin movere meaning to move, in reference to internal processes involved in initiating, directing, maintaining, and terminating a behavioral response.Iz3Feeding is a motivated behavior that is objective and readily quantifiable. Hence, eating behavior has been studied extensively, having traditionally been treated by psychologists as a model for the physiologic study of other motivated behaviors. Eating is an important system of motivated behavior necessary for survival and certainly merits study in its own right. To understand eating as a physiologically complex, motivated behavioral system, one must understand the underlying mechanisms allowing an organism to (Fig. 1) (1) detect hunger signals indicating a biologic deficit and the need for food, (2) seek food and initiate eating behavior in response to hunger signals, (3) monitor kilocalories and specific nutrients ingested, and (4) detect signals to terminate eating when sufficient kilocalories and nutrients have been ingested. Based on this model, physiologic psychologists have long been concerned with the study of the physiologic signals that motivate an organism to initiate a meal and those that motivate an organism to terminate a meal. HOMEOSTATIC FEEDBACK THEORIES OF INGESTIVE BEHAVIOR Historically, conceptual models of the physiologic control of eating behavior have been based on homeostatic feedback. According to the homeostatic models, the body has mechanisms allowing it to monitor and regulate physiologic variables within a narrow range of limits. This tendency for the body to selfFrom the Pennington Biomedical Research Center; and the Department of Psychology,
Louisiana State University, Baton Rouge, Louisiana ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA
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Satiety Satiation
Figure 1. The control of food intake as a physiologically complex, motivated behavioral system. Satiation refers to the processes involved in terminating a meal, and satiety refers to postprandial inhibition of food intake. That is, satiety refers to the proccesses occurring after satiation to a meal and before hunger signals occur again.*.i'6
regulate, or self-stabilize, is achieved by a system of both physiologic and behavioral control mechanisms activated by negative feedback, which is, of course, a motivational concept. Therefore, the homeostatic feedback model is essentially a restatement of the study of eating as a system of physiologically complex, motivated behaviors (Fig. 1).According to this model, an organism initiates feeding in response to the detection of hunger sensations. Eating behavior continues while the total quantity and specific nourishment of the ingested food is being monitored. With repletion, the organism becomes satiated and responds to signals to terminate the meal. During the subsequent intermeal interval, endogenous fuel is depleted as satiety wanes, and, eventually, the organism will detect hunger signals to initiate another meal. Several homeostatic feedback theories have been proposed to explain the control of food intake! Some of these theories are based on the regulation of a specific nutrient. According to the glucostatic theory:', 69, 70, 71 specialized cells regulate glucose utilization. During the intermeal interval as glucose utilization in these cells becomes lower, hunger signals will be generated. In response, the organism will begin to eat and will continue to eat until satiation signals terminate food intake when glucose utilization in these cells has become high. The aminostatic theory maintains that eating behavior regulates blood levels of amino acids. The lipostatic proposes that body fat, especially triglyceride stores in adipose tissue, is the regulated variable. According to the lipostatic theory, an organism has a set point for body fat, and any deviation from the set point will produce changes in feeding behavior that will correct the body fat deviation. In this way, a lipostatic mechanism may account for long-term regulation and the difficulty that frequently is seen in individuals who are trying to lose weight with a weight-reduction diet or who are trying to maintain such a weight loss.
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Other homeostatic feedback theories proposed that metabolic processes (rather than specific nutrients) are regulated. The thermostatic theory proposes that metabolic heat production is being regulated in the control of food intake. Obesity has been associated with reduced activity of the thermogenic component of the sympathetic nervous system.loNicolaidis and Even’s ischymetric theory7h maintains that hunger is produced by a decrease in metabolic rate and thus is focused on heat production but takes other factors such as the cost of movement into account as we1L8The energostatic theory encompasses the other homeostatic feedback theories in postulating that the regulated variable is the energy yielded by the liver from the oxidative metabolism of all nutrient^.^, 38 All of the homeostatic feedback models make the following assumptions: (1)detector cells in the brain monitor the body’s level of the regulated variable; (2) activation of a system of physiologic and behavioral controls subserves meal initiation, meal continuation, transport, digestion, absorption, metabolism, and the storage of nourishment; and (3) negative feedback mechanism(s) signal correction of the deficient variable and lead to meal termination. This article discusses putative signals for hunger (meal initiation), satiation (meal termination), and satiety (continuing inhibition of food intake during the intermeal interval until signals are detected to initiate another meal). It does not focus on the brain structures and their neurotransmitters involved in the control of food intake (for a review, see the articles by Bray? Leibowitz,61and Plata-Salamans8). PUTATIVE SIGNALS FOR HUNGER, SATIATION, AND SATIETY
Physiologic psychologists and other investigators have been strongly interested in hunger signals since at least the 1950s, but it has proven difficult to identify the physiologic mechanisms that signal meal initiation. Moreover, it is generally agreed that feeding stops in most cases before the initiating cause has been corrected. It has been a relatively easier task to identify physiologic factors associated with meal termination. As a result, we know much more about satiation and satiety than we do about hunger.
Sensory Feedback Positive Sensory Feedback
Sensory information on the appearance, odor, taste, texture, and temperature of food is conveyed to the central nervous system (CNS) via cranial nerves I, 11, V, VII, IX, and X. The senses of sight and smell can provide important cues for locating food sources and initiating a meal. Once the oral receptors have made contact with food, the taste and tactile (texture) sensory input combined with the sight and smell of the food can provide positive sensory feedback in stimulating further hunger motivation and ingestive behavior.118“Positive alliesthesia,” which is an increased positive response to taste, is well-documented as being associated with hunger motivation5*It is assumed that the cephalic-phase responses are related to the palatability or hedonic value of the f00d.l~When meal-fed rats are presented with a diet that has been made more palatable with sucaryl, they have a significantly greater preabsorptive insulin response and ingest a significantly larger meal in comparison with their responses when given a control dietffi, 66 Furthermore, the
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amplitude of the cephalic-phase insulin response to the taste of saccharin in normal-weight rats is a predictor of susceptibility to dietary-induced obesity: These data suggest that the cephalic-phase insulin response is involved in the mediation of the hunger-stimulating effects of palatable, sweet-tasting substances. Negative Sensory Feedback E p ~ t e i nhas ~ ~suggested that total caloric intake monitored by oropharyngeal receptors may contribute to signals for meal termination. Oropharyngeal signals are important in providing meal termination cues to a novel food for which there has been no opportunity to learn gastrointestinal signals for satiation. Cues from the sight, smell, taste, and tactile sensations of food can also provide negative feedback signals for terminating a meal (see the article by G e i ~ e l m a nfor ~ ~ a discussion of specific tastants and other food stimuli that are mo$ associated with either positive sensory feedback or negative sensory feedback.) Scott and Mark'"* have demonstrated that taste sensitivity is dependent on what has been ingested, and it is well-known that palatability is a major factor in determining meal size.25These results are consistent with the foodspecific satiation and satiety effects that have been extensively documented by Rolls and colleagues,g6showing that a food that has been ingested continuously becomes less palatable and is eaten in smaller amounts than a previously nonconsumed food. Bedard and Weingarten3 have provided data demonstrating that postabsorptive increases in plasma glucose levels can decrease the excitatory effects of taste that drive ingestive behavior. This attenuation of motivation from positive tastes may contribute to spontaneous meal termination. Bedard and Weingarten's3 behavioral data are consistent with electrophysiologic data showing that firing rates in the nucleus tractus solitarius in response to tastants administered to the tongue are reduced by both increased levels of blood glucose5"and gastric distension.51The data provide an animal model of Cabanac's extensive studies of negative alliesthesiaIsin which human subjects reported a decrease in the pleasantness of a taste cue from before a meal to after or with a gastrointestinal load.16, Distension in the Gastrointestinal Tract
Stretch receptors in the gastrointestinal tract can monitor the volume of ingested food; and pharyngeal, esophageal, gastric, and intestinal distension may provide signals for meal termination through negative feedback. Evidence suggests a role of gastric distension in response to a large volume in the ratz8 and the monkeyh7as a meal-termination signal relayed to the brain by the vagus nerve.28,46 However, these vagal signals seem to operate only when gastric volume is high, because vagotomy does not block the satiating effect produced by a small gastric load.57Gibbs and c o - ~ o r k e r shave ~ ~ additionally provided evidence that duodenal distension, in the absence of gastric distension, can produce satiation, and that this effect can be inhibited by vagotomy. Effects of Nutrients, Nutrient Reserves, and Metabolism in Producing Signals to the Liver or Brain Carbohydrate, fat, and protein metabolites may act on central and peripheral structures to control food intake. Centrally, it has been shown that glucose
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and free-fatty acids can act directly on hypothalamic sites involved in the control of food intake and can influence their firing rates.84 In 1970 R ~ s s e kproposed ~~ that the liver also has an important role in the control of food intake. Certainly, the liver is in a position to serve as an early warning signal for hunger, because it is the first organ to encounter most absorbed nutrients including glucose. In addition, the liver oxidizes most metabolic fuels, including glucose, amino acids, glycerol, and fatty acids, and can store glucose as glycogen.1uuChemoreceptors in the gastrointestinal tract may provide satiation signals to the liver or brain. Deutsch and Jang AhnZ8have shown that the nutrient content of the stomach may act as a satiation signal relayed by the splanchnic nerve, whereas satiation signals elicited by nutrients in the intestines are mediated by the vagus nerve.47Nutrients infused into the intestine can inhibit gastric emptying67 and thus enhance gastric distension satiation signals as well. Debate continues as to whether the various chemical stimuli act on different chernoreceptors with nutrient-specific sensitivities or on a single chemoreceptor responsive to energy in general. Data reported by Deutsch and colleagues support the argument for chemoreceptors with nutrient-specific sensitivity. Deutsch and Tabuenaz9have tested for satiation and demonstrated that rats can distinguish intragastric infusions of amino acids from infusions of breakdown products of oil emulsion (see the article by Novin and VanderWeele*l for data in support of nutrient-specific sensitivity). Other data support the existence of chemoreceptors with nutrient specificity.
Glucostafic Theory According to the glucostatic theory, glucose (together with insulin’”) and the size of glycogen reserves9*are monitored and regulated in the control of food intake. Glucose is the primary metabolic fuel in the CNS, thus it seems reasonable to assume that glucose can act directly on the brain. Centrally, there is support for the concept of glucoreceptor mechanismsToo operating in the shortterm control of feeding by producing hunger signals when glucose utilization is low in the ventromedial hypothalamus (VMH)54.83 and the caudal especially the nucleus tractus solitarius” (see study by OomuraMfor additional evidence that glucose directly affects the activity of hypothalamic sites involved in the control of food intake; also see study by Scharrer and LanghanslUofor further discussion of CNS glucoreceptors) and the caudal especially the nucleus tractus s ~ l i t a r i u s . ~ ~ Chafetz and co-workersZ2have reported an association between decreased glucose availability and increased norepinephrine turnover in the hypothalamus. Activity of the alpha-2 noradrenergic system in the paraventricular nucleus (PVN) is positively correlated with an animal’s total daily food intake.6’Injection of norepinephrine or the alpha-2 agonist clonidine into the PVN stimulates food intake, especially carbohydrate intake, and restores circulating levels of glucose. This effect, which is accompanied by decreased energy expenditure, is dependent on and potentiated by corticosterone.lO, 61 There is also support for the existence of hepatic glucoreceptors.8z,yR Infusion of 2-deoxy-D-glucose (2-DG), an inhibitor of glucose metabolism, into the hepatic-portal system of the intact rabbit stimulates feeding to a greater extent and with a shorter latency to meal initiation than do comparable injections into either the jugular vein of intact rabbits or into the hepatic-portal vein of vagotomized rabbits.82Conversely, intraportal infusion of glucose has been shown to suppress food intake in food-deprived rabbits, and this effect can be blocked by vagotomy.8’ Hepatic receptors are able to distinguish among energy-yielding fuels, and this suggests a special role for glucose because the effect of intraportal
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glucose in suppressing food intake in the deprived rabbit was greater than were the effects of glycerol or amino acids.8l Electrophysiologic data also indicate that hepatic signals for hunger and satiation are relayed to the brain by vagal afferents. Niijima78has shown that the infusion of glucose or its metabolite pyruvate into the hepatic-portal circulation of the guinea pig decreases hepatic vagal afferent firing rates, whereas intraportal infusion of 2-DG increases hepatic vagal afferent firing. Considerable data suggest a causal relationship between spontaneous transient declines in blood glucose and meal initiation. Louis-Sylvestre and LeMagnen=,66 first reported that blood glucose decreased prior to spontaneous meals in rats, and this effect has been replicated by Campfield and colleague^.^^ When glucose is infused intravenously to block partially the premeal decline in blood glucose, meal initiation is significantly delayed,ls but meal size is not affected.'Ol Campfield and SmithI9have concluded that blood glucose dynamics per se provide the signal for meal initiation because intravenous infusions of other substrates (amino acids, ketone bodies, hexoses) after the premeal glucose decline has begun do not affect latency to meal initiation. Normal transient declines in blood glucose occur following total subdiaphragmatic or hepatic vagotomy, indicating that this signal is not dependent on the efferent vagus.19 However, meal initiation did not occur following a decline in blood glucose in approximately 45% of the trials in both vagotomized groups, indicating that detection of the transient decline by vagally innervated peripheral glucoreceptors is important in coupling meal initiation to the blood glucose dynamics. A transient spike in insulin levels has been observed immediately prior to the transient decline in blood glucose that precedes meal initiati~n.'~ Insulin can act either to stimulate hunger or to suppress food intake.42, 90 When the transient spike in insulin was induced experimentally by an acetylcholine analog, it was followed by a transient decline in blood glucose that mimicked the pattern of blood glucose before spontaneous meals, and this manipulation also resulted in meal initiati~n.'~ Consistent with these results, Vasselli and Sclafani115 have reported that tolbutamide, which stimulates endogenous insulin release, produces hyperphagia in rats. However, Vasselli (personal communication) has found that the hyperphagic effect does not occur until the rat has become hypoglycemic. Similarly, Woo and co-w~rkers"~ have reported data in humans indicating that increased insulin levels that do not produce hypoglycemia also do not stimulate appetite or hunger. Additional studies have been performed by Rodin and colleagues95and Friedman and G ~ a n n e m a nData . ~ ~ reported in the rabbit have shown that a spike in acute endogenous insulin levels that is sufficient to produce a precipitous decline in glycemic levels but not absolute hypoglycemia is associated with increased food intake following fast intraduodenal glucose infusion." On the other hand, moderate elevations in acute endogenous insulin levels that are insufficient to produce a significant reduction in glycemic levels below baseline produce a suppression of food intake following intraduodenal infusions of glucose at a slow rate in the rabbitj4 Lipostatic Theory
The lipostatic theory makes the assumption that receptors in the CNS monitor and regulate circulating levels of fat metabolites (e.g., fatty acids, glycerol, and 3-hydroxybutyrate)which signal the size of body fat depots. Consistent with this theory, Oomuras4has reported that free-fatty acids directly affect the firing rates of hypothalamic sites involved in the control of food intake. In
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addition, several investigators have shown that manipulations that either increase or decrease the size of fat depots result in compensatory hypophagia or hyperphagia, respectively.88,loo It has been proposed that this change in food intake together with a change in metabolic rate functions to return body fat depots to normal size, thereby integrating the control of body fat with the control of food intake. Although it has been demonstrated that the compensatory decrease in food intake observed in rats recovering from insulin-induced obesity is associated with an increase in blood levels of fatty acids, glycerol, 3-hydroxybutyrate, and glucose,4O,92 it has further been shown that the hypophagic effect cannot be blocked by either antilipolytic drugsgZor hepatic vag~tomy.~’ In addition, Egli and co-worker~~~ have shown that the compensatory hyperphagic response to a manipulation that has decreased the size of fat depots also cannot be inhibited by hepatic vagotomy. Considered together, these results lead to the conclusion that hepatic receptors as well as their afferents may not be necessary in the lipostatic control of food intake?’, I w Evidence suggests that insulin may be an important humoral factor by which the periphery communicates with central body weight control mechanisms. Woods and have proposed that insulin informs the brain about body fat depot size and links the control of food intake with long-term control of body fat reserves. A.considerable body of evidence has demonstrated that plasma insulin levels co-vary with the degree of adiposity,’21including data in humans showing that blood insulin is elevated in individuals with hypertrophic 0 b e ~ i t y .Woods l ~ ~ and co-workers121have demonstrated that very low doses of insulin infused into the lateral ventricles of rats and baboons produce a decrease in food intake. A nutrient-specific satiety effect of insulin has also been demonstrated by Arase and colleagues,2 who reported that intraventricular insulin infusion suppressed food intake in animals maintained on a high-carbohydrate diet but not in animals fed a high-fat diet. It has been suggested that insulin may leak from the ventricles to the VMH, which contains specific receptors for binding insulin, or, alternatively, that insulin may be actively taken up from the cerebrospinal fluid by cells located in the ventricle wall and having connections with the VMH.Io7Insulin binding in the VMH can be reduced by food and Plata-Salaman and Oomuras9 have demonstrated that intraventricular insulin infusion suppresses food intake in free-feeding rats but has no effect in food-deprived rats. Strubbe and Meinlo$have shown that specific insulin antibodies infused into the VMH stimulate feeding behavior during the rat’s active feeding period (dark phase) but not during the light phase. The data described previously have led to the conclusion that insulin may be an important factor integrating the control of food intake with the control of adiposity. Strubbe107has concluded that this lipostatic control mechanism sets the “motivational background for feeding behavior,” and that superimposed on this long-term mechanism are short-term signals in the control of food intake operating on a meal-to-meal basis. The gene product of the recently cloned mouse obese (oh) gene has an important role as part of the signaling pathway in the regulation of adipose tissue mass.62~68,*22 The 0 8 protein, which has been termed le~tin,5~ is a hormone secreted by adipocytes. Both central and peripheral injection of microgram doses of leptin produce a reduction in food intake and body weight in oh/ob and dietary-induced obese mice but not in db/db obese mice.*O The behavioral effects following the central administration of leptin led Campfield and colleagues to conclude that the OB protein can act directly on neural circuitry that controls feeding and energy balance.zoLike insulin, leptin co-varies with the degree of
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adiposity.24,33 This correlation would be expected because the level of secreted leptin is apparently regulated by insulin.62 Other Homeostatic Theories
Historically, most of the emphasis in the control of food intake has been placed on the study of (1) glucose utilization according to the glucostatic theory in the short-term control of food intake and (2) on the metabolism and storage of body fat according to the lipostatic theory in the long-term control of body weight. It has always been assumed that these two mechanisms are coordinated and complementary, and it is of interest that the brain's adrenergic system has been implicated in both the glucostatic and the lipostatic controls of food intake and body weight.IooHowever, as far back as 1961, work by Ugolev and Kassil"* suggested that a common metabolic pathway for fuels may be important in the control of food intake.36More recently, a considerable body of research has focused on oxidative phosphorylation and electron transport, and the data suggest that the liver integrates control of food intake across metabolic fuels. Several investigators have reported that, independent of fuel type, decreases in oxidation are associated with hunger, and increases in oxidation are associated with ~ a t i e t y . ~77,1M) ~ , These ~ ~ , ~data ~ , are consistent with the energostatic theory first proposed by Booth7in 1972. Moreover, the heat generated by the metabolism of nutrients would increase body temperature, which, in turn, would suppress food intake according to the thermostatic theory.lo7 G e i ~ e l m a nhas ~ ~ previously reported seemingly paradoxical hyperphagic effects following fast infusions of hexoses into either the duodenum or hepaticportal vein. Novin and c o - ~ o r k e r shave ~ ~ more recently reported that fast infusion of either glucose or fructose into the hepatic-portal vein of rabbits increases lipid formation, reducing mitochondrial uptake and glycogen formation, and replicates the hunger-enhancement effect. Slow hexose infusion, which has consistently produced a feeding suppression effect, is associated with substrate uptake into mitochondria and glycogen with reduced uptake into fat. These findings all are consistent with the positive correlation reported between mitochondrial oxidation and satietyImand can be incorporated into the energostatic theory as well. Peptides and Hormones Released in Response to Nutrients in the Gastrointestinal Tract
Putative Satiation Signals. A number of peptides that are released during or after a meal (Table 1)have been implicated in providing signals for satiation and satiety, often for specific nutrients. These peptides can be released to act locally in the periphery in a paracrine fashion, or they can be released into the vasculature to act in an endocrine manner.8RAdditionally, these peptides may be released in the brain to act centrally. Among the gastrointestinal peptides, cholecystokinin (CCK) has been the most extensively studied. In 1973 Gibbs and c o - ~ o r k e r sfirst ~ ~ reported that intraperitoneal administration of CCK suppressed food intake in rats. This group subsequently reported that rats exhibit the entire normal behavioral sequence of satiety following peripheral injection of CCK.' More recently, the satiation and satiety effects of CCK have been shown in a number of species including and it has been shown that CCK especially inhibits carbohydrate intake. The satiating effects of CCK seem to be physiologic because antibodies to CCK and CCK receptor antagonists produce an increase in food intake.x5,88,93
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Table 1. PEPTIDES AND HORMONES IMPLICATED IN THE CONTROL OF FOOD INTAKE Stimulation of Food Intake
Suppression of Food Intake
Aldosterone Dynorphin Beta-endorphin Beta-casomorphin Corticosterone Galanin Growth hormone-releasing hormone Insulin Neuropeptide Y Peptide YY
Anorectin Bornbesin Calcitonin Calcitonin gene-related peptide Cholecystokinin Corticotropin-releasing factor Enterostatin Gastrin-releasing peptide Glucagon Insulin Neurotensin Oxytocin Somatostatin Thyrotropin-releasing hormone Vasopressin
During a meal, CCK is released from the duodenal mucosa in response to food and acts on CCK-A receptors in the gut. Peripheral CCK decreases the rate of gastric emptying and thus contributes to gastric d i ~ t e n s i o n An . ~ ~important effect of peripheral CCK in producing satiation and satiety may be that it is acting on CCK-A receptors to produce pyloric constriction to inhibit gastric emptying. Feeding also stimulates the release of CCK in the brain where it can act on CCK-B receptors. Although some studies have suggested that central CCK-B receptors are less important than peripheral CCK-A receptors in meal termination, it has been demonstrated that CCK administered into the third ventricle or the VMH suppresses food intake.26,35 In addition, it has been reported in the baboon that CCK given centrally is more effective than intravenous administration in decreasing meal ~ i z e . 3 ~ The effects of peripherally administered CCK can be abolished by vagotorny,Z7,Io4 indicating that CCK acts on afferent vagal pathways. However, destruction of the nucleus tractus solitarius also disrupts the satiating effects of CCK. Because CCK-releasing neurons and CCK receptors are found along the entire chain from the intestines via the afferent vagal pathway to the nucleus tractus solitarius and from there via the parabrachial nucleus to the VMH, it has been suggested that CCK influences ingestive behavior at all of these levels.1o7 Interestingly, the injection of CCK into the VMH (which has a well-documented role in satiety13,91, 103, 116) suppresses food intake and increases sympathetic activity. Although not so well-studied as CCK, other peptides also may provide signals for satiation and satiety. Bombesin, neurotensin, anorectin, calcitonin, enterostatin, and corticotropin-releasing hormone have all been shown to suppress food intake when injected into the third ventricle or VMH. Bombesin has received considerable attention as a potential satiety signal, having been found to act as a potent suppressor of food intake across a number of species including Bombesin does not affect meal initiation but, rather, specifically acts to decrease meal size, suggesting that this peptide contributes to satiation and satiet~.~~ gear^^^ has demonstrated that glucagon suppresses food intake when given
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in low doses and seems to have some specificity for protein. The satiating effect of glucagon has been reported across species including humans,39,58,74 and it has been shown that this effect is vagally mediated.Io4Furthermore, following the suppression of food intake in response to glucagon, animals exhibit the normal behavioral satiety 49 The satiation produced by glucagon seems to be a physiologic effect because intraportal infusion of glucagon antibodies produces the expected increase in food intake.39 Another peptide that may be involved in satiation and satiety is enterostatin. Lin and c o - w ~ r k e r reported s~~ that intraperitoneal injection of this peptide before meal presentation did not affect meal initiation but specifically shortened the duration of the meal which was then followed by the normal behavioral satiety sequence. Enterostatin, along with corticotropin-releasing hormone and vasopressin have each been demonstrated specifically to inhibit fat intake. Somatostatin, also has been reported to suppress food intake across species,@ but M ~ r l e has y~~ reported that it can produce nausea in humans. Additional peptides and hormones that have been shown to suppress food intake are listed in Table 1. The reader is referred to reports by Bray9 and Plata-Salamana8for further discussion of putative satiation and satiety peptides and of the nutrient-specific satiety effects of peptides and hormones. Plata-Salaman has reviewed putative satiety growth factorsa6and putative satiety immunomodulators.87Several investigators have studied the combined effects of two or more putative satiety peptides and hormones, and the data suggest that these putative satiety factors are interacting to suppress food intake." Putative Hunger Signals. Although less is known about the role of peptides in hunger (as compared with the role of peptides in satiation and satiety), several peptides seem to act as hunger stimulants. Opioids (beta-endorphin and dynorphin) stimulate food intake by acting directly on CNS structures that are known to be involved in the control of food intake (VMH, PVN, nucleus accumbens, and a m ~ g d a l a ~whereas ~), opioid antagonists inhibit eating. Betaendorphin, dynorphin, and beta-casomorphin have hunger-stimulating effects for highly palatable foods with some specificity for Neuropeptide Y stimulates food intake when delivered into the VMH, PVN, or lateral hypothalamus but does not act peripherally.60This peptide specifically stimulates carbohydrate intake, is most potent at the beginning of the rat's active feeding period, and is dependent on circulating levels of corticosterone.61 Leibowitz6I has discussed the role of corticosterone in stimulating a specific carbohydrate appetite. Galanin can stimulate a specific appetite for fat or carbohydrate. The carbohydrate-stimulating effect is short-term and occurs at the beginning of the active feeding period in the rat.61This effect is dependent on circulating corticosterone and the rapid release of norepinephrine in the PVN.61The role of galanin in stimulating fat appetite in rats is the more potent and long-term effect. Galanin stimulates fat appetite independent of either corticosterone or norepinephrine. However, the fat appetite stimulated by galanin may be associated with aldosteAldosterone strongly enhances fat intake in rats and, to a lesser extent, potentiates carbohydrate intake.3o, SUMMARY
This article has examined the control of food intake as a physiologically complex, motivated behavioral system. During the past four decades, considerable progress has been made in understanding putative signals for hunger,
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satiation, and satiety, although hunger signals have proven to be more difficult to identify. The putative physiologic controls of food intake include positive and negative sensory feedback; gastric a n d intestinal distension; the effects of nutrients, nutrient reserves, a n d metabolism i n producing signals t o the liver or brain; and peptides a n d hormones released in the gastrointestinal tract or the brain. However, food intake is not influenced solely b y physiologic signals for hunger, satiation, and satiety. To comprehend feeding behavior more thoroughly, current physiologic models must be extended to include modulating factors such as feeding-associated responses adapted through learning processesZ7and the influence of circadian rhythms,'05 which can be dominating over hunger, satiation, and satiety signals.
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