w )<:
j:!:
0 0 0 LL
>-_J
<
0 35
30
25
20
1 5
RANGE OF CALORIC COMPENSATION
1 0 PRE-INFUSION
BASELINE NUTRIENT INFUSION DAYS
POST-INFUSION PERIOD
5
0 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 20
SUCCESSIVE TEST DAYS
Figure 9.2. Daily food intake of rats during a nine-day period when animals receive approximately a quarter of their daily caloric intake directly into the stomach, but all of the nutrients infused are fats, proteins, or carbohydrates. (Adapted from Panksepp,
1971;
see n.17.)
Methodological Difficulties in Sifting Important Regulatory Energy Balance Effects from Trivial Feeding Ones
Before discussing what we do know about long-term energy regulation, let us not underestimate the complex�
ity of short-term feeding control mechanisms. The sig
nals include ( l ) many oral factors; (2) a large array of stomach and gastrointestinal factors that act upon vari
ous brain mechanisms; (3) a diversity of metabolic fac
tors from various body compartments, especially the liver, which are reflected in circulating nutrients, some of which can affect the brain;
(4)
a great many neurochemical factors; and (5) a vast array of nonspecific influences that have little to do with energy regulation, such as feelings of sickness and malaise, as well as emotional and mood changes that can dramatically af
fect feeding behaviors. Indeed, an enormous number of short-term factors have been shown to control feeding
from rattling an animal's cage to giving drugs that make them ill-but most tell us little about the mechanisms that normally mediate long-term body-energy regula
tion. On the other hand, various short-term controls, such as rapid distention, and also metabolic signals from the gastrointestinal system, which ascend into the brain via the vagus nerve, are essential for the normal short
term patterning of food intake.1s Obviously, we must
always be concerned about the behavioral specificity of our manipulations and must utilize various experi
mental means to distinguish nonregulatory affective influences from those that normally control appetite.
Since so many factors can reduce feeding in the short term without having much to do with the physiology of normal regulatory mechanisms, how shall we dis
criminate the important physiological factors that nor
mally reduce feeding from those that decrease intake for trivial and temporary reasons?
This is no simple matter. Obviously, such issues are especially problematic in studies that analyze feeding for short periods after experimental manipulations, es
pecially when psychoactive drugs are used. We must seriously consider the feeling states of animals in order to avoid misleading ourselves about the types of effects that are reducing appetite. Accordingly, manipulations that increase feeding generally provide more insight into the nature of the underlying physiological controls than manipulations that reduce feeding. However, ongoing research is still strongly biased toward the study of agents that inhibit feeding, because the discovery of a truly effective long-term appetite control agent would be financially lucrative. In any event, careful investi
gators agree: To interpret appetite-inhibition effects cor
rectly, one must conduct a variety of controls to evaluate whether the effects are behaviorally specific.
Unfortu-nately, the recognition of such interpretive problems is more widespread than are empirical solutions.
The most common way to evaluate behavioral speci
ficity is by determining whether agents that reduce food intake also produce conditioned taste aversions (CTAs).19 This procedure relies on the fact that animals will typi
cally not eat foods that have been followed by illness.
All drugs that make animals sick will provoke learned rejections of novel foodstuffs with which the feelings of malaise have been associated. A single incidence of sickness is usually sufficient to establish a specific food
· aversion, and the illness can even occur many hours after exposure to a new food source. Thus, if appetite
reducing drugs also produce conditioned food aver
sions, investigators typically infer that the agent reduces food intake by nonregulatory means. For instance, one widely touted "satiety agent" called cholecystokinin (CCK), a neuropeptide, has been found, upon close analysis, to reduce food intake by causing gastrointes�
tina! distress, transmitted up to the brain via the vagus nerve, rather than a natural feeling of satiety.20 It has also recently become apparent that CCK fragments may precipitate panic attacks in humans.21 Many other puta
tive "satiety agents" may be comparably flawed.
One potential shortcoming of the CTA criterion is that animals can also learn "conditioned satieties." Thus, the reduced intake of a novel foodstuff that has been associated with an experimental treatment may simply indicate that the animal is treating it as a very high
energy food source. Of course, this could be evaluated by testing the animal under conditions of hunger. If the aversion persists, it is unlikely to have been a
"condi-ENERGY IS DELIGHT
171
tioned satiety," but investigators rarely implement such control maneuvers.22 Another shortcoming is that many substances produce CTAs, including presumably plea
surable items such as amphetamines and opiates, so it remains possible that the CTA measure also detects agents that simply produce new and powerful feelings other than malaise.
Another suggested control procedure has been to monitor the behavior patterns of animals after a normal, satisfying meal. This typically consists of a sequence of grooming, exploration, and then a nap.23 However, this is a fairly diffuse behavioral criterion of satiety, since an animal behaves in this way even if a meal is prematurely terminated or following other satisfying activities such as sex. Thus, it would be useful to have more specific behavioral assays that leave less room for ambiguity.
One measure that has not received the attention it deserves is the tendency of animals to rapidly eat mas
sive amounts of tasty food they receive only occasion
ally, even when they are not hungry. Indeed, well� fed rats will eat as much of foods they greatly prefer, such as raw ground meat, as very hungry rats. By compari
son, starved animals eat much more of their normal maintenance chow than nondeprived animals (see Fig
ure 9.3). This "pig-out" phenomenon, whereby animals become quite insensitive to the cues of long-term energy balance because of the overwhelming effect of taste, could be used as a credible measure of normal satiety.
For instance, if one has a drug that is presumed to evoke a normal feeling of satiety, the drug should selectively reduce intake of a maintenance food to which an
ani-Intake as a Function of Level of Deprivation With Two Incentives
18 16 14 (i) 12 E S?- 10
w"' -ro 8 .5 "0 0
6
� 4 2 0
HAMBURGER Treat
&;----------------------------------- -- -----·
Maintenance CHOW
Ad Lib. 24 Hrs.
Deprivation Level of Food Deprivation
Figure 9.3. A summary of the effects of high-incentive (raw hamburger) and much lower-incentive food (the animals' normal maintenance chow) on intake as a function of degree of prior food deprivation. (According to unpublished data, Panksepp,
1974.)
mal is habituated but have little effect on the intake of a very tasty food that is provided infrequently. A feel
ing of sickness should reduce the intake of both types of food. Unfortunately, this test has rarely been em
ployed in feeding research.24
An even better way to evaluate this troublesome issue might be to identify an active behavior that is markedly increased by normal satiety. We have identi
fied one such behavior: rough-and-tumble social play in young rats.25 Hunger produces a dramatic reduction in their play behaviors, as do other aversive states (see Figure 1 . 1 ), but a single meal brings play right back to normal. One could argue that the ability of a substance to restore play could be used to determine that a nor
mal "satiety process" has been activated. Thus, not only should an agent reduce feeding; if it produces normal satiety it also should increase play. In our attempt to evaluate several agents in this way, we have found that opiate antagonists, which are quite effective in reduc
ing eating, have no ability to increase play in hungry animals. Similar problems have been observed with CCK. However, some increase in play was observed following treatment with bombesin, another potential satiety peptide that is released into the circulation from the stomach following eating. More recently, I evalu
ated the ability of another new "satiety agent," named glucagon-like peptide-1 (GLP-1 ),26 to reverse play inhi
bition caused by hunger; if anything this "satiety fac
tor" reduced play even further, suggesting it was pro
voking anxiety rather than satiety.27
Much more work needs to be done on the many pos�
tulated "satiety agents." Until adequate work along these lines is conducted, we simply will not know whether the ability of specific agents to reduce feeding should be deemed important for clarifying the underlying physi
ological issues. For this reason, the exceedingly long list of substances that have been found to reduce short-term food intake will not be discussed in this chapter. There are many reasons to believe that short-term satiety pro�
cesses and long-term regulatory processes, which surely interact, can also be distinguished in the brain.2&
The Underlying Nature of Energy Regulation
We have already seen that feeding controls are subser
vient to the body's energy-regulating processes (Fig
ure 9.2). To understand how animals maintain their body energy at stable levels, we must examine the na
ture of the specific nutrient detector systems that moni
tor bodily energy transactions, especially in the long term, and we must clarify their interconnections to be�
havioral control networks such as the SEEKING sys
tem (Figure 9.1 ) . .In other words, to fathom the under
lying regulatory processes, we need to know as much about what food does to the animal's body as we know about what animals do to food.
To maintain a stable level of energy and hence stable body weight, animals must consume as much food as
750
KCal +20,000
KCal �1000
KCal +19,750
KCalRAT CHOW RAT H EAT
Daily Intake Error
< 0.7 KCal
Figure 9.4. A female rat's approximate yearly energy balance equation. A great deal is eaten without much change in body weight. With the small increase in body weight, the daily intake error was less than a kilocalorie.
The remaining energy was dissipated as heat, most of it in the conduct of essential metabolic transactions. (Adapted from Panksepp, 1978; see n. 32.)
.,.__... Normal rats Y ' 2-47+ 0·66 COS ( X )
o-o Diabetic rats Y ' 1·08 + 0·33 COS ( X )
5 Day 1 Day 2 Day 3
4 .!? a 3 � �
-.; "' U) 0
10 20 30 40 50 60 70
Day 4
80 90 100
Time ( ho u rs )
Figure 9.5. Average daily feeding cycle across three to four days in a group of 10 normal rats and 10 diabetic rats given free access to food. The satiety ratios (postmeal interval/meal size) reflect the duration of feeding inhibition for each unit of food eaten. The low points indicate where the animal is eating many meals that do not quell its appetite for a long period, while the peaks reflect periods during the day when the animal eats fewer meals and the meals are much more satiating. The equations reflect the best-fitting cosine function for these results. (Adapted from Panksepp, 1978; see n. 32.)
they dissipate in metabolic activity (Figure 9.4). In animals maintained under routine laboratory conditions, the daily difference or error in input and output is mi
nuscule. This is also generally the case in most humans across long spans of time, even though inactivity and free access to many tasty foods promote instabilities in the regulatory system.29
Unlike energy utilization, depicted on the right side of the equation in Figure 9.4, the process of energy acquisition (i.e., meal taking) is discontinuous. Feed
ing is a periodic series of discrete events, and a great deal of effort has been devoted to analyzing the tempo
ral structure of these events in the laboratory rat. One finding stands out: Animals can maintain stable body energy patterns through a variety of behavioral strate
gies.30 Even under conditions where animals are al
lowed to eat a single large meal a day, they tend to maintain a weight only slightly below normaL Also, this is the type of regulation animals exhibit when they are given distasteful food or when they must expend a great deal of effort to get meals. In other words, when rats must work on very high fixed-ratio schedules (see the
"Afterthought" of Chapter 1 for a description of sched
ules of reinforcement) to gain access to a feeding dish, they typically take infrequent, large meals. On less de
manding schedules of reinforcement, they take smaller and much more frequent meals. Thus, under various economic conditions, animals regulate their energy
bal-ance equally welL However, the behavioral details dif
fer,31 indicating that regulation can be achieved through several distinct behavior patterns.
Overall, one of the strongest influences on the pat
terning of feeding when there is plenty to eat is the in
fluence of circadian variables (see Chapter 7). Humans and animals alike eat quite differently at different times of day. A key to understanding the nature of energy regulation is that circadian differences are also evident in the way our bodies process food.
Meals and the intervals between them have differ
ent effects depending on the time of day. The satiating capacity of food and the hunger-inducing capacity of time without eating vary across the day.32 Units offood are more satiating during the half day when animals normally sleep. Similarly, long intervals between meals are less likely to evoke hunger during those times of day (Figure 9.5). Conversely, during the half day or so when animals are typically active, food is relatively less satiating, and time without eating is more liable to pro
voke hunger. The overall result is that during half of the day, animals typically consume more energy than their bodies need, whereas during the other half, they eat less than they need. Of course, nocturnal animals such as rats and light-loVing animals such as humans exhibit these phases at different times. The two distinct phases of the daily feeding cycle correspond to high energy storage (i.e., the anabolic phase when fat is
174 BASIC EMOTIONAL AND MOTIVATIONAL PROCESSES
deposited) and high energy utilization (the catabolic phase when lipids are extracted from stores) of the daily energy cycle.33 This cycling is distally due to the inter
nal 24-hour clock of the suprachiasmatic nucleus (see Chapter 7). It is proximally linked to the cyclic hor
monal tides that control the dispersion of energy throughout the body (e.g., Figure 7.3).
The body's daily energy cycle is largely regulated by the pancreatic secretion of insulin,34 the primary energy storage (anabolic) hormone. Insulin allows glu
cose to enter cells in most tissues, especially ih adipose tissue. The brain is the only organ that extracts glucose from the bloodstream completely without assistance from insulin, except for the small groups of neurons at the base of the hypothalamus that regulate long-term energy balance. This insulin insensitivity allows animal brains to continue to function efficiently when energy resources are low so they can continue to seek food.
Indeed, when animals are starved, their insulin levels drop to very low levels.
Insulin secretion normally occurs promptly at the outset of eating as a conditioned response to the taste of food; this is called the cephalic phase of insulin secre
tion. 35 This anticipatory surge of insulin reduces glu
cose output by the liver and allows increased absorp
tion of blood glucose into muscles and adipose tissue.
These rapid changes probably contribute to the "appe
tizer effect" that small units of tasty food exert when given just prior to a larger meaL It is known that in rats a small reduction of blood sugar begins to occur a few minutes before the initiation of meals, suggesting that such a reduction either triggers meal irritation or is a conditioned "appetizer" response when animals begin to "think" about eating.36
After the meal is consumed, there is a larger surge of insulin secretion in the metabolic phase, which is proportional to the food consumed. This serves to dis
tribute the incoming energy to long-term storage pools of adipose tissueY There is no reason to believe that the energy deposited in these peripheral fat stores has any direct effect on the brain's feeding�control mecha
nisms, since surgical removal of body fat has relatively little effect on appetite.38 However, as will be discussed later, molecules signaling satiety do appear to emanate from the fat. Fat stores may also affect feeding meta
bolically when the energy CUITency is slowly withdrawn during the course of each day. During the half day when these stores are being utilized, appetite remains low for long periods, and eating tends to be light and infrequent.
One can easily imagine the weight problems that could emerge if the normal mechanisms that control this energy withdrawal process were compromised. If one stored energy effectively but could not retrieve the stores, one would get hungry easily, overeat, and soon become obese. Indeed, many feeding and body weight disorders arise because certain organisms tend to per
sist in the storage phase of their daily energy cycle. In short, the normal balancing of the daily energy account
has gone awxy in certain forms of obesity. Some of the problems arise from peripheral dysfunctions, while oth
ers, as we will see, reflect disorders in several brain mechanisms that monitor energy flow within the body .39 These issues cannot be overstated. To really under
stand the manner in which the brain regulates long-term energy balance, we will need to know as much about the details of energy metabolism, and correlated neu
rochemical events, as about feeding behavior. It will probably be in the area of long-term metabolic and regu
latory feedback processes that truly effective medical maneuvers for the control of eating disorders will even
tually be found. Indeed, results obtained in the last few years are true breakthroughs.
Recently it has been found that genetically obese rodents (i.e., ob/ob mice) lack certain fat-derived plasma proteins, called leptins (after the Greek leptos for "thin"), that are abundant in their lean counterparts. When leptins have been restored by injections, the obese mice begin to sustain normal body weight.40 Although we do not yet understand what these proteins normally do within the metabolic system, the lure of profits has led biotech firms to spend fortunes to purchase the patent rights to develop and market such gene products as potential weight-control agents. Obviously, an effective medicine to control obesity will reap great profits, but it presently seems unlikely that much money will be made directly from leptin. There is no evidence that obese humans typically have a deficit of this protein.41 As I will describe in detail later, some forms of human obesity may be due to a lack of the receptor for this peptide signal rather than to a deficit in the amount of leptin released from the adipose tissue.
Brain Mechanisms of Energy Balance Regulation
The promise of substantive biomedical help for long
term body-weight problems remains on the horizon.
Most of the pertinent work has been conducted on the omnivorous laboratory rat, which, fortunately, appears to have an energy regulatory system closely resembling
Most of the pertinent work has been conducted on the omnivorous laboratory rat, which, fortunately, appears to have an energy regulatory system closely resembling