Discussion

Philip James, M. D., Moderator

James: I should like to welcome you all to this af- ternoon’s discussion. I should like to sug- gest four topics around which we might or- ganize this discussion: 1) physiologic control of hunger and satiety by central and peripheral mechanisms; 2) short- vs. long-term control; 3) the integration of ex- ternal vs. internal factors; and 4) individual- ity of persons characterized by culture, so- cial events, physiologic variance, and the entrainment of eating habits. Let’s start with physiology and the nature of signal- ing.

Stricker: I wanted to say something about the para- ventricular nucleus (PVN) and its possible integrative role. The nucleus has projec- tions to the pituitary by which oxytocin and vasopressin travel for secretion. We think that the PVN is extremely important in the control of food intake through an inte- grated mechanism with the gastrointestinal tract. We are using the oxytocin secretion as a marker for activity in the parvocellular neurons in the rat. Magnocellular and par- vocellular activity are closely associated: when PVN activity is elevated, oxytocin is secreted, and there is a decrease in food intake and gastric function. The animal is not only disinclined to eat, but stops di- gesting the food that it has eaten-a per- fectly sensible coordination of behavior and physiology. When animals have been poisoned and when they are dehydrated, this sequence is seen. As was mentioned this morning, there are also oxytocin-con- taining neurons coming from the PVN down to the dorsal motor nucleus of the vagus in the brain stem. So, oxytocin may act as a neurotransmitter in the brain to

control behavior as well as being involved in the gastrointestinal function. Following a small meal there is no oxytocin secretion in rats, and of course gastric motility shows very nice contractions. Thus, this system is not involved in the normal process of satia- tion.

Uvnas-Moberg : I am surprised by what you say. I am also convinced that oxytocin is important in the intraneuronal pathways from the PVN. There are studies showing that if you put oxytocin in the dorsal vagal nucleus, it ex- cites cells there and you get enhanced gas- tric acid secretion and increased gastric motility. Situations such as suckling and pregnancy are also associated with oxyto- cin release, but these conditions are not associated with nausea and sickness.

James: I am not quite clear whether you both agree that oxytocin in the blood is simply a marker for control systems in the brain that affect the gut or whether it is the peripher- ally circulating oxytocin that in some way is modulating gastrointestinal function.

Stricker: We have given oxytocin into the circulation in physiologic and pharmacologic doses, and it has no effect on gastric function. We believe that it is a marker rather than a me- diator, and that it is oxytocin in neurons going from the PVN to the brain stem that in teg rates behavior, not pituitary oxytoci n .

Uvnas-Moberg : You claim that oxytocin inhibits the relax- ation of the stomach, whereas I believe the effect is exactly the opposite.

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Stricker: My recollections of Roger’s’,* findings are that, whereas there was an increase in gas- tric acid secretion, there was a decrease in gastric motility when oxytocin was infused into the brain stem; when he stimulated the PVN electrically but gave the oxytocin an- tagonist, he thereby blocked the decrease in gastric motility as measured by a strain gauge. This implies that the PVN induces a decrease in gastric motility via an oxytocin- ergic mechanism. We have a different way of measuring motility, but the results are similar. Suckling is the only condition we have seen in which magnocellular and par- vocellular activities are not linked. We have measured gastric motility during suckling; under circumstances in which there is clear pituitary oxytocin secretion, no effect on motility is seen. And under these special circumstances, presumably because the animal is “wired” differently, there is no ef- fect on parvocellular activities.

James: We need to make a distinction between the central effects of oxytocin released in one or another part of the brain and the effects of peripheral oxytocin. What is the best pe- ripheral index of central activity?

Hautvast : If I am doing studies on satiety in my de- partment, should I measure oxytocin in the blood?

St ric ker : We don’t have any reason to think that pe- ripheral oxytocin levels in the rat are a marker of hunger or of satiety. There are circumstances in which oxytocin release from the pituitary is associated with cessa- tion of eating. Dehydration is one, poison is another, administration of cholecystokinin (CCK) is a third. Under those circum- stances, peripheral oxytocin levels are in- versely correlated to the rat’s food intake, but I would not say that the animals are sa- tiated: they are not eating because they are thirsty or nauseated. If your department in- vestigates human subjects, then that’s an-

other reason for not using oxytocin be- cause many of the treatments that cause oxytocin release in rats induce vasopressin release in humans. Satiety is not related to vasopressin in humans anyway.

Uvnas-Moberg : Oxytocin is related to maternal behavior. When CCK is injected into the periphery as a bolus, it induces satiety; however, i f ani- mals are primed with estrogen first, they exhibit maternal behavior, not behavior as- sociated with nausea. There is a high rate of release of oxytocin in relation to sexual behavior, and animals eat immediately af- terward if they are allowed to.

James: The question of whether the responses to peripherally injected CCK is physiologic or pathologic remains a problem, and its pe- ripheral effects may differ from its role in central mechanisms. As I understand it, Dr. Stricker is saying that vasopressin is the human marker for the same sort of events that you would see in the rat when you monitor oxytocin, whereas Dr. Uvnas-Mo- berg is saying that centrally released oxyto- cin is very important in terms of the physio- logic regulation of behavior within the brain and that CCK acting peripherally is acting in a physiologic way and that its ac- tion is to some extent modulated by central events. Is that correct?

Uvnas-Moberg : CCK given peripherally is activating, via the vagal afferent nerves, a cascade of events in the brain; among these central events are the release of oxytocin and central CCK; the latter may be related to satiety.

Blundell: If we make the distinction between central and peripheral mechanisms, there are cer- tain peripheral effects of peptides, e.g., of CCK and oxytocin, and different effects generated by them at particular loci in the brain where they act as neurotransmitters. If there is a similarity between the effect of the peptide peripherally and its effect in the

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brain, are these synchronized? The pep- tides come from different sources, but are they integrated to produce a coherent re- sponse?

Uvnas-Moberg : Yes, there is a series of linked events, and depending on steroid levels and other con- ditioning hormones or events, the result will be different. Thus, estrogen is needed for maternal behavior. However, I think that maternal behavior is a rather nonspecific response that can be induced by many pe- ripheral stimuli. But depending on avail- able steroids, etc., you will have different responses.

Blundell: If the principle is accepted that there are peptides in the periphery doing one thing, but that this activity is coordinated with the same peptide emanating from a different source in the brain doing something else, then it is an important organizing principle for synchronizing physiologic events and behavior.

Stricker: I wouldn’t agree with any of that. I don’t think there is a single example in which it is true, much less in the ones that we have just been talking about. It is true that CCK is released in the periphery and there is CCK in brain neurons, but that isn’t to say that they are released at the same time, much less that they serve complementary functions. I would say the same thing about pituitary oxytocin and its functions and about central oxytocin and its functions.

Blundell: I think there is perhaps more evidence than Dr. Stricker is prepared to give credit for, particularly in relation to CCK, where the effects, to some extent, are harmonized. CCK in the brain does appear to influence food consumption and produces a satiety sequence similar to-but obviously at dif- ferent dose levels from-CCK in the pe- riphery. You can demonstrate this by using

CCK antagonists that cross or those that do not cross the blood-brain barrier.

Stricker: When CCK is given systemically, its effects are mediated through the gastric vagus; if the gastric vagus is cut, you eliminate the effect of peripheral CCK completely. Now if there were a central CCK effect, you would think it would remain active after vagot- omy. In fact, you could give a huge dose of CCK systemically, i.e., up to 100 k/kg, and it has no effect on food intake if the gastric vagus has been cut. I don’t see what the ev- idence is that centrally released CCK has anything to do with food intake.

York: I know of little evidence showing that if you give CCK centrally, you actually suppress feedings. It has a much bigger effect when given peripherally.

Uvnas-Mogren: Yes, I agree. You have to inject CCK cen- trally with the other transmitters in the brain with which CCK is stored; only when they are given together will you see an ef- fect.

York: Everyone is trying to find or identify a sin- gle so-called “satiety factor.” As with lipol- ysis in adipose tissue, which is stimulated by a multiplicity of hormones according to physiologic status, so the satiety signals are also likely to be many and varied ac- cording to the physiologic status of the an- imal. I think the other real problem is that when one begins to look at the neuropep- tides in the central nervous system (CNS) and their distribution, we find that the cor- ticotropin-releasing factor (CRF) is mainly in the PVN, which is clearly a carbohydrate feeding center. But we don’t know what the effects of feeding and nutrient intake are on CRF secretion in all other areas where CRF is present. It may well be that measur- ing total brain neuropeptide is not really going to tell us much about what affects satiety. We really need to begin to look at

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the specific secretion or activation of the neuropeptides in particular loci. That may require us to start measuring mRNA changes in particular regions to get the in- formation.

Stricker: Could I add a warning on interpreting ces- sation of feeding as satiety in animals who cannot talk. When you give CCK to people in very small doses, i.e., five hundredths of a microgram per kilogram, then these doses cause severe abdominal cramps. There isn’t a dose given in humans to de- crease food intake that doesn’t cause ei- ther malaise, abdominal cramps, or dis- comfort.

Pi-Sunyer: Dr. K i ~ s e l e f f ~ - ~ and I have given many infu- sions of CCK to people: we can give doses of CCK that do not cause abdominal cramps and still inhibit food intake.

James: When you give CCK, do the levels in blood accord with what you actually find periph- erally when you measure it under normal feeding conditions?

Pi-Sunyer: Well, we have never measured the levels in the blood because, as you know, the radio- immunoassays for CCK are poor. 1 think we are probably working with higher than physiologic doses, but even at those doses we don’t get abdominal cramping or dis- comfort, although we do see an inhibition of food intake. At higher doses the subjects report feeling sick. We have never had a pa- tient vomit. However, CCK, in our hands, only works in humans if they have a full stomach. In other words, we have to give a preload of food for the CCK infusion to work. A few years ago Gerry Smith6 found the same thing in rats. What is probably happening is an enhancement of the sig- nals from a full stomach, induced peripher- ally by CCK.

Stricker: We studied the effects of CCK in a series of 14 subjects who had food in their stomach. We found no difference as a result of the preload in terms of the effect of CCK on subjective feelings or on vasopressin levels.

Pi-Sunyer: We have never measured vasopressin. Whether you want to call one mechanism nausea and the other satiety, and specify gastric fullness not as nausea but as sa- tiety, then you are dealing with two differ- ent concepts. Food intake is inhibited, for one reason or another.

Rosenberg : Is satiety defined as a behavior or as a feel- ing? As a gastrointestinal physiologist, I would ask whether there is satiety when a subject has no stomach?

Stricker: Individuals who have no stomach report that they experience satiety. It’s hard to know what they refer to when they say that, but it is a sensation. In rats you have to as- sume the sensations. One has to try to infer from the animals’ behavior whether or not satiety is the reason they stop eating. A pattern of behavior, the satiety sequence, can ensue if the behavior is the same as that seen when animals have eaten nor- mally; they then drink water, groom, and lie down. The sequence of drinking, groom- ing, and resting is called the satiety se- quence. You see the same sequence fol- lowing CCK administration in rats. Smith and his colleagues therefore suggested that CCK might be acting as a satiety hor- mone. Now you would have to be sure that the animals did that only when they were satiated. Instead of giving the animals CCK, we gave them lithium chloride, which also made them stop eating. They then drank a little water, groomed, and rested! If you simply reached in and pulled the food out of the rat cage so that the animal was not

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satiated, then again he would drink, groom, and sleep.

Booth: We mustn’t define satiety as cessation of eating. Operational definitions will get us nowhere. We are trying to answer the ques- tion, “What is there, as a result of normal eating, that inhibits the disposition to eat?” That, if you like, is the definition of satiety. The theoretical mechanistic question is, “What physiologic events, as a result of normal eating, inhibit further eating?”

Blundell: I agree in part with Drs. Stricker and Booth. I think we must have some sort of descrip- tion of satiety that is more than the cessa- tion of eating. One of the things that we must rely on is the way in which animals behave, as well as the way in which physiol- ogy changes after eating. This gives a clue to understanding what is going on. After eating, rats do behave in a particular way. The behaviors displayed are not exclusive to the posteating sequence, but the way in which they appear is. I think there is a way in which we can use that behavior to tell us something about the effects that food is having.

Van Itallie: I think we have been focusing on that part of satiety when normal cessation of eating occurs. But there is another component that could be called satiety, i.e., how long it takes for the desire to return. And no one has commented on that despite its impor- tance because it determines how fre- quently the animal will eat. It may have something to do with the control of food intake.

Blundell: Can I just mention something about differ- entiation of satiety and hunger in animals and humans? In animals the terms hunger and satiety are often contraposed; an ani- mal is hungry, therefore it eats, and i f it

doesn’t eat, then it’s in a state of satiety. These are in fact constructs that refer to processes. We might be able to describe the physiologic and behavioral events that go along with those processes. In humans the terms hunger and satiety, I think, have to be used a little bit differently. Satiety, in my view, is still a state that follows the con- sumption of food, and this state is de- scribed by certain physiologic processes in the periphery and certain events in the brain, most of which we don’t know much about. When we deal with humans, we are using hunger in two separate ways, i.e., a sensation and a willingness to approach food. When we define the word hunger as a feeling, then hunger can be used to define satiety. As we eat food, the feelings of hunger diminish. After eating they are low for a time, and then as satiety-the state of satiety-dissipates, hunger returns. So, in humans the feeling of hunger can be an in- dicator of the intensity of satiety.

Knoll: The intensity of the hunger drive is, within reasonable time limits, proportional to the duration of food deprivation. This is the physiologic mechanism determining that the animal will be ready to surmount many obstacles to seize its food. With rats de- prived of food for 132 h, we found that feeding for 30 min decreased the intensity of the hunger drive dramatically. During this short period, clearly, neither the en- ergy stores nor the amount of the essential nutrients in the organism changed much. This means that the brain is sated before the deficits in the organism are corrected. Thus, ingestion of food in appropriate qual- ity and quantity may lead to an immediate activation of a satiety signal, which termi- nates the hunger drive.

This hypothesis initiated the search for a substance that 1) easily penetrates across the blood-brain barrier; 2) is active by intra- cerebroventricular administration; 3) is present in detectable amounts in the blood of different species; and 4) can block the

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hunger drive at its peak intensity, i.e., in- hibits food intake in rats deprived of food for 96 h. Here you have to remember that CCK does not act in animals deprived of food for longer than, say, 16-18 h.

I established the existence of satietins, a previously unknown alpha-l-glycoprotein family of substances, possessing an anor- ectic profile consistent with the role of a satiety signal in the control of food intake. The chemical nature of the satietins was found to be unique. Two anomalous carbo- hydrate constituents, rhamnose and glu- cose, were detected in satietin. Human serum contains a large number of glyco- proteins, i.e., proteins containing cova- lently linked carbohydrates. The hexose in all the glycoproteins in human serum de- scribed in the literature is fucose. In strik- ing contrast to the known glycoproteins in human serum, the hexose constituent in satietin is rhamnose. The hexoses found in the glycoproteins in human serum are mannose and galactose, exclusively. Satie- tin contains three hexoses: mannose, ga- lactose, and glucose. The apparently highly individual carbohydrate composition in sa- tietins hints at the specific nature of the protein.

Satietin activity, first demonstrable in humans, was then detected in the sera of mammals belonging to different orders. Anorectics are known to act either by inhib- iting the activity of the feeding center or by activating the satiety center. A compound that inhibits feeding increases the time elapsing before a rat takes the first tablet in an eatometer, whereas a compound acting via a satiety mechanism leaves the time in- terval unchanged. Analysis of the effect of satietins on the microstructure of eating re- vealed that they act through a satiety mech- anism. Satietin may therefore serve as the essential link in the regulation of feeding, connecting the gastrointestinal tract and the brain via the bloodstream.

James: Where do satietins come from?

Knoll: I believe they are synthesized in the liver.

We have some data on that. There are two forms of satietin in human blood; one is a 64-kDa compound, and the other is a 43- kDa compound. We were successful in iso- lating larger amounts of the bovine serum satietin, which is a 30-kDa compound, and we are now near clarifying the chemical nature of that compound. The carbohy- drate content of bovine satietin is the same as that of human satietin. Thus, all satietins that we have checked up to the present time have this unique carbohydrate com- position.

James: Dr. Bjorntorp, what about peripheral sig- nals from adipose tissue?

Bjorntorp: There are a couple of other factors that have not been discussed here: serotonin, for example, and a corticotropin-releasing factor. Colipase is another recently dis- cussed peptide that seems to be promising. There has been a lot of discussion about a lipostatic mechanism of some sort. If you look at what could possibly be the regula- tor in adipose tissue, it seems to be the de- gree of expansion of the adipocyte. Then one should also ask what is regulated. Is it really energy intake or is it energy output? I think evidence is pointing to the signal to energy output rather than energy intake. Then we need a signal from adipose tissue, and this has been the subject of much dis- cussion. It is probably not glycerol or free fatty acids. A compound like adipsin would fit nicely in this story, but this idea is purely speculative.

York: Levels of adipsin seem to go completely the wrong way in order to regulate feeding behavior. As regards satietins, I think it is very difficult to understand a system where- by the liver, which is receiving all the nu- trients, would release a protein into the cir- culation that will then be monitored by the brain, when the liver itself has such good vagal contact that it already relays all the needed information to the brain. So, I think

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teleologically it is very difficult to under- stand the satietin system.

Knoll: Satietin is probably synthesized in the liver, but in plasma satietin probably is in an in- active form: it has to be activated by some mechanism, perhaps in response to food.

York: There clearly is evidence for some circulat- ing satiety factors. The parabiosis studies done with obese and lean rats and different types of obese rats seem to indicate the presence of circulating factors that regu- late feeding. What they are, I think, is open to question.

James: There is a point in Dr. Knoll’s argument about the rapid satiety effects after a meal. Would you not expect glucose and other substrates to reach the liver within minutes and therefore to begin this process of feed- back and signaling?

York: I think glucose does hit the liver very quickly-the sympathetic system is acti- vated as soon as the animal starts eating. This system provides a very strong drive to the periphery-maybe to the liver and to other sites. I think that probably the vagal input, or signals from the oropharyngeal axis, or even from the stomach or small in- testine, activates the sympathetic system.

Olson: Well, I am fascinated by Dr. Knoll’s report that there are 30-64-kDa glycoproteins cir- culating in the blood and made by the liver. I’d just like to inquire whether or not any of the molecular biology for this family of compounds has been done. Has the gene been identified? Has the gene been cloned? Do we know the entire amino acid sequence of these proteins? Do we know where the satietin receptor is? And do they, in fact, pass the blood-brain barrier? I think these questions have to be answered be-

fore we will accept the satietins as bona- fide mediators of satiety.

Knoll: I agree that all those parameters have to be measured. At the moment we have evi- dence suggesting that satietin is entering the brain. It’s effective whether given intra- venously or intraventricularly into the brain. So, satietin has to get through the blood-brain barrier. This doesn’t mean that the whole molecule goes through; perhaps it is split before a subfraction passes into the brain. First, we have to clarify the chem- ical nature of the structure and then apply highly sensitive techniques to detect physi- ologic amounts. These are now the next steps, which we are working with.

Stricker: One wonders how a vagotornized individ- ual could ever survive, given the fact that all the signals we are talking about are pre- sumably vagal signals. However, some nonvagal signals are involved, and thus hu- moral signals are being proposed. The fact that the amount of a circulating substance decreases in response to food deprivation does not permit us to conclude that the substance works at a physiologic level to cause a decrease in food intake. If we were to look for agents that decrease food intake and that might cross the parabiotic circula- tion, we have to consider insulin.

James: I thought there was a problem with the in- sulin-parabiotic story because the fast turn- over of insulin was such that, given the very slow cross-circulation, it was highly un- likely that something with that turnover rate could actually be an important signaler in the paired animal, which is responding to some mysterious substance coming from the first animal.

Stricker: Right. I wasn’t suggesting that insulin is a satiety hormone. Nor did David Booth when he pointed out the connection be- tween insulin and satiety. What we have

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been proposing instead is that insulin helps to make carbohydrates especially sa- tiating. lt’s not a satiety hormone, but it contributes to satiety. So, in the presence of insulin carbohydrates become more sa- tiating and, in that sense, it contributes to satiety. I think there is rather good evi- dence for that as a physiologic role.

York: I had hoped to convey in my talk this morn- ing that there are basic metabolic signals, endocrine changes, that terminate feeding or initiate feeding and neuropeptides and other factors that affect the response to signals.

Pi-Sunyer: We did some studies years ago infusing in- sulin and trying to find the effect on short- term food intake with eating monitored. We were never able to show any satiety effect of insulin at levels that would be compara- ble to those after a meal. Also, I think those of us who work with insulin-requiring dia- betics know that even though many of them are actually hyperinsulinemic a great deal of the time, they don’t seem to have any enhanced satiety effect.

York: But, there is the issue of insulin-resis- tance?

Pi-Sunyer: That’s true, but we are giving them insulin at levels that are very hyperinsulinemic to break that insulin resistance. In fact, their serum glucose level responds.

Booth: If the gastric emptying rate is one of the major controls of meal-to-meal physiology, as well as the day-night physiology in ani- mals that have strong activity patterns, then whatever setting the brain and the rest of the body have for this variation in the gastric emptying rate will, by its very persis- tence, make a considerable contribution to the balance between the stopping and the starting of eating. In other words, one of

the ways to look for long-term regulation is in the stability of short-term regulation.

Rolls: I enjoyed your talk, Dr. Pi-Sunyer. I wish it were all so simple. Some people will be surprised at what I have to say because a lot of my work on human feeding has em- phasized the lack of regulation and the way palatability, variety, etc., can override phys- iologic controls of food intake. But we have just finished a long-term study manipulat- ing specifically carbohydrate and fat in the diet.7 There have been very few studies se- lectively manipulating nutrients, and it be- came clear to me that the way you set up these human experiments is absolutely crit- ical to the outcome. In previous studies en- ergy density is manipulated across the day, with subjects offered different foods, e.g., high-fiber vs. low-fiber, high-energy foods. What we did to manipulate carbohydrate and fat was to vary one meal; we were able to manipulate by 400 kcal of either carbo- hydrate or fat. We used four different con- ditions: two 800-kcal meals, which were ei- ther high in carbohydrate or high in fat, and two 400-kcal lunches either low in carbohy- drate or low in fat. At Johns Hopkins we have an environment in which people can live and which enables us to measure ev- erything they do over long periods of time. This particular experiment lasted for 13 days with a run-in day and three days on each of the four different kinds of lunch.

We found that when we reduced the car- bohydrate and fat content of the lunch, the subjects made up the 400-kcal difference by the next meal, i.e., within 4-5 h. The subjects couldn’t tell the difference when we did sensory testing afterward. When we looked at total intake over the three-day pe- riods of any one diet type, intake was the same overall. In our study, subjects had a lot more opportunity to make up the calo- ries than in studies where subjects have only the manipulated food throughout the day. So, to have the opportunity to com- pensate is extremely difficult in some of these studies. When setting up the experi- ments, many investigators don’t think

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about this aspect. You must have the op- portunity to adjust intake at other times of the day.

Van Itallie: I think that in making the transition from satiety signals to energy balance, it’s im- portant to keep in mind that the responses to these signals are conditioned, in many instances at least, by the nutritional status of the organism. If you give CCK to an ani- mal that has been deprived, it won’t re- spond, because there seems to be some modulatory effect on the response to sa- tiety signals.

We should be talking about how the body is refueled and maintains its energy ho- meostasis. We could focus on energy fluxes and the interrelationship between liver glycogen as one source of substrate for the body and brain and on the adipose tissue, which provides free fatty acids, par- ticularly during the postabsorptive state. Dr. Flatt’ss recent review suggests that the control of food intake is related to a rela- tionship between fat and glycogen as sub- strates. Since glycogen is periodically de- pleted, it would be the logical substrate to be monitored by the brain if a depletion- control mechanism operates. When Mark Friedmang gave agents that blocked both oxidation of fatty acids and glucose, he found that small amounts of either type of blocker failed to stimulate food intake but that the two types together did promote eating. And then there is the other view that since there is always a supply of fatty acids, perhaps there is some relationship be- tween the rate at which fatty acids are re- leased by adipocytes and the extent to which they spare the rate of liver glycogen depletion. With large fat cells, more fatty acid will be released and glycogen will be depleted more slowly, and this factor may tend to cut back food intake.

York: Our glycogen stores are very limited, and we eat the equivalent of our glycogen stores every day in dietary carbohydrate. So, we would expect the system to be very

responsive to depletion of carbohydrates. However, we are only eating a very small percentage per day of our total store of fat; thus we would need an extraordinarily sen- sitive system if we could actually monitor its depletion in a given day. Therefore, I was actually very surprised by the results that Dr. Pi-Sunyer presented, that we are able to adapt to a depletion of fat as easily as we were to carbohydrate because that implies an incredibly sensitive system.

Olson: I too thought there would be more vigorous debate between Dr. Rolls and Dr. Pi-Sunyer about this short-term response. I take this opportunity to remind you of the study of Lissner et al.1° They changed the density of food by reducing fat from 40% to 20% of calories, with correction for sensory input. They used graduate students and young faculty members as subjects. The conclu- sion from studies lasting six weeks was that energy intake was reduced on the low- fat diets and the subjects lost weight. Only a small amount of caloric compensation occurred, particularly in the lean subjects.

Rolls: But the study of Lissner et aI.lo involved manipulating all the foods within all the meals, and that may make a big difference. I think if we could all be eating these low- fat, reduced-sugar foods all the time and not be tempted to eat more fattening foods, then it looks from a number of studies (e.g., Duncan et al.,” Glueck et a1.,12 Lissner et al.lO) that you can keep food intake down and lose weight. We, however, were look- ing at manipulation of just one meal. Most of my studies until now have been done with even shorter times, within 1 or 2 h. I find that aspartame-sweetened foods are just as effective in reducing hunger as su- crose-sweetened foods over 1-2 h, which is quite different from what we find when studying the effect of the next meal. An- other point that hasn’t been raised is that there is probably some kind of threshold caloric difference (10-15%) that you need before the difference is detected.

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Olson: Could the difference in results reflect gen- otypic differences in signal recognition rather than the results of changes in caloric density because none of us is using many subjects?

Rolls: I think that is one of the major challenges. In some of these caloric compensation studies with humans, you get subjects going in exactly opposite directions; you look at mean data and it all evens out, so that it looks like perfect compensation. But that wasn’t the case in the study that we have just done. I think the big challenge is going to be trying to figure out why some people can regulate better than others. It’s very clear that people are different.

Blundell: It has just struck me that during the last 2 h we have been in a state of satiety after lunch. And this satiety has been dissipating during the afternoon. We are having great difficulty describing this state and much greater difficulty describing the physio- logic changes responsible. The distinction between short-term and long-term studies is important. Most of the short-term studies are designed to define biologic character- istics of the system that produces a biologi- cally relevant response to the food con- sumed. The long-term studies are designed to show the efficacy of a particular treat- ment on body weight. But people can delib- erately override the biologic signals and still undereat or overeat. An interesting study was done by the Unilever group in Vlaardingen (The Netherlands). Van Amels- voort and his colleague^'^ published it very recently; it was a short-term study to inves- tigate the satiating capacity of either car- bohydrate or fat. The subjects had four meals varying in carbohydrate and fat ratio from 2.4 down to 0.6. The interesting fea- ture was that the meal with the greatest proportion of fat in it was the least satiat- ing. In other words, it seems that our bio- logic system is less prone to sense dietary

fat, so fat can be smuggled into the body undetected.

Bjorntorp: Is there a role for fiber here, and if so, is its effect via dilution?

James: Ken Heaton14 would have us believe that there is a sensory input after a meal, based on distension of the gut; this may make high-fiber diets very important. Whatever the mechanisms of appetite control, we know from studies showing the poor flexi- bility in energy expenditure that food in- take must be controlled to within 215% of the prevailing intake if energy balance is to be preserved.

Garn: How much can the control of energy intake explain the large population differences in fatness? How much does food selection help to explain the very large differences in fatness in different socioeconomic groups? In the United States the group dif- ferences may amount to 10-15 kg of fat. Do you have explanations for these differ- ences between or within populations and can we make animal and human studies coherent ?

James: There have been a series of models con- structed on the basis of physiologic data on humans. Payne and Dugdale15 were the first to suggest that if you assume that food intake is random (within certain limits) but that you have metabolic regulators that dis- criminate between individuals in the min- ute energetics with which they dispose of food after a meal, then the cumulative, sus- tained discrimination between those indi- viduals is manifested by a slow, evolving change in weight, which is different for dif- ferent individuals and would take a sub- stantial period of time-they said two years or so-before there is a new period of weight stability. We have done similar mod- eling but we used calorimetric data, and we

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can show that if intake changes by 1000 kJ (roughly 250 kcal), then it takes up to five years to increase your weight by about 8-1 1 kg, depending on what assumptions you make, e.g., about physical activity. The implication is that if you don’t put on weight in a slow and evolving way, then you must either spontaneously change your physical activity patterns or spontaneously show regulatory changes in food intake. You can’t have it both ways, because if you look at the energetics of energy balance, we don’t have a mechanism for instantly disposing of lots of excess calories. The rate of change of body weight of people within the community is such that you are usually dealing with people who change their weight at a rate signifying a difference between intake and expenditure on a chronic, sustained basis of only about 2-3% per day.

Garn: That is correct. A small change in either di- rection in the caloric balance over the years accounts for what we see. These are the weight- and fatness-changing people. Then, at the other end, there is another substratum of people who show very, very little change over a five-, ten-, 20-, or even a 40-year period.

Booth: We don’t have coherent theories to trans- late our experiments on short-term control in animals or people into the longer-term control of intake. The largely genetic deter- mination of differences in obesity exists despite the high intensity of dieting in the American culture. Dieting doesn’t do any- thing to the genetics of obesity. So, one point is that, insofar as genetics has the upper hand in that environment, there is no effective environmental control of intake, or indeed expenditure, of the energy bal- ance. We too have done modeling of long- term regulation based on a short-term con- trol system with negative feedback systems and found that things tend to be buffered -by intake in this case. And it happened

that the systems we concentrated on were meal-to-meal satiety, meal size, learning of controlled meal size, conditioned satiety, and the gastric emptying rate. When we coupled those three sorts of controls of variations in food intake with a very weak representation of feedback from the long- term size of the fat cells, then we too got the computer model regulating its body weight over about 18 months, with a large excursion of about 10 kg of fat content ei- ther way. So, when you couple a set of short-term control mechanisms and let them cooperate and let their effects aver- age out over a long term, you can get any sort of precision, or lack of precision, of regulation you want from the calculations.

Van Itallie: The Japanese Ministry of Health did a sur- vey on 21,000 Japanese and found that their weights were very close to Metropoli- tan Life Insurance standards for desirable weight, whereas Americans of comparable ages were substantially heavier and, by Japanese standards, people considered by Americans to be of normal weight are sig- nificantly overweight. So, one question is to try to explain why the Japanese are as slender as they are vis-a-vis Americans. And, as you know, one explanation has been the Japanese diet. Although there may be genetic reasons also, Japanese who emigrate to the United States gain sig- nificant amounts of weight when they take on the American way of life.

As to groups in the United States, 61% of middle-aged black women are obese or overweight, as compared with a 31% preva- lence among white women. The multiple- logistic analysis done by the National Center for Health Statistics indicates there are two independent contributory factors to this obesity. One is race, and the other is socioeconomic status. As you know, the prevalence of obesity among women below the poverty line in the United States is al- most double that of women above the pov- erty line. Men’s obesity rates do not seem to be affected by the socioeconomic level.

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Some obesity can be explained on racial grounds, e.g., Pima Indians. In Phoenix they found that energy expenditure per kg of lean body mass in the Pima Indians who later become obese is lower than in those who do not become obese. So, there is some indication that there may be some genotypic thriftiness in Pima Indians and probably in other people who, from a racial standpoint, are predisposed to become obese. It is really surprising that many Americans are not obese, given the envi- ronment in which they live. It seems to show that the adipose tissue is a flexible organ that will respond to different dietary environments in an appropriate way. I don’t think there is a regulatory system in the body that is trying to achieve Metropolitan Life standards for body weight. I think it is an issue of physical activity and diet, and probably genetic factors, that determine the way people respond to diet. And it does seem that populations who subsist on high-fat diets are particularly vulnerable to having a high prevalence of obesity.

Rosenberg: Dr. James, I’d like a point of clarification. It seems to me you made the point that the nature of the fluctuations within calories expenditure differences is not likely to ex- plain long-term changes in regulation of body weight. What I thought I heard you say was that one needs to look at dietary modifications in order to understand en- ergy regulation. On the other hand, there has been discussion here that very small differences in energy expenditure can re- sult in changes in body weight over periods of time. Is it likely, going back to the ge- netic model, that the genetic differences are in fact being expressed by thriftiness or lack of thriftiness in energy utilization, as opposed to the other possibility that ge- netic factors may influence controls of di- etary intake? I have talked to psycholo- gists, who say that there isn’t much evidence that genetics influence taste pref- erence and so forth, so is there any evi- dence that genetics influence dietary in- take, as opposed to energy utilization?

James: A long time ago Griffith and Paynel6 showed that the offspring of obese parents expended 20% less energy than the chil- dren of lean parents. And therefore, be- cause they were in rough energy balance, their energy intake was also 20% less. If you look at the data on Pima Indians, there is a very small difference between the basal metabolic rate of those Pima Indians who do put on weight and those who do not. In- dividuals who do put on weight, however, have a lower resting energy expenditure. And that low rate is sufficient to account for a progressive increase in weight if food intake is identical in the two groups. And that’s the problem. If you have a 1% differ- ence in energy balance that is sustained, then you will put on 2, 3, or 4 kg per year. You will continue putting weight on until your adipose tissue and lean body mass increase and thereby cause more energy expenditure. This then buffers the small increase in intake that genetically pre- disposed persons must have developed for initiation of the change in energy balance.

Garn: Change in fatness is the rule, and it hap- pens on a family basis. Husbands and wives go up and down in weight together. And since they are not genetically related, that is not a genetic phenomenon. Parents and children go up and down together in relative fatness. Siblings living together at home go up and down together in relative fatness. But of course all of these associa- tions change when the children grow up and move away. Then the parent-child correlations drop way down, except for the 40-year-olds still living together with their parents in Tecumseh, Michigan.

Pi-Sunyer: I find it very surprising that one can corre- late this small difference in energy expen- diture with weight increase over such a short period of time. Why were these peo- ple hypometabolic before the investigators got there and had not increased their

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weight before? These are not children; they are young adults who presumably had this problem not only when they were 22 but when they were 18. And so why was it in just those few years of a study that they increased their weight and not before? I find it a very puzzling study.

Booth: I think we are confusing within-individual variability and between-individual variabil- ity. Documenting a 15% variation in intake is a huge problem because of the unreli- ability of intake measurements, which are at best + 10% That is within-individual vari- ability. But what we are trying to deal with is the problem of explaining the between- individual variability. I think one of the clearest ways to try and deal with this prob- lem of between-individual variability is to pick up the concept of vulnerability. What we need to look for is evidence of variation in the environmental factors bearing on people’s intake and expenditure; that varia- tion would explain a difference between vulnerable people. Someone with a genetic predisposition to obesity, with perhaps a thriftiness in energy expenditure, may ex- press it by a gain in body weight when on a high-fat diet. There are also the differ- ences, clearly evident in secular and cross- cultural terms, in the amount of physical activity, e.g., in the labor-saving activity of a transport culture. If we can increase physi- cal activity in some individuals susceptible to weight gain, we would be able to in- crease the environmental control of obesity and decrease the genetic control. Probably more important in the British culture than getting more exercise or even reducing the fat intake of people with a disposition to get fat is avoiding the calories slipping past the short-term regulatory mechanism be- tween meals. These calories are in the soft drinks used in the studies of Porikos17 and in the high-fat snack foods used in some of the studies on high-fat diets. These are three ways of providing environmental control in those individuals with a heavy genetic propensity to obesity.

James: Data from Patrick Franqois (personal com- munication) show that if you study 50,000 families in Brazil, and look at the diet and the physical characteristics of the people, the single most important discriminator of the weight-for-height, in other words, the degree of adiposity of the families, is the proportion of energy derived from fat in the diet; and that is notwithstanding differ- ences in diet, in income, and any other pa- rameters.

York: Most rats get fat on a high-fat diet. There is one type of rat that doesn’t get fat on a high-fat diet; that’s the S5B/P1 rat, which stays thin on a high-fat diet. It maintains a low food intake on a high-fat diet. And the difference between the S5B/P1 rat and all other types of rat (e.g., the Osborne-Men- del rat) is that the former has run a much higher blood level of ketone bodies, and ketone bodies are a major inhibitor of food intake. So, it may all come down, then, to a genetic difference in one’s ability to oxidize fatty acids. And if you can produce the ke- tone bodies-and these are very good in- hibitors of feeding-you will maintain a low body weight under that sort of dietary pressure.

Rozin: On the biologic side, there is a fair amount of evidence for inheritability of obesity. And that could easily differ across different eth- nic and cultural groups. However, most American women are on diets, so their weights are not going to be, as it were, rep- resentative of their free-eating weights. And in many other cultures, e.g., India, peo- ple are not concerned about overweight, thus they are not monitoring their intake. Therefore, one reason why you get popula- tion differences is different attitudes about what’s appropriate. The social impact of even a short period of overeating can last for days or weeks, and yet people tend to manage to control their weight over years.

Kare: I just wanted to correct one comment. If

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you present a male mouse with two fe- males, he is not attracted to the best-look- ing of the two females; he is attracted to the female whose genes are least like his own, and he does that on the basis of odor. And my colleagues have identified the locus on the gene of the 17th chromosome that prepares him to be attracted to those odors.

James: Bouchard18 looked at the variance in adi- posity within populations and looked at his genetic analyses and so on and put forward the proposition that about 25% of the inter- individual variance in adiposity might be ascribable to genetic factors mediated by either expend i t u re or intake, sensitivities, or absolute differences in control mecha- nisms.

Blundell: I’m still a little uneasy about the potency of these correlations. They seem to be reliable when derived from big populations. And if they are firm, they ought to be biologically relevant and there should be some inter- pretation of these very interesting correla- tions.

Stun kard : Bouchard’s estimates have challenged our traditional twin studies, which undoubtedly overestimated heritability. We have just fin- ished a study in Sweden (with Nancy Pe- dersen and Jennifer Harris) using sepa- rated identical twins that still shows a remarkably high heritability (about 65%). There is presumably no environmental con- tamination. But to get back to this issue of the interaction: there is a kind of paradox. There is quite a high correlation between socioeconomic status and prevalence of obesity, particularly among women. And there is almost no correlation between re- ports of food intake and obesity or body mass index until you get to be quite obese. That’s always been the big puzzle, and one possible explanation comes from the work that R~lland-Cachera’~ has been doing in Paris.

She has been doing some very careful studies of children and monitoring their food intake by social class. She found that the food intake of lower-class children is significantly higher than that of middle- class children, which is higher than that of upper-class children. Possibly what’s hap- pening is that you have different thresholds for a genetic effect. Therefore, in the upper-class children, since their general food intake is lower, a smaller percentage reach that threshold and manifest their ge- netic potential to obesity. A middle-class child has a larger food intake, and there- fore more genes are brought into play; fi- nally, you consider the lower-class children with a very high food intake, and more of them then show this gene-environment in- teraction.

Rolls: For those of us who study food intake, one of the big problems is that unless we are going to study each person as an individ- ual, we have to lump people into groups. In the 1960s and 1970s subjects were put into categories by body weight. And that has turned out not to be a very productive way of looking at things. Now, Dr. Stunkard*O has described his eating inventory, which we use to assess dieting behavior of sub- jects (i.e., dietary restraint). However, we have done studies of people with eating disorders (i.e., anorexia, bulimia, and un- successful dieters). Although all those groups show high dietary restraint, they show very different eating behavior in re- sponse to different caloric loads. Dietary restraint isn’t going to be the only answer because it is one of the characteristics we have to use in the absence of guidelines. One question that I often ask is, “How do we know who our control or reference sub- jects should be?”

Typically, in our studies we choose peo- ple who show low dietary restraint and who don’t have a history of a lot of body weight fluctuations; we also make sure they don’t have any history of an eating disorder or depression. We go through many question- naires to try to get a control subject. But

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such people are hard to find. How “typical” are they? So, who is our standard person against whom we compare? How we lump all these other people into different catego- ries makes a big difference to the results that we get.

Let me also say that it’s not typical in eat- ing studies to screen for a human subject’s ability to taste and smell. We are doing it now in our studies of eating disorders, and we are also going to be doing some studies across different age groups. For example, what Morley Kare said last night about the elderly eating normally may be correct. There is a tremendous lack of data on the elderly. We know that the elderly show a decrement in their ability to smell. Taste, as Dr. Kare said, is not so clear. The elderly have tremendous malnutrition problems. Nobody has ever looked at the elderly’s ability to regulate food intake in response to challenges. We know that the elderly can’t regulate fluid intake in response to challenges. We have shown that quite clearly, but we don’t know how these sen- sory impairments ultimately are going to tie up with eating behavior.

Rozin: In picking subjects or grouping them, psy- chologists have paid too little attention to cultural factors. I think the single best pre- dictor of what someone will eat and how he or she will eat is the individual’s ethnic or cultural group. If I were to balance sub- jects, I’d just balance ethnic origin. I think i f you have to know about someone’s atti- tudes toward food and food preferences and you could ask only one question, the question you should ask is, “What is your cultural or ethnic group?” With respect to food intake, you should also know the gender because gender has an enormous influence-at least in many cultures-hav- ing to do with attitudes toward body image and monitoring of weight. There are very few other predictors. Personality tests, for example, are not very good predictors of how people behave toward food. The pow- erful thing is the whole cultural view of what food is, ho:v you eat, what a meal is-

those things are going to be powerful influ- ences. I think it would be dangerous to mix cultural groups across experimental and control groups, particularly.

James: But you have no evidence that, when in terms of the control systems we have been talking about, there are ethnic or gender- based differences in their responses, do you?

Rozin: No, except that the notion of a meal is so different across cultures or even within cul- tures. For example, if you give someone a breakfast vs. a dinner experimental meal, the whole expectation for what the meal is, what its size ought to be, and so on is very different. You can see it even within a cul- ture. However, people tend not to notice whether it’s a lunch or supper you’ve given them. Usually lunches are given in the ex- perimental studies because that’s when people are available. That’s perfectly OK, but it doesn’t follow that you’d get similar data for breakfast. Breakfast, after all, fol- lows the longest period of food deprivation and, for many people, is their smallest meal. Now this is a very complicated situa- tion that undoubtedly has to do with things other than energy balance.

Stricker : I’d like to raise a question of the people who study human feeding. I have always thought of the problem of human obesity as the problem of human obesities-plural. Having looked at many different animal models of obesity, I find that some are based on overeating, with nothing wrong with the metabolism, i.e., the animals be- come fat because they overeat. There are other models that are primarily metabolic, i.e., the animals overeat because they are becoming obese. I assume that there must be many different types of human obesity, perhaps many more than there are among the rats. 1 would therefore assume that if you were studying a collection of people whose only salient feature was being over-

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weight, then you would see a lot of variabil- ity among the individuals. If you were look- ing for any significant variable, you might not be able to find it because a proper sort- ing of groups hadn’t been done in the first place.

Booth: Maybe we ought to do our dieting studies by just asking the subjects whether or not their natural parents are both obese. That would be picking up on some sort of ge- netic factor by which people might be made vulnerable by their energy intake and energy expenditure habits. I suggest that we should respond to your question by asking what mechanisms you are inter- ested in and what ideas as to individual dif- ferences we have that would be most im- portant to control or measure.

Garn: For American, British, French, and other women, the husband’s education is the best single determinant of their level of fat- ness. For our American women, the wife’s fatness goes down by 0.7 kg of fat per year of a husband’s education. That’s a lot. And what is also interesting is that when highly educated men marry uneducated women they marry the skinny ones, whereas uned- ucated men marrying college-educated women marry the fat ones. So, the men marry those types expected for their own sociaVeducationa1 class.

MacFie: I was thinking about Dr. James’s original question. And I think Dr. Booth was quite correct. If you have a specific hypothesis in mind, there is a whole rationale of experi- mental design from the statisticians that will assist you in doing that very effectively. If, on the other hand, you are looking at a very large population, as the epidemiolo- gists do, then obviously you want to do some sort of blanket coverage. However, the most likely situation is that you haven’t got the money to do a very large study, and yet you don’t want to be always pinned down on exactly what mechanism you are

postulating. In a small study you wish to do something that provides the answers rele- vant to an epidemiologic study. Now that is exactly the position that market research consultants dealing with a food company are always faced with. They are up against a very tight budget, and what they are com- ing round to doing is to dispense with de- mographics; they are beginning to look at people’s behavior and to try to cluster them. The consultants ask themselves, “What is the minimum number of ques- tions to select these people on the street so that we can cover the spread of the popula- tion effectively?” And it seems to me that may be the way to answer your question. You need to have a preliminary look and use cluster analysis to deal with the natural segregation of groups by their behavior. In this way one tries to span the population as effectively as possible.

Stunkard: There are two methods that I think might be quite useful in selecting people for studies. One is to take the children of two fat and two thin parents, which actually Griffith and Payne16 did 12 or 13 years ago. This method gives a very high probability that the children are going to be either fat or thin. The other one that we have started to use is simply the metabolic response to two or three days of a very low-calorie diet. This is something that is built into weight-re- duction programs. Perhaps the people who respond rapidly with a large decrease in metabolic rate may have a more metabolic kind of obesity than people who respond very little or almost not at all, who might then be retrospectively classified as people who have had an increased food intake to explain their obesity.

MacFie: Dr. Kare said last night that people actually experience different sensations. That is perhaps not the model that I have thought about. I imagined that people get the same sensations, and I have explained the differ- ent responses to the attention they pay to a particular sensation. That would show in

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the multidimensional scaling work that I presented. You see, for example, that two people perceive a dimension quite repro- ducibly to start with, but that they swap over during the trial. I think that probably has to do with attention. In terms of the free-choice profiling, I am postulating that people are perceiving the same thing but describing it differently. Now if you look at preference, we do seem to find that we can classify and map very accurately the sen- sory perception of products. If we then take products out to consumers and ask them how much they like them, then we do seem to get proper sensory scores. David Booth and I have had an argument before about my not actually asking them what their ideal product was; I might then elicit a to- tally different psychologic process and get a totally different answer. So, I think there are several methodologic issues here.

Shepherd: Several points follow from what Dr. MacFie has just said and what Dr. Kare said yester- day. There is the world of difference be- tween measuring thresholds for individual taste compounds or odor compounds and trying to characterize foods. And, in gen- eral, it’s foods that people eat, it’s not nu- trients, and it’s not particular taste or odor compounds. Very often in foods the appro- priate compounds are not at threshold levels. And threshold levels don’t always predict very well even sensitivity above that level and quite often don’t relate to prefer- ences for the compound in a particular food above a certain level. We’ve looked at taste sensitivity and taste preferences for salts and tried to relate them to salt intake, and we’ve shown that taste sensitivities are a relatively poor predictor of salt intake. Taste preference is also a relatively poor predictor of salt intake. There is not a sim- ple relationship between sensory re- sponses or even preferences and the per- son’s actual behavior in consuming certain foods or altering his or her food habits.

James: Why don’t they do what they want to do?

Shepherd : Because, I think, there are a lot of external constraints. If you look at things like total salt intake, as you know well, most of the salt is not added by the individual. It’s in- herent in foods. When you eat certain foods you get a large amount of salt. You are likely to be eating those foods for rea- sons other than the taste response. Even for use of table salt, which we have looked at and Dr. Mattes2’ has studied, there is not a very close correspondence between sen- sory measures in the lab and behavior out in the real world. And there are several po- tential reasons having to do with people’s attitudes, beliefs, habits, and all kinds of expectations.

James: Thank you, very much. I think that’s a neat way of finishing off. We have to recognize that by tomorrow you’ll be able to look at the summary, which will attempt to at least highlight some of the issues that have de- veloped at this symposium. We have dis- cussed the balance of peripheral and cen- tral controls, the multiplicity of signals, and the new putative mechanisms for appetite control. From animal data it seems clear that food intake is regulated and that a whole set of mechanisms is involved, which may not have the same dominant components when it comes to humans. We also have to recognize that we have some confusion when relating short-term to even medium-term intake. But intake regulation of some sort seems to be quite important- how it relates to the behavioral patterns of people, how it relates to their body weight and to their genetic type, and how all this is integrated-and is one of the great mys- teries that we are going to have to tackle in the future. Certainly we know now, it seems to me, at the end of today, that the issue of looking at individuals is very important, and the challenge now is how to character- ize those individuals so that we can begin to become a little more discriminating in the questions that we ask in attempting to determine how food intake is controlled in humans.

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