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Critical Reviews in Food Science and Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/bfsn20

The influence of food on food intake: Methodological problems and mechanisms of action a

Karla L. Roehrig & Mark I. Friedman B.S., Ph.D.

b

a

Department of Food Science and Technology , The Ohio State University , Columbus, Ohio, 43210 b

Monell Chemical Senses Center , 3500 Market Street, Philadelphia, PA, 19104 Published online: 29 Sep 2009.

To cite this article: Karla L. Roehrig & Mark I. Friedman B.S., Ph.D. (1991) The influence of food on food intake: Methodological problems and mechanisms of action, Critical Reviews in Food Science and Nutrition, 30:6, 575-597, DOI: 10.1080/10408399109527557 To link to this article: http://dx.doi.org/10.1080/10408399109527557

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Critical Reviews in Food Science and Nutrition, 30(6):575-597 (1991)

The Influence of Food on Food Intake: Methodological Problems and Mechanisms of Action Karla L. Roehrig Department of Food Science and Technology, The Ohio State University, Columbus, Ohio 43210

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Referee:

Mark I. Friedman, B.S., Ph.D., Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104.

ABSTRACT: Emphasis has been placed on the understanding of the regulation of food intake in the hope of aiding the battle against obesity and of helping to ameliorate the anorexia of cancer and eating disorders. Available data suggest that the regulatory system is multifaceted and complex. This review focuses on current research on the regulation of appetite and satiety by carbohydrates, fats, and proteins as well as by artificial sweeteners. Some methodological problems and potential mechanisms of action at the biochemical level are iscussed. Evidence suggests that organisms are more successful in defending against calorie dilution than in adjusting to increases in calories. The implications of that defense relative to the use of ersatz nutrients are explored. KEY WORDS: food intake, carbohydrates, fat, saccharin, aspartame, appetite, food intake, satiety, central and peripheral control mechanisms.

I. INTRODUCTION In an increasingly weight conscious Western world, there has been a greater focus on understanding the control of appetite, food intake, energy balance, and satiety. Although much em-, phasis has been on controlling appetite and food intake in order to effect body weight reduction in the battle against obesity, the opposite side of the question is also of considerable medical importance. The anorexia seen in anorexia nervosa and in cancer has profound consequences for those with negatively impaired appetite/intake controls. An additional issue arises with the use of ersatz nutrients, for example, artificial sweeteners and fats: how do these compounds impact the regulation of food intake? It is well accepted that both central and peripheral mechanisms are involved in regulation of food intake. 13 Since body weight seems to be fairly tightly controlled in adult animals of most species, except for certain seasonal variations

(e.g., hibernation) and physiological adjustments necessitated by pregnancy and lactation, there must be a complex set of interacting factors involved in control. Regulation of appetite and food intake in humans likely has both genetic and cultural components, and much of what is known is inferred from animal studies. Further, it is clear that certain nutrients have a greater satiety value than others. The understanding of the regulation of food intake was much more clear-cut several decades ago: appetite (the desire to eat) was believed to be controlled in the lateral hypothalamus, while satiety as evinced by the cessation of eating was controlled in the ventromedial hypothalamus.4 It is now widely accepted that while the hypothalamus is undoubtedly involved in the regulation of food intake, a yin-yang mode of control by the hypothalamus is inadequate to explain the experimental observations5 and that much of the control attributed directly to the hypothalamus is a secondary effect of other mechanisms.

1040-8398/91/$.50 © 1991 by CRC Press, Inc.

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The available evidence indicates that both sides of food intake (appetite and satiety) are controlled processes. Since adequate long-term intake of required nutrients and calories is an absolute necessity for the continued existence and well-being of an animal, it is reasonable to suppose that more than one mechanism exists to encourage food intake and to override suppression of food intake. Overabundance of food has not been the normal situation faced by most species over their evolutionary history, and it is possible that many of the satiety mechanisms are very short term. Our evolutionary heritage thus militates against our desire to control aggressively our intake of calories. Regulation of food intake by specific macronutrients likely involves very rapid as well as moderate term central and peripheral control mechanisms. Very long-term controls, however, may not be dependent upon nutrients at specific meals but rather are more likely to be linked to body composition in some way. Regulation of food intake is an exciting, multifaceted field, and several recent conferences have been held on various aspects of appetite and satiety. Experimental approaches range from the biochemical to the psychological. Current research findings are described in this review that focus mostly on studies since 1988 on the regulation of appetite and satiety by specific nutrient- or nonnutrient-containing foods in nonruminant species. The impact of the methodology used on the interpretation of available data will be considered because it very directly impacts interpretation of results. Suggested mechanisms of action at the biochemical/cellular level and the implications of the use of low-calorie foods in reducing nutrient intake will be discussed. It should be noted that some factors have been more widely studied than others. That does not imply, however, that they are the only or even the main factors for regulating food intake. Throughout this article, the reader is referred to a number of excellent reviews on issues in food intake regulation not specifically dealt with here, such as the roles of restrained eating,6"8 cancer cachexia,9-10 sensory properties of food,1115 and the effect of pharmacological agents on appetite and satiety.16"19

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II. IMPACT OF METHODOLOGY A number of methodological problems complicate the study of the regulation of food intake. In considering the literature dealing with this area, it is important to keep in mind the substantial effects of various experimental designs may have on interpretation of results. These include such parameters as species variations, circadian rhythms, determining intakes accurately, effects of dilution of calories, effects of exercise separating central from peripheral effects, and establishing direct, causal links in defining mechanisms. These problems are compounded by the possibility of artifacts induced by the setting of the research, i.e., the laboratory or a more natural setting. The following discussion will consider some of these parameters in greater detail. Rolls20 enumerated these problems relative to sweetener research, but her comments apply more broadly to all appetite and satiety research.

A. Determining Intakes In short-term, on-site studies in humans, it is possible to determine accurately the amount of food consumed. It is less easy to rule out the social or self-imposed restraints that may lead to alterations in food intake even in controlled laboratory situations. While the problems can often be circumvented in the short term, they may cause conflicts with the ethics of obtaining fully informed consent from participating subjects if those subjects are misled about the purpose of the studies. In free-living subjects on longer duration studies, the problem is more complicated. Schoeller21 has recently reviewed problems in validation of self-reporting of dietary energy intake based on energy expenditure studies using doubly labeled water and assuming that energy efficiency did not change. It was argued that in developed countries, intakes are probably often underestimated that would tend to overestimate the effect of some parameter on satiety. On the other hand, in underdeveloped countries there may be a tendency to overestimate food intake, thus diminishing the apparent effect of a factor on satiety. This methodological problem may in

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part be compensated for by simultaneous determination of body weight changes and body composition. Over short periods, degree of hydration and gut fill could affect these measurements to a significant degree. With animal studies, some of these problems can be effectively eliminated, while others are substantially more difficult to overcome. Determining food intake, for example, can be done using a number of protocols ranging from simple to elaborate.22 One must consider, however, whether the experiment should be performed using food-deprived or nonfood-deprived animals. Difficulties in interpretation may arise if such factors as meal initiation, meal duration, and meal frequency are not taken into account. Davis and Smith23 have suggested that for liquid sugar solutions, analysis of lick rate can provide information about palatability (initial rate of ingestion) and development of satiety (constant rate of ingestion). Attempting to compare solutions of differing osmolarities, however, could complicate elucidation of a mechanism of action. Further, motivation for eating is less easy to establish in animals. From a physiological viewpoint, what matters is energy intake and energy expenditure over some relatively long period of time in the absence of such complicating factors as changes in ambient temperature or the amount of exercise. It is over the long term that the importance of the regulation of food intake becomes apparent. Kissileff and Van Itallie in their review24 addressed the issue of consistency of food intake in a variety of species over time. From a mechanistic view, meal initiation, duration, and frequency are extremely important in establishing the mechanisms involved in appetite and satiety at the biochemical level. It is with these parameters as markers and endpoints of the process that the biochemical changes can be investigated in the causal sense and placed in perspective in the temporal sense.

B. Allowing for Effects of Circadian Rhythms Food intake patterns vary dramatically among species ranging from nibbling to meal eating with a variety of behavior in between. There is also

variation in the photoperiod in which the major amount of food is consumed. One must take into account the total calories consumed throughout a 24-h cycle as well as the size, frequency, duration, and interval between meals. With species accustomed to nibbling, this may pose an especially difficult problem in the study design because of the randomness of feeding periods.25 Savory has described an operant conditioning paradigm based on a study of the effects of ascending and descending series of procurement costs in hens that reduces the randomness in feeding.25 This complexity can obviously be abolished by shifting to a mandatory meal pattern. Although nibblers can be adapted to meal eating, it should not be assumed, however, that all the parameters impacting appetite and satiety will remain unchanged if a normal meal eating pattern is imposed. At what time during the photoperiod the experiment is conducted may dramatically influence results.26 This is particularly true of comparisons between different types of the same species. For example, Ho and Chin27 reported that genetically lean or obese mice had not only altered total intakes but also a different temporal intake pattern. In addition to genetically caused variations, it is necessary to rule out drug-induced changes in circadian rhythms when evaluating research on the effects of drugs on food intake. There may be shifts in intake rhythms due to surgical procedures. For example, Shinomura et al.28 recently reported that in ovariectomized rats, weight gain was a function of the time of feeding. While the gain might have been altered by a change in metabolic efficiency, previous research indicated altered food intakes in these rats. Smith et al.29 have reported time-dependent effects of IV fructose on blood glucose levels and subsequent feeding behavior. Even during the feeding period, differences in macronutrient preferences have been reported in the rat as well as a timedependent calorie compensation ability.30 One might therefore draw rather different conclusions about the effect of a particular agent on food intake, depending upon the time of day when the experiments had been performed. It has been assumed that a number of external factors might contaminate the experimental process. De Castro31 has published data that indicate

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that multivariate analyses can be used to assess eating behaviors in a free-living situation. Such an approach may simplify interpretation of data from appetite/satiety studies with a number of interacting factors.

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C. Substituting or Diluting Calories If one wishes to consider the impact of a particular nutrient on food intake, there are several difficult choices to make concerning experimental design. These have been reviewed by PiSunyer.32 The first is whether to dilute the particular nutrient with a noncaloric source; for example, substituting fiber for starch thus diluting calories. The second alternative is exchanging calories from one nutrient for those of another as would occur when carbohydrate calories are replaced by an isocaloric amount of fat. Neither of these approaches is physiologically innocuous. In the first case, the calories themselves rather than a particular nutrient might alter food intake, or the ratio between calories from two nutrients could be important. One must also consider that if the diluent is fiber, colon fermentation of the fiber may occur, and the products of fermentation may themselves alter food intake. In the second case, it is generally impossible to attribute an effect to the nutrient of interest when it is equally likely that the change in the second nutrient that is being substituted for the first is responsible. Also, as in the first case, it may be the ratio of two nutrients that is important rather than the absolute amount of either. In addition, changing the ratios of macronutrients may alter the palatability or sensory properties of the diet, resulting in changes in intake. 3334 Ramirez and Friedman35 have discussed the potential interaction of nutrients that may lead to hyperphagia. One must also consider whether the length of time it takes to eat a diet plays a role in satiety. It has long been postulated that low-energy-density diets prolong eating time, and thus satiety is reached at a lower total calorie intake than for high-energy-density diets. Using human subjects, Duncan et al.36 evaluated the effects of lowand high-energy diets on intake, satiety, and duration of feeding on male and female lean and obese adults. They found that the two diets were

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equally acceptable to both lean and obese groups. Eating time was 33% longer on the low-energydensity diets, and satiety was reached at lower total calorie intake for both lean and obese subjects. Based upon a satiety rating scale, subjects on the high-energy diets reported greater satiety ratings and lower hunger ratings after breakfast and lunch. Since these subjects could consume food only during set times, it is not clear whether people in a free-living situation would compensate for the difference in energy density with extra snacks. Moreover, a single nutrient cannot be studied over extended periods of time because deficiencies of other required nutrients would be induced. Sometimes, this can be a very rapid effect as in the well-established cessation of eating in dogs during amino acid imbalances. A number of investigators have recently discussed the control of food intake at the level of calories. In six adult males studied for 2 weeks in a residential laboratory setting, Foltin et al.37 found that the subjects compensated readily for covertly reduced calories but not for covertly increased calories. The rapidity of caloric compensation was in contrast to several earlier studies [for a review see Foltin37], which the authors suggested was due to subject-controlled food intake in a natural setting as opposed to the use of liquid diet or set meal times. Since this study varied both carbohydrate and fat calories and the subjects had free choice of food items, it was not possible to ascribe the compensation to a particular type of nutrient. Lack of direct contact of the subjects with the experimenters during the experimental period eliminated some of the psychological/social difficulties that might otherwise have occurred. In another study of teenage boys in a boarding school, it was reported that a 200 kcal difference in a strawberry mousse was not compensated for at dinner an hour later, but after 5 d of habituation to the snack, calorie compensation was exact.38 Another consideration in evaluating intake is the form of the food or nutrient to be tested. It has been widely reported that liquid diets do not produce the same physiological effects as solid food. Engell39 has recently reviewed the relationship between food and water intake. Considerable data exist in animal studies to suggest that

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food and water intake are fairly tightly coupled at least in temperate environments. In Engell's 2-d study using young, adult males, it was found that about 2/3 of the fluid intake occurred with meals and that restricting liquids resulted in the voluntary reduction of food intake. The restriction was uniform across calorie groups (carbohydrate, fat, and protein) as would be expected in a mixed meal situation where subjects could not segregate nutrients. Based upon a lack of difference in hedonic ratings of food in fluidrestricted and nonrestricted groups, Engell argued that an increase in palatability of food did not account for the higher intakes when fluid was not restricted. It is clear from this study that attention should be paid to fluid intake and to relative hydration levels in test meals in any food intake studies. Another consideration is the dietary state of the experimental subjects. If they are fasted and are very hungry, it would be difficult to demonstrate an increased appetite induced by a compound beyond the control. On the other hand, if the subjects are well-fed, it may be difficult to demonstrate that intakes are substantially depressed more than the controls by some compound. In addition, the duration of a fast or a period of reduced calorie intake may influence a number of food intake regulatory mechanisms involved. For example, Yang et al.40 reported that long fasts (8 to 25 d) in obese and lean rats reduced body stores of glycogen, fat, and protein, and a change in food efficiency was a function of fat cell size. The lipostatic theory of appetite regulation postulates a role for body fat stores in food intake control. Thus, dietary regimens that significantly alter fat cell size/number might be expected to have additional impacts on intake behavior both in quantity and type of macronutrient ingestion. Finally, one must consider the level of activity of the experimental subjects, bearing in mind that this parameter may be time, gender, and species specific. Compensatory intake in response to long-term exercise has been reported in lean but not obese women (see Reference 41). With strenuous exercise, however, food intake after an exercise bout was reduced in lean but not obese women.41 In a recent study comparing lean males and females, Staten42 observed partial

calorie compensation in males but not in females. Differences in results from various studies could be a function of differing levels of exercise intensity, durations of experiments, or time of food intake relative to the exercise period. In addition to energy expenditure that is directly the result of exercise, there may be an effect on metabolic rate.43-44 Nicolaidis and Even45 have reviewed the possibility that food intake is under the control of muscle contraction-free metabolic rate.

III. CARBOHYDRATES AND FOOD INTAKE Interest in the role of carbohydrates in food intake stems from several factors. As people have been advised to reduce their percent of calories from fat and increase their fiber intake, that necessitates increasing calories from carbohydrates and perhaps from proteins, although price and metabolic constraints usually indicate increases in carbohydrates. The mechanisms whereby dietary fibers exert their actions, including those on appetite and satiety have been investigated widely.46 Finally, there has been a substantial shift in our patterns of carbohydrate consumption. For example, high-fructose corn syrups are being favored increasingly in the food industry over high-glucose corn syrups for technological reasons.47 More striking is the dramatic and widespread increase in the use of noncarbohydrate artificial sweeteners, e.g., saccharin, aspartame, and acesulfame-K. The bulk of this use is motivated by the desire to reduce calorie intake and particularly the intake of simple sugars. This section of the review examines the research on the role of carbohydrates and their substitutes on food intake.

A. Complex Carbohydrates Addition of fiber to human diets has been recommended to ameliorate a variety of conditions, including diverticular disease, abnormal glucose tolerance, elevated serum lipids, and risk of colon cancer.46 Fiber has often but not always been found to reduce food intake (for a review

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see Levine et al. 48 ). Understanding the effects of fiber is complicated by the multiplicity of fiber types. Although fibers can be lumped into soluble and insoluble groups, this does not necessarily imply a physiological mechanism. Dietary fiber might work in multiple ways: by gastric distension, triggering release of regulatory peptides, causing bloating in the colon, products of fiber fermentation, or regulation via some as yet unidentified compound bound to fiber. Effects of pectin, a soluble fiber, have been reviewed recently.49 Although pectin delays gastric emptying and was reported to increase selfreported satiety in obese subjects, it did not raise levels of two peptides believed to be important in regulating food intake, cholecystokinin (CCK) or pancreatic polypeptide.50 It should be considered, however, that this study was conducted using obese humans where there could be some impairment of satiety mechanisms. The subjects also were not adapted to high-fiber diets, and only the two test meals were randomly provided. Comparison to normal subjects at multiple times during the day would be helpful. Levine et al. 48 evaluated the effect of highor low-fiber cereals at breakfast on the subsequent ingestion of food at lunch and found that fiber reduced calorie intake at lunch. Although they reported increased breath hydrogen, a measure of colonic fermentation, there was not a well-defined relationship between hydrogen production and food intake. Blundell and Burley51 reviewed a number of studies on fiber and food intake and found that the majority (12/15) reported reduction in hunger with fiber feeding independent of fiber source. Studies to date clearly indicate an effect of fiber on food intake, and the reduction in food intake might be sufficient to account for some of the other putative effects of fiber. The mechanism(s) of the effects of fiber on food intake, however, remains largely a mystery. Since different fibers have distinguishable impacts on gastric emptying, GI transit rates, and colonic fermentation, it would seem unlikely that a single mechanism of action could explain the available data.

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B. Simple Sugars In humans, the consensus is that simple sugars are not especially associated with the development of human obesity.52 However, in rats, sugar in solution or in gels induces hyperphagia and weight gain compared to chow-fed rats. Scalfani53 has reviewed findings that led him to conclude that postingestive effects of carbohydrates are important in carbohydrate-induced hyperphagia, and that taste alone cannot account for the effect. In an experiment employing chronic gastric catheters, Scalfani's group was able to sort out preference from aversion in a conditioning study with flavored corn starch hydrolysate and to determine that the preference was independent of taste. Sugar-induced hyperphagia is not restricted to the rat but has also been described in the rabbit.54 The mechanism of this effect, however, remains unclear. Insulin levels or level of glycemia are attractive possibilities, but Geiselman has argued55 that neither hyperinsulinemia nor hypoglycemia alone is a sine qua non for food intake. She suggested that perhaps two pathways (storage and "satiating") compete for absorbed glucose. Smith et al.56 infused fructose (IV) into cannulated female rats to test the specificity of hexose-induced delay of meal initiation. They found that the fructose effects were circadian rhythm dependent. Further, fructose was effective only when infusion resulted in declines in blood glucose. It has been suggested that an "appetite" for carbohydrate is induced by a regulatory loop in the brain involving 5-hydroxytryptamine (serotonin).57 This loop is envisioned to work as the result of a carbohydrate-induced rise in insulin that stimulates uptake of certain amino acids, thus lowering their serum concentrations, thereby enhancing the competitive uptake and subsequent conversion of tryptophan to 5-hydroxytryptamine by the brain. Fernstrom has pointed out several difficulties with this model.58 These include a lack of evidence of control over long-term carbohydrate intake levels, including defense of a certain level of carbohydrate intake and lack of

a selective effect on carbohydrate by fenfluramine that acts at the level of 5-hydroxytryptamine. Fernstrom also argued that such a loop is not likely the site of aspartame effects because of the enormous amounts of aspartame that would be required.

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C. Noncarbohydrate Sweeteners There has been increasingly widespread use of noncarbohydrate sweeteners. With the exception of World War II when artificial sweetener use was prompted by a limited supply of sucrose, much of the use of these products is motivated by an attempt to reduce caloric intake. While the metabolic fate, pharmacological effects, and hedonic responses of these sweeteners have been studied extensively, it is only recently that scientists have questioned whether these compounds do in fact lower food intake even when an individual is consciously substituting them for sucrose with that purpose in mind. Experiments in animals and humans suggest that substitution of artificial sweeteners does not decrease food intake in terms of total calories. One difficulty in interpreting data from these studies arises from trying to separate palatability due to sweetness from calories. Blundell59 has proposed an experimental 2 x 2 design comparing calories and sweetness with at least two levels each. Most laboratory studies have not employed this design requiring greater inference in interpreting the data. The other approach is to assess self-reported artificial sweetener and nonsweetener use and calorie intake in free-living population groups. Interpretation of results from such an approach involves several key assumptions: intakes of both sweetener and food are accurately reported, and there is no difference in motivation, metabolism, etc. between groups being compared. Considerable evidence suggests that neither of these assumptions is valid. The more usual type of study has been conducted in a laboratory setting under more controlled conditions. In one study, Rogers et al.60 compared effects of 200 ml preloads of glucose, aspartame, saccharin, and acesulfame-K to water in young adults fasted about 4 h. They reported glucose to be effective in depressing hunger and desire to eat

and in increasing fullness. Except for the first few minutes after consumption, nonnutritive sweeteners increased subjective ratings of hunger and desire to eat and decreased feelings of fullness relative to water alone. Aspartame produced the most exaggerated responses. In a study by Rolls et al., reported initially at a symposium,61 and in more detail later,62 comparing high- and low-calorie jello and pudding sweetened with sucrose or aspartame, there was consistent but not statistically significant calorie compensation in a meal offered 1 h after consumption of the jello or pudding. Being informed or uninformed about the calorie content of the meal had no effect on the results. Studies have been conducted in children using liquid preloads63 or iced slurries.64 In the first study in young children (2 to 5 years), the effect of time after consumption of the preload was determined from 0 to 60 min. In this study, there was caloric compensation by sucrose, and aspartame was less effective than sucrose at suppressing subsequent food intake. Suppression was greater for nonpreferred than preferred foods as one would expect. In contrast, in the second study using older children (9 to 10 years), no caloric compensation occurred with sucrose compared to aspartame, and aspartame was also not different than cyclamate. The authors suggested that the form of the food they used might have resulted in finding no calorie compensation. It is also possible that the age of the children played a role, since 9- to 10-yearold males would be at or near a growth spurt and might be expected to have larger calorie needs and thus less control on food intake. Tordoff and Alleva65 tested the effects of aspartame or highfructose corn syrup-sweetened soda on food intake and body weight for 3 weeks in men and women. The aspartame-sweetened drink lowered calorie intakes of both sexes, but only men lost weight relative to the "no soda" controls. Somewhat surprisingly, both sexes on both types of soda reduced their simple sugar intake. There was partial calorie compensation in this study, but compensation was not greater for fructose than for aspartame. In a longer-term metabolic ward study, Van Itallie et al.66 tested the effects of caloric dilution with aspartame in obese and nonobese adults. They found a partial though not statistically

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significant caloric compensation when aspartame was substituted for sucrose. The investigators suggested that perhaps the initial intakes were elevated due to the novelty of the situation, thus potentially obscuring effects. It would have been useful perhaps to know whether there was a change in the body weight of the subjects over the course of the experiment. Since the subjects seemed to be consuming about 3400 kcal/d (calculated from data in the article), it would appear that over the course of the study, there should have been a measurable weight loss, assuming no compensation in metabolic rate or in energy expenditure. The potential mechanism(s) involved in the effect of aspartame on food intake have been discussed by Anderson and Leiter,67 particularly those based on the amino acid composition of this sweetener. From their studies, as well as previous work by others, they concluded that the amino acid constituents of aspartame are unlikely to account for any effects of aspartame on food intake. Fernstrom reached the same conclusion relative to 5-hydroxytryptamine.58 Saccharin has also been studied with respect to food intake. It has been recently reported68 in a study with adults that saccharin-sweetened yogurt stimulated food intake relative to plain yogurt, and that there was calorie compensation in the starch- or glucose-containing yogurt groups. A recent study in rats69 reported a substantial increase in food consumption and weight gain with saccharin-containing diets with the effects increasing with the duration of the experiment. The water content of the diet mediated the effects, but the investigator did not believe osmotic factors explained the findings. In a series of elegant experiments,70"73 Tordoff and Friedman examined the effects of saccharin in rats. Although several previous studies did not show increased food intake after saccharin consumption (for a review see Tordoff and Friedman70), in this study there was a decreased consumption in rats after a 10% glucose solution and increased consumption after ingestion of 0.2% saccharin or 0.45% NaCl. The investigators suggested that this discrepancy might have been due to the dietary state of the rats or the longer test duration since they did observe a lag in increased food intake in response to saccharin. In the second part of the

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experiment,71 Tordoff and Friedman sought to determine whether the saccharin-enhanced eating was prompted by the hypoosmotic saccharin solution by dissolving an equivalent amount of saccharin in isotonic saline compared to saccharin or isotonic saline alone. The use of an isotonic solution abolished the effect of saccharin. When the rats were treated with antidiuretic hormone intramuscularly and given saccharin, they also showed increased food intake. These data and work of earlier investigators suggest that the hydrational state of the animal is important in food intake. Whether it solely explains the saccharin effect, however, is cast into doubt by the finding that intubation of water (0 to 8 ml) did not significantly increase food intake. In the third part of the study,72 Tordoff and Friedman conducted experiments to determine to what extent learning due to sweet taste was responsible for the apparent effects of saccharin. They tested the hypothesis that effects were based on saccharin-dependent food flavors by studying saccharin-consuming rats with or without food flavor cues. It was found that saccharin consumption increased food intake independent of food flavors, although the authors suggested that there might be subtle interactions not visible because of statistical overlap. They did not find that rats drinking saccharin after eating showed a more powerful reinforcement of associative processes than rats drinking before eating, contrary to what would be expected in forward conditioning studies. This study used rats trained to eat for 2 h in the 8 to 10th h of the light period, and was designed to account for differences in eating time before offering saccharin. Since rats preferentially feed in the dark portion of the cycle, it is not clear what effect feeding during the light portion of the cycle might have had. In the last experiment of this series,73 these authors determined whether cephalic phase insulin release was responsible for saccharin-induced increases in food intake in three ways: (1) celiac or hepatic vagotomy or sham surgery, (2) extension of the time between saccharin intake and offering food, and (3) induction of diabetes by streptozocin. Only rats receiving hepatic vagotomy failed to demonstrate saccharin-induced food intake, leading the authors to conclude that some aspect of liver metabolism was responsible.

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They suggested that as the liver is progressively adapted to fuel storage, there is less substrate available for oxidation thus generating some signal that increases appetite. This work has been reviewed recently to put the findings into context for human studies.74 The implications of nutritive and nonnutritive sweeteners on long-term body weight have been discussed. Poirikos and Koopmans75 reported that in an 8-week study with ad libitum fed female, Sprague-Dawley rats, access to an 11% sucrose solution promoted weight gain relative to controls, while saccharin- or aspartame-fed rats did not. During a second 8-week period, rats receiving sucrose were switched to nonnutritive sweeteners and vice versa. The rats fed sucrose initially lost weight. Unlike shorter studies showing caloric compensation, the rats in this study did not increase caloric intake to compensate for maintenance of their higher body weights. Kanarek and Marks-Kaufman76 have reviewed some of the factors that can influence the effects of carbohydrate on food intake, including the form of the carbohydrate and the micro- and macronutrient contents of the diet.

IV. FATS AND FOOD INTAKE It has long been known that dietary fat delays gastric emptying. The mechanism(s) whereby fat affects appetite and satiety, however, is not completely understood. With the advent of dietary fat substitutes, there is increasing need to elucidate the role of fat in regulation of food intake and eventually to determine whether ersatz fats impact the intake of food as well. Scalfani has reviewed the effects of fat type, form, and palatability on food intake.77 He has suggested that some of the variability among experiments with respect to caloric compensation could be a function of the age, strain, and sex of the animal, as well as to differences in diet composition. Although palatability differences have also been frequently cited to explain data, it should be considered that short- and long-term palatability may be quite different. It would be unwise to generalize short-term studies to long-term situations. Infusion of corn oil emulsion (50%) into the jejunums or ileums of humans (healthy, nonobese

males) reduced food intake and the total time of eating.78 Only jejunal oil infusion reduced the rate of intake and sensations of hunger (as determined by subject scores on analog scales). Previous studies by Welch et al.79 have indicated that IV infusion of a similar oil emulsion did not alter food intake ruling out a direct effect of blood lipids. Walls and Koopman also concluded that blood lipids have little impact on food intake.80 This is also supported by data81 from patients receiving total parenteral nutrition where reports of hunger sensations were not different between lipid infusion and noninfusion days. There were, however, more aversive sensations during periods of lipid infusion. In a follow-up study, Sepple and Read82 tested the effects of ingesting a high- or low-fat soup on subsequent intake of two different solid meals 20 min later and found no effect. A high-fat breakfast did, however, reduce food intake and sensations of hunger at lunch 4 h later. There was no calorie compensation for the two meals, although others have not reported calorie compensation over a longer period if appearance and palatability are unchanged (for a review see Sepple and Read82). Since it was determined that little of the breakfast remained in the stomach by lunch, using scintigraphy with technetium sulfur colloid, and glucose levels had returned to fasting levels, it was deemed that gastric distension or blood glucose levels per se played a small role in regulation of satiety. In a slightly different situation,83 four different types of fat (safflower oil, olive oil, butter, or mediumchain triglycerides) fed at supper had no effect on glucose, insulin, or free fatty acid levels in response to a standard breakfast the following day. This suggests that dietary fat does not have a persistent metabolic effect. Diabetic rats reduced food intake to a greater extent than control rats in response to a fatty test meal,84 but gastric emptying was not well correlated with food intake particularly in normal rats. The effect was unlikely to have been due to absolute amounts of circulating triglycerides or ketones since the levels of these substrates were higher in the diabetic rats, and still these rats ate more than the controls unless challenged with dietary fat. Gregory and Rayner85 reported that the infusion of emulsified fat duodenally but not ileally

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inhibited food intake. They have suggested86 that control of gastric emptying may be a significant site of food intake regulation in the pig. Duodenal infusion of glucose or intralipid equicalorically delayed gastric emptying and paralleled reductions in food intake seen previously. The rate of infusion, however, affected the results. In a subsequent study,87 this group designed an experiment to determine whether cholecystokinin released by fat infusion was responsible for the satiety effect in the pig. To do this they injected a potent, specific CCK antagonist arterially into the pig. The antagonist reversed cholecystokinininduced inhibition of food intake but did not itself stimulate food intake. It was also effective against duodenal infusion of emulsified fat and monoglyceride but not against free fatty acid (oleic acid), glycerol, or glucose, suggesting that there may be cholecystokinin-independent mechanisms also involved in fat-induced satiety. CCK was released in rats by intragastric delivery of corn oil, beef tallow, fish oil, or medium-chain triglycerides (most effective of the group).88 The amount of CCK released appeared not to be a function of the degree of saturation but was sensitive to chain length. There may be considerable species variation in this respect, because in humans longbut not medium-chain triglycerides are most effective (for a review see Reference 88). Although protein has often been considered to be more important in CCK-dependent pancreatic secretion, these data as well as earlier data from this group suggest that fat (as well as carbohydrate) raise plasma CCK levels sufficiently high to stimulate pancreatic secretion. In corn oil, sham-fed rats, Weatherford et al.89 presented evidence that central dopaminergic Dl and D2 receptors are involved in sensory effects of corn oil based on studies with selective Dl and D2 receptor antagonists. It is interesting to determine whether animals or humans can specifically defend their intakes of fat under caloric dilution conditions. When fat calories were diluted with cellulose, streptozocin-diabetic rats were capable of compensating for changes in fat intake at both 25 and 50% levels of dilution.90 They did not compensate for protein dilution at both levels but rather compensated for calories by increasing fat calories. On the other hand, normal rats could compensate

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for both protein and fat. Since rats are capable of some hind gut fermentation of cellulose, it is not clear what effect the potential fermentation products might have had. Further, the rats in this study did not evince the same degree of diabetes as measured by blood glucose levels in the protein dilution group compared with the fat dilution group that also could have impacted the results. Earlier work in humans reviewed by Pi-Sunyer32 had indicated that there was a lack of ability to compensate for increased fat calories. Subjects ate more calories on high-fat diets and did not report differences in satiety. The role of dietary fat in the regulation of food intake is of special concern because it has long been argued that body fat is somehow involved in the long-term regulation of food intake. This is known as the lipostatic theory of appetite regulation. Many important concerns still exist relative to this theory. As discussed earlier, the control cannot simply be a function of circulating lipid levels because obese diabetics often have higher circulating lipid levels including free fatty acids and ketones and yet are hyperphagic. Friedman et al.91 have suggested that rather than circulating lipid levels, the rate of fatty acid oxidation might be a regulatory point for food intake. This suggestion was based on the observation that a carnitine acyl transferase I (CAT-I) inhibitor, methyl palmoxirate, increased food intake in rats on a high-fat diet composed of long- but not medium-chain fatty acids. Since medium-chain fatty acids do not require CAT-I for entry into the mitochondria for subsequent oxidation, this would be the expected result. These data are also consistent with the observation that CCK release was a function of fatty acid chain length.92 Ramirez93 has argued that dietary hyperphagia should be self-limiting as soon as moderate obesity is attained, and has examined the data contradicting this hypothesis. He has suggested several possibilities to explain the conflict, including that diet may supersede normal control points and that body weight may not be a good indicator of dietary effects on body fat content. The age of experimental subjects may also impact the influence of adiposity on food intake. The effect of overfeeding in young (4-week-old) rats has been examined.94 This study design is

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important because it is a step toward evaluating the potential effect of "youthful food indiscretions" on long term regulatory control of food intake. Young rats were fed ad-lib or by oral gavage 100 or 150% of the ad-lib amount for 1 week. Rats from each group were examined at 0, 4, and 29 d after the gavage period. Overfed rats were fatter than the other two groups and experienced declines in food intake; by 29 d there was no difference in weight or body composition of the groups. These results suggest that compensation occurs even during growth periods. It would be interesting to repeat this experiment using young lean and obese rats to measure the ability to compensate in the obese animals during a growth period. Based on available evidence in adult animals, it seems likely that compensation would be impaired in the obese animals.

V. PROTEINS AND FOOD INTAKE Unlike carbohydrate or fat for which there is no specific dietary requirement, protein is required in varying amounts depending upon the species. Further, the capacity of the liver and the kidney to deal with protein nitrogen is finite so there is also an upper limit on the amount of protein with which an animal can cope. Therefore, it would be reasonable to assume that protein (or certain amino acids) would have substantial effects on food intake. The direction of those effects might be expected to be different based on the quantity of protein available and the balance of the amino acids present. For example, considerable earlier work suggests that many species of animals reduce their intake of a diet with an amino acid imbalance. One would also expect a voluntary cessation of feeding when the physiologic capacity to process nitrogen is exceeded. On the other hand, protein deprivation of a balanced amino acid protein should stimulate food intake. Recently, a study using young rats95 from protein-deprived mothers indicated that these animals readily increased their intake of a balanced diet immediately after weaning without adverse consequences to their proportion of lean-to-fat body mass. The investigators concluded that protein restriction in gestation, lactation, and the neonatal period did not alter food intake control.

In a different type of study with young pigs fed a balanced liquid diet,96 injection IP of a balanced amino acid solution did not depress food intake in very young pigs but did in older pigs nearer to the time of weaning. Several studies have addressed the issue of appetite for protein97-98 with self-selection paradigms. Protein-deprived rats chose protein sources97 to a greater extent than nondeprived animals, but they did not choose all protein sources equally. In a subsequent experiment by the same group,98 rats did not actually receive a protein diet but instead selected a nonprotein diet with the odors of certain proteins. As in the first study, protein odors were not selected equally. Since this experiment did not use the real proteins, effects of taste, texture, and amino acid composition (except perhaps as it contributes to odor) could be ruled out. Further, the proteindeprived rats chose protein-scented diets over a butter-scented diet. One potential mechanism for an influence of protein-amino acids on food intake would be via its influence on insulin secretion99 (see Section VI below).

VI. POTENTIAL MECHANISMS FOR REGULATING FOOD INTAKE Potential mechanisms involved in control of appetite and satiety can be divided into two categories: central and peripheral. In 1985, Nicholl et al. reviewed the evidence for these controls.100 They concluded that mechanisms for peripheral control of appetite were still mostly obscure, but that the evidence for peripheral control of satiety was more solid. Liebowitz has reviewed the evidence for an epinephrine/norepinephrine stimulation of food intake via a 2 receptors in the hypothalamus.101 A hierarchal model of control involving a number of putative regulatory factors has been proposed.102 This model includes signals from the viscera to the lower brain stem that then relays information to higher centers and loops back to the viscera. The higher centers include the pons and the hypothalamus. Peripheral control of satiety might be the product of neural pathways or humoral factors. One of the most probable and most often studied possibility for

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neural control is vagal pathways coupled to receptors sensing gastric distension.

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A. Gastric Distension The effect of gastric distension on food intake has been evaluated in lean and obese subjects by filling a balloon inserted into the stomachs of volunteers with varying amounts of water.I03-104 The authors found no differences in the rate of stomach emptying when the balloon was filled with the maximum amount of water, and they concluded that the reduction in food intake was related to gastric distension. The reduction was not different between lean and obese subjects. It has been suggested that prolonged gastric distension contributes to undereating in anorexia nervosa.105 In studies with fistulated (gastric, duodenal, and esophageal) dogs, Pappas et al.106 found that liquid nutrient, an inert liquid, or a water-filled balloon all inhibited sham feeding. Since pretreatment with atropine did not block the effect, the investigators concluded that gastric distension inhibits food intake by a noncholinergic mechanism. This is in contrast to the studies of Sepple and Read82 in humans discussed earlier that seem to support a lack of an effect of gastric distension. Using a Garren-Edwards gastric bubble in ten obese humans, Velchik et al.107 found significant weight loss and a delay in gastric emptying, which they postulated might contribute to early satiety. Other surgical interventions have also been evaluated for their effects on food intake. Horizontal gastroplasty and Rouxen-Y gastric bypass surgery were compared by Kenler et al.108, and Roux-en-Y gastric bypass surgery was found to result in greater lowering of caloric intake and weight loss than the other procedure. It was suggested that specific food preferences contributed nonuniformly to the relative success of the Roux-en-Y gastric bypass surgery because consumption of milk, sweets, and ice cream led to unpleasant side effects, and ultimately to avoidance of these foods.

B. Central and Peripheral Regulatory Factors A number of humoral factors have been sug-

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gested as possible mediators of satiety.109 In order to be a true satiety factor, humoral compounds must meet a number of criteria. The first is that the purified, isolated factor must be able to produce an effect in a physiological concentration range. A number of putative regulatory peptides have pharmacological effects but are largely inert at physiological concentrations. Second, the factor must be found in circulation in satiated animals. Third, the effector must be released in a time course consistent with the observed physiological effects. For example, if satiety is induced in 10 min by some manipulation, but the factor is not released until 30 min later, it clearly cannot be responsible for satiety. The fourth criterion is that antagonists of the factor (e.g., antibodies or inhibitors of the factor/receptor interaction) should block satiety. The final condition to be satisfied is that in physiological conditions where satiety is impaired, there should be reduced quantities of the humoral factor. Unfortunately, it is not so clear cut as the above discussion implies because a sizable number of regulatory compounds are now known to act not in an endocrine manner but rather in an autocrine or paracrine manner. A number of peptides have been proposed as satiety factors and may play additional roles in digestive processes besides impacting appetite/ satiety. The most widely studied of these is CCK. The actions of CCK have been reviewed recently,110-111 and its involvement in eating disorders has been examined.112113 CCK may promote satiety by both central and peripheral means and not necessarily by the same mechanism(s), or it may be involved in aversive mechanisms rather than in a pure satiety response. An aversive factor would be expected to inhibit further food intake but would not be a true satiety factor. CCK stimulates gallbladder contraction and pancreatic secretion and inhibits gastric emptying. Moran and McHugh114 have suggested that the effects of CCK on food intake are mediated via gastric and nongastric mechanisms in rats because only part of the CCK effect could be accounted for by rate of gastric emptying. An initial CCK effect appeared to be due to something else. While the authors postulated a neural site of action, direct verification remains to be accomplished.

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There may be considerable species variation in which food components most effectively raise serum CCK levels and stimulate pancreatic secretion. Liddle et al.115 have reported that intact protein but not protein hydrolysates, fat, or carbohydrates is a potent stimulator of CCK release in the rat. Further, the relative potency of various proteins for CCK release was a function of their ability to inhibit trypsin. These data fit with their previous hypothesis that trypsin in the lumen of the upper jejunum inhibits pancreatic secretion and that proteins that inhibit trypsin thus permit pancreatic secretion. These data are in contrast to those of Douglas et al., 88 cited earlier that showed CCK release in response to fat and carbohydrate, although with reduced potency compared with casein. Still, the amount of CCK released was sufficient to stimulate pancreatic secretion. Fasted, adult male Wistar rats were used in all the protocols, so species differences are unlikely to account for the anomalies. Moreover, the absolute CCK concentrations and time frame of the response were essentially similar in each case. In mouse studies,116 it is clear that a number of parameters discussed previously in the methodology section (time of day, dietary state, and genetic strain) can influence the data obtained on CCK. Central vs. peripheral sites of action for CCK have been reviewed.84 Central sites of CCK action have been mapped by injecting CCK into various regions of the brain via implanted cannulae.85 Results of the mapping study indicated that CCK was most effective in the lateral medulla, the medial pontine, and the lateral hypothalamus. Since these were dose response studies, it obviously cannot be determined whether these regions actually encounter similar concentrations of CCK as the result of changes in appetite or satiety. In cats,119 CCK can be released from neurons in the lateral hypothalamus in response to gastric infusion of nutrients as well as to volumetric distension by water alone. Peripheral CCK was demonstrated not to be involved using a set of control cats infused IV with exogenous CCK. In rats, abdominal vagal fibers may mediate the effects of moderate doses of CCK.120 A recent study by Garlicki et al.121 reinforced the notion that the vagal nerves are important in CCK effects when CCK concentration

is in the physiological range, but that nonvagal mechanisms may be involved with pharmacological levels of CCK. Conover et al.122 concluded that CCK-induced delays in gastric emptying cannot explain the actions of CCK because other peptides that delay gastric emptying do not elicit a similar effect on food intake. A study in healthy men led Muurahainen et al.123 to a similar conclusion. The issue of whether CCK functions centrally or peripherally has also been examined with the aid of receptor antagonists124127 or the neurotoxin capsaicin.128 Based upon differential effects, it appears that CCK can function both centrally and peripherally to alter food intake. It has been suggested that the central effects of CCK might be mediated through 5-hydroxytryptamine because of the differential effects of central and peripheral blockers of 5-hydroxytryptamine receptors.129 It is difficult to determine, however, whether the effects are primary or secondary. For example, in the dog, CCK injected intraventricularly into the brain inhibited food intake and stimulated insulin and pancreatic polypeptide release as well.130 A similar action occurred with CCK administered IV, but the mechanism of the effect might be substantially different depending upon the site of action. Greenberg and Smith131 concluded that CCK actions must be paracrine in nature because of the effective removal of CCK from portal blood by the liver. To complicate elucidation of the mechanism of CCK action further, it may be that its effects are potentiated by diet.132 If this is indeed the case, greater attention may need to be paid to the diets being used to determine the mechanisms of CCK effects. The age of the test subjects may also be important if observations in mice on CCK effects as a function of age can be extended to other species.133 Other less-well studied peptides that may be involved in regulating food intake are neuropeptide Y134 and galanin.101 One attractive feature of these peptides relative to food intake is their localization with norepinephrine and 5-hydroxytryptamine neurons in the central nervous system. Oxytocin has also been linked with satiety.135137 Oxytocin, the hormone responsible for milk letdown in mammals, may actually have much

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broader central actions functioning as a neurotransmitter in several regions of the brain. Its implication in the regulation of food intake is based on several observations (for a review see Uvnas-Moberg137): release into circulation after feeding in multiple species and increase after treatment with agents that stop feeding behaviors. Uvnas-Moberg has proposed that oxytocin might actually be involved with appetite rather than satiety. This assertion is supported by the observation that in lactating rats, lesions to neural paths such that oxytocin is no longer released inhibits compensatory eating. Clearly, the role of oxytocin in food intake still remains to be defined. Bombesin, a tetradecapeptide with a blocked amino terminus, belongs to a family of peptides having C-terminal homology. Bombesin too is a putative satiety inducer under a variety of conditions.138"141 The inhibitory effect on food intake of bombesin, which is widely distributed in the brain and gut has been observed in many species with both central and peripheral bombesin administration. In studies of bombesin's central effects, injection of bombesin (or calcitonin or neurotensin) into the rostral portion of the nucleus of the tractus solitarius produced a 50% reduction in food intake in rats trained to a 3-h meal feeding pattern.142 The investigators were thus led to suggest a nonhypothalamic site of action for bombesin. It should be noted, however, that diffusion to surrounding structures was not rigorously ruled out. Bombesin has been reported to function more efficiently in the hind brain of rats,139 and in this study, bombesin injected into the fourth ventricle was shown to be effective at one to two orders of magnitude lower concentrations than required if the injection site was the lateral ventricle. In addition, there was no concomitant effect on water intake or locomotor behaviors as is usually observed with higher doses of bombesin. A peripheral site of action for bombesin has also been suggested. In an effort to determine the contributions of central and peripheral bombesin actions, Merali et al.143 cannulated the third ventricle of the brains of rats and injected either bombesin or antibombesin antibody. They also administered both systemically. They found that centrally administered bombesin but not the antibody alone reduced meal size in food-deprived rats. The centrally administered antibody did,

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however, effectively block centrally administered bombesin. Peripherally administered antibody was unable to block the effects of central bombesin, but did potentiate peripheral bombesin as would be expected. Although the data were not shown, the investigators also reported that central bombesin antibodies could also block peripheral bombesin, suggesting possible central and peripheral regulatory interaction. A potential peripheral bombesin site is the stomach,144"146 which contains a higher concentration of bombesin and bombesin-like peptides than either the brain or the rest of the gut. In response to bombesin, there is a dose-related release of gastrin in humans and rats. In humans, the gastrin release results in stomach acid release as expected, but such is not the case in rats. An inhibitory effect of bombesin on acid secretion perhaps via somatostatin145 has been postulated, but additional evidence of such a mechanism is needed. Makhlouf and Schubert146 reported that noncholinergic mechanisms for gastrin secretion are bombesin mediated. It has been suggested that bombesin exerts its effects independent of a gastric site of action. This suggestion was based upon a comparison of bombesin analogs with respect to their abilities to inhibit feeding vs. their affinities for gastric bombesin receptors. Since the relative potencies differed from their receptor affinities, Hostetler et al.141-147 postulated that the stomach was an unlikely site of action for the effects of bombesin. It is possible that multiple classes of bombesin gastric receptors could cloud the issue. Considerably more research is needed to define more clearly the role and mode of action of bombesin in food intake. The regulatory tridecapeptide, neurotensin, a brain/gut hormone, alters several parameters that may contribute to the control of appetite. Neurotensin is located in both the brain and the gut,148 but quantitatively about 85% of the body's neurotensin is in the gut with the ileum being a major site.149 Several lines of evidence point to a contribution of neurotensin in the complex regulation of appetite, including localization of neurotensin in structures thought to be involved in appetite regulation, effects of injections of neurotensin, interaction with certain neurotransmitters, and levels in genetically obese animals.

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Based upon the observation that neurotensin injected into the hypothalamus depressed food intake, Beck et al. measured neurotensin in brain nuclei and pituitaries of obese Zucker rats, heterozygotes, or homozygous lean control rats.150 They found the greatest levels in the anterior pituitary. Injections (IV) of neurotensin into conscious pigs resulted, as would be expected, in dose-dependent increases in serum neurotensin based on immunoreactivity and in increases in pancreatic volume, and bicarbonate, and protein output.151 Food intake, particularly of carbohydrate, promoted neurotensin release in this study. Although pancreatic secretion was elevated by food intake, the amount of neurotensin release was just about half of what was required for significant effects with injected neurotensin. Thus, based on these experiments, it is unclear what the true significance of the neurotensin effect is. Central injection of neurotensin may mediate dopamine release from mesolimbic paths152 and acetyl choline release from the frontal and parietal cortex but not the basal forebrain.153 One of the effects of neurotensin on the GI tract is altered gastric acid secretion and gut motility. Unlike the effects of bombesin, which do not require an intact vagus,138 the action of neurotensin on acid secretion does require an intact vagus system. Two reports by the same group150-154 in genetically obese animals indicate lower neurotensin levels. Since other putative regulatory peptides are also different in the brains of obese compared with lean rats, this is not particularly convincing evidence for a pivotal role for neurotensin in food intake. However, a lack of difference in neurotensin levels in the circulation between these two groups does suggest that if there is indeed a role for neurotensin in regulation of food intake, particularly in obese animals, then the site of action is likely central rather than peripheral. Future research efforts regarding neurotensin must continue to focus on the site and mechanism of action, taking care to use physiological doses of this peptide. Because children with Prader-Willi syndrome show marked hyperphagia due to delayed satiation and also have low pancreatic polypeptide levels, Zipf et al.155 tested the ability of pancreatic polypeptide infusion to reduce food intake

in these patients. Even though blood levels of pancreatic polypeptide were normalized, there was no apparent effect on food intake, calling into question the role of this peptide in food intake. Since pancreatic polypeptide shares considerable sequence homology with neuropeptide Y,134 it will be necessary to rule out the possibility that the putative effects of pancreatic polypeptide are not due merely to cross-reactivity with neuropeptide Y receptors. One would expect to observe this phenomenon at pharmacological levels of pancreatic polypeptide. The apparent lack of effect at near physiological levels155 is consistent with this possibility. Glucagon stimulates a rise in blood glucose levels and has been proposed as a satiety signal working at the level of the liver via vagal afferents that are separate from those associated with CCK effects.156 Strubbe et al.157 have questioned the role of the liver in the process because intracardiac glucagon infusion yielded the same results as intraportal infusion did. Others have indicated that the role of the liver in satiety is subtle and perhaps fairly complicated.158-159 Means and Burns160 were unable to detect an effect on food intake even when glucagon was undetectable in circulation due to the presence of glucagon antibodies. This could signify that glucagon has little role in the control of food intake, or that effects are not mediated by circulating glucagon but rather by a paracrine action of glucagon. Since insulin regulates circulating glucose levels as well as levels of other macronutrients, such as amino acids and fats, and the distribution of nutrient stores, it is natural that insulin has been considered to be a potential controller of food intake. Because the degree of body fat is relatively constant, it has long been supposed that body fat content is somehow a controller of food intake. It has been suggested161 that insulin in the central nervous system might be the signal relating degree of adiposity to food intake over an extended period of time. Woods and Porte161 have reviewed the evidence for this role of insulin that includes: 1. 2.

Slow change of insulin concentration in cerebrospinal fluid Decrease in food intake and weight gain

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3.

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4.

after infusion of insulin into cerebrospinal fluid Increase in food intake after injection of anti-insulin antibodies into the hypothalamus Decline in food intake after peripheral insulin administration if hypoglycemia is prevented

This evidence is consistent with a link between adiposity and the lipostatic theory of food intake, but it does not rule out glucose as the actual regulator since circulating glucose levels are a function of insulin level and a determinant of the ability of adipocytes to synthesize and store fat. It should be recalled, however, that in the uncontrolled diabetic, glucose levels are quite high and yet there is hyperphagia. Thus, it is unlikely that glucose alone could account for the complete regulatory loop. Insulin might work directly or by altering the concentration of glucose, or fatty acid, or some other regulatory compound in the blood. Some of the work on the role of insulin in food intake has been reviewed recently.162-163 Part of the problem in determining whether the effect of insulin on intake is direct or secondary to insulin's alteration of some circulating nutrient stems from the difficulty in finding experimental conditions where insulin concentration changes, but other parameters do not (for a review see Vanderweele et al.164). Confirming earlier studies (see Reference 161), Vanderweele et al. using low doses of tolbutamide showed that increased insulin levels were associated with decreased food intake if hypoglycemia was prevented. A complicating factor with the use of tolbutamide, however, is its potential influence on tissue insulin sensitivity. Bellinger and Williams have reported data165 that support the notion that hepatic glucose receptors are probably not involved in the insulin and/or glucose effects on food intake. In this study, dogs with chronic jugular or portal vein cannulas received glucose, saline (volume control), or mannitol (osmotic control) after a 23-h fast. No reduction in food intake of glucose-infused dogs relative to the controls was observed even if the dogs were prefed 20% of their daily intake regardless of the infusion site. In approximately 5% of the trials, however, there was nausea in the dogs infused

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portally regardless of the infusate. There was also a reduction in food intake in all infusion trials relative to intake on days with no infusions. Taken together, it seems that aversive behavior might be a problem in this type of experimental design. The investigators also pointed out that cannula placement might be a factor in obtaining results that differed from earlier work. The glucocorticoids, which in effect prepare the body to meet stress by redistributing nutrient pools, have also been implicated in the control of food intake (for a review see Kumar et al.166). They have examined adrenalectomy and corticosterone implants and concluded that corticosterone affects, as would be expected, influenced circadian patterns of intakes, as well as total caloric intake and selection of specific nutrients. They speculated that the corticosterone effects were mediated by the a2 noradrenergic system of the paraventricular nucleus. The opioid peptides also appear able to influence food intake.167'168 This notion is supported by alterations in food intake in people addicted to exogenous opiates and by the impact of the opiate antagonist naloxone, which decreases food intake in a wide variety of species from roaches to humans. Also, there is a difference in the concentrations of opioid peptides as a function of dietary state. In obese humans and rats, higher levels of brain p-endorphins have been observed, but causality between p-endorphin level and obesity has not been observed. On the other hand, anorexic humans and rats appear to have reduced levels of some of the opioids. Injection of various opioids increase food intake mildly and transiently. Opioids seem to interact with target tissues through multiple types of receptors that have varying degrees of influence on food intake.168 The epsilon receptor may be coupled to an a adrenergic mechanism. The |JL receptor is sensitive to peripherally injected morphine, but not to a centrally injected morphine agonist. The 5 receptor may be coupled to dopaminergic mechanisms. Stimulation of the K receptor, however, gives the largest increase in feeding. Opioids also seem to enhance preference for particular nutrients. Investigators have reported greater preference for sweet solutions, high-fat diets, and protein depending upon the conditions

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employed (see Levine and Billington168). The role of opioids in food intake, however, is somewhat ambiguous. There seems to be no long-term effect on body weight by opioid antagonists. In the other direction, it is difficult to observe a consistent opioid-stimulated increase in food intake over control animals. This could be merely a problem related to choice of food-deprived or nondeprived animals. Other potential satiety agents have been studied, including the serum glycoprotein satietin169'170 as well as anorexigenic substances in urine171 and feces.172-173 Although these compounds show substantial biologic activity, not nearly as much is known about them relative to a number of other more thoroughly investigated agents. Satietin infused daily into rats reduced food but not water intake. The effect, however, was transient and disappeared after several days. The rats did lose weight and maintain that loss for a longer period; An important contribution of this experiment169 was the use of rat satietin. Previous work using semi-purified human satietin in rats could have caused an aversion affect simply due to the potential antigenicity of the human satietin. Of course, with semi-purified fractions there is the additional possibility of the effect being due to a contaminant in the preparation. If satietin circulates in the plasma as an inactive peptide as hypothesized by Bellinger and Mendel,169 then it is also possible that the form of satietin used is not the physiological form normally encountered by the regulatory system. As a consequence, the satietin receptors could have down-regulated, resulting in the attenuation of the effect on food intake. Like satietin, a 50 kDa peptide has been found in rat urine,171 but unlike satietin, it appears not to be a glycoprotein. While a number of compounds in urine might be expected to depress appetite, this one does not make rats ill and there is more of it in fed than in starved rats. Since trypsin and proteinase K treatment did not destroy the activity of the factor, the actual anorexigenic agent may be a peptide piece contained in the longer peptide. The anorexigenic substance in feces172-173 is much less well characterized. Since heat treatment destroys its activity, the authors postulated that it is a protein. It was less effective in obese Zucker rats than in lean controls in in-

hibiting food intake. Since the substance was delivered as a single bolus injection, the possibility of altered circadian patterns between the two groups might be responsible.

VI. CONCLUSIONS Humans and many animals maintain body weight in a fairly narrow range. This can be managed by controlling food intake either on the side of appetite or satiety or by controlling the efficiency of nutrient utilization. Our history has conditioned us to make aggressive use of what historically were limited feeding opportunities. Available evidence suggests that the genetic/ physiological/psychological bases for control of appetite and satiety are not easily overridden. If a single event controlled either appetite or satiety, it should eventually be possible to design safe, effective pharmacological agents or to substitute noncaloric ersatz nutrients to disrupt a unitary control device. Attempts are, for example, being made to determine the utility of cholecystokinin174 and its analogs175 for long-term suppression of food intake (reviewed in Lukaszewski and Pressman174). Cholecystokinin (the octapeptide) was useful for lowering food intake for a few days, but for no longer. Eventually, perhaps when more of the regulatory system has been worked out, it should be possible to impact food intake at sites with maximum effect and minimum homeostatic regulation. Whether the most useful of these exogenous agents will be currently recognized peptides or their analogs remains to be seen. Delivery systems will, of course, have to be designed to maximize potential effects. It seems likely, however, that multiple mechanisms singly or interactively control food intake. Blundell has argued that differential nutrients interact with different satiety regulatory mechanisms and thus have different apparent satiety values.176 To some extent, this might be a function of the sensory properties of a particular nutrient or to our ability to detect and quantitate a nutrient physiologically.177 Advances are being made in the ability to delineate sensory properties of food coupled to acceptability.178 The challenge is to establish at the biochemical level the impact of sensory properties on food intake. As our un-

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derstanding of the chemistry of taste perception grows, it will be possible to elucidate the mechanisms, whereby oral or nasal stimuli are transduced to biochemical signals at receptor cells, and ultimately to understand how that signal transduction leads us to believe we are consuming sugar or salt or some other nutrient. Particular attention will need to be paid to the choice of model systems for these studies because it is clear that not all species respond to these cues alike.177-178 Humans are not always the best choice for these studies because we have considerable societal and individual conditioning with respect to food preferences. It has been argued that there is a substantial genetic component to dietary selection.179 This is an inherently attractive hypothesis because it allows various species to have separate nutrient niches.180 Even among omnivores there is evidence of food preference. Clearly, on a macroscale nutrient niches do occur because animals do not readily switch from preferred foods until starvation conditions occur. Some of the preference can no doubt be accounted for by the need to meet certain nutrient requirements; felines, for example, could not consume enough hay to satisfy their high protein requirement. On the other hand, not every nutrient needs to be consumed at every meal. Thus, for most species there should be considerable latitude in acceptable food. The regulation of food intake is a complicated process.181 Some of the apparent complexity may be the product of inadequate models or experimental designs that do not control for all the parameters that can interact. Changing nutrient density and substituting noncaloric sweeteners and ersatz fats may in theory meet our objectives to be "slimmer" or "healthier". Evidence to date seems to support the notion that organisms defend more successfully against calorie dilution and are less able to adjust to calorie increases. This would be expected in light of eons of difficulty in obtaining adequate calories. Although more work needs to be done, it seems that use of artificial sweeteners probably is not very effective in reducing food intake at least in some situations. In fact, "tricking" this complicated regulatory system may be difficult or impossible. As it was said in a margarine com-

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mercial of a decade ago "it's not nice to fool mother nature".

ACKNOWLEDGMENTS Salary and support for this work were provided by state and federal funds appropriated to the Ohio Agricultural Research and Development Center, The Ohio State University, Columbus, Ohio, Journal article 313-90.

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The influence of food on food intake: methodological problems and mechanisms of action.

Emphasis has been placed on the understanding of the regulation of food intake in the hope of aiding the battle against obesity and of helping to amel...
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