Stability of the body's total mass and composition over long periods requires that energy intake match energy expenditure. As discussed in Chapter 72, only about 27 per cent of the energy ingested normally reaches the functional systems of the cells, and much of this is eventually converted to heat, which is generated as a result of protein metabolism, muscle activity, and activities of the various organs and tissues of the body. Excess energy intake is stored mainly as fat, whereas a deficit of energy intake causes loss of total body mass until energy expenditure eventually equals energy intake or death occurs.
Although there is considerable variability in the amount of energy storage (i.e., fat mass) in different individuals, maintenance of an adequate energy supply is necessary for survival. Therefore, the body is endowed with powerful physiologic control systems that help maintain adequate energy intake. Deficits of energy stores, for example, rapidly activate multiple mechanisms that cause hunger and drive a person to seek food. In athletes and laborers, energy expenditure for the high level of muscle activity may be as high as 6000 to 7000 Calories per day, compared with only about 2000 Calories per day for sedentary individuals. Thus, a large energy expenditure associated with physical work usually stimulates equally large increases in caloric intake.
What are the physiologic mechanisms that sense changes in energy balance and influence the quest for food? Maintenance of adequate energy supply in the body is so critical that there are multiple short-term and long-term control systems that regulate not only food intake but also energy expenditure and energy stores. In the next few sections we describe some of these control systems and their operation in physiologic conditions, as well as in obesity and starvation.
The sensation of hunger is associated with a craving for food and several other several physiologic effects, such as rhythmical contractions of the stomach and restlessness, which cause the person to search for an adequate food supply. A person's appetite is a desire for food, often of a particular type, and is useful in helping to choose the quality of the food to be eaten. If the quest for food is successful, the feeling of satiety occurs. Each of these feelings is influenced by environmental and cultural factors, as well as by physiologic controls that influence specific centers of the brain, especially the hypothalamus.
The Hypothalamus Contains Hunger and Satiety Centers.
Several neuronal centers of the hypothalamus participate in the control of food intake. The lateral nuclei of the hypothalamus serve as a feeding center, and stimulation of this area causes an animal to eat voraciously (hyperphagia). Conversely, destruction of the lateral hypothalamus causes lack of desire for food and progressive inanition, a condition characterized by marked weight loss, muscle weakness, and decreased metabolism. The lateral hypothalamic feeding center operates by exciting the motor drives to search for food.
The ventromedial nuclei of the hypothalamus serve as the satiety center. This center is believed to give a sense of nutritional satisfaction that inhibits the feeding center. Electrical stimulation of this region can cause complete satiety, and even in the presence of highly appetizing food, the animal refuses to eat (aphagia). Conversely, destruction of the ventromedial nuclei causes voracious and continued eating until the animal becomes extremely obese, sometimes as large as four times normal.
The paraventricular, dorsomedial, and arcuate nuclei of the hypothalamus also play a major role in regulating food intake. For example, lesions of the paraventricular nuclei often cause excessive eating, whereas lesions of the dorsomedial nuclei usually depress eating behavior. As discussed later, the arcuate nuclei are the sites in the hypothalamus where multiple hormones released from the gastrointestinal tract and adipose tissue converge to regulate food intake as well as energy expenditure.
There is much chemical cross-talk among the neurons on the hypothalamus, and together, these centers coordinate the processes that control eating behavior and the perception of satiety. These nuclei of the hypothalamus also influence the secretion of several hormones that are important in regulating energy balance and metabolism, including those from the thyroid and adrenal glands, as well as the pancreatic islet cells.
The hypothalamus receives neural signals from the gastrointestinal tract that provide sensory information about stomach filling, chemical signals from nutrients in the blood (glucose, amino acids, and fatty acids) that signify satiety, signals from gastrointestinal hormones, signals from hormones released by adipose tissue, and signals from the cerebral cortex (sight, smell, and taste) that influence feeding behavior. Some of these inputs to the hypothalamus are shown in Figure 71-1.
The hypothalamic feeding and satiety centers have a high density of receptors for neurotransmitters and hormones that influence feeding behavior. A few of the many substances that have been shown to alter appetite and feeding behavior in experimental studies are listed in Table 71-2 and are generally categorized as (1) orexigenic substances that stimulate feeding, or (2) anorexigenic substances that inhibit feeding.
Neurons and Neurotransmitters in the Hypothalamus That Stimulate or Inhibit Feeding. There are two distinct types of neurons in the arcuate nuclei of the hypothalamus that are especially important as controllers of both appetite and energy expenditure (Figure 71-2): (1) proopiomelanocortin (POMC) neurons that produce a-melanocyte-stimulating hormone (a-MSH) together with cocaine- and amphetamine-related transcript (CART), and (2) neurons that produce the orexigenic substances neuropeptide Y (NPY) and agouti-related protein (AGRP). Activation of the POMC neurons decreases food intake and increases energy expenditure, whereas activation of the NPY-AGRP neurons increases food intake and reduces energy expenditure.
Feedback mechanisms for control of food intake. Stretch receptors in the stomach activate sensory afferent pathways in the vagus nerve and inhibit food intake. Peptide YY (PYY), cholecys-tokinin (CCK), and insulin are gastrointestinal hormones that are released by the ingestion of food and suppress further feeding. Ghrelin is released by the stomach, especially during fasting, and stimulates appetite. Leptin is a hormone produced in increasing amounts by fat cells as they increase in size; it inhibits food intake.
As discussed later, these neurons appear to be the major targets for the actions of several hormones that regulate appetite, including leptin, insulin, cholecys-tokinin (CCK), and ghrelin. In fact, the neurons of the arcuate nuclei appear to be a site of convergence of many of the nervous and peripheral signals that regulate energy stores.
The POMC neurons release a-MSH, which then acts on melanocortin receptors found especially in neurons of the paraventricular nuclei. Although there are at least five subtypes of melanocortin receptor (MCR), MCR-3 and MCR-4 are especially important in regulating food intake and energy balance. Activation of these receptors reduces food intake while increasing energy expenditure. Conversely, inhibition of MCR-3 and MCR-4 greatly increases food intake and decreases energy expenditure. The effect of MCR activation to increase energy expenditure appears to
Neurotransmitters and Hormones That Influence Feeding and Satiety Centers in the Hypothalamus
Decrease Feeding (Anorexigenic)
a-Melanocyte-stimulating hormone (a-MSH)
Corticotropin-releasing hormone Insulin
Cholecystokinin (CCK) Glucagon-like peptide (GLP)
Cocaine- and amphetamine-regulated transcript (CART) Peptide YY (PYY)
Increase Feeding (Orexigenic)
Neuropeptide Y (NPY) Agouti-related protein (AGRP) Melanin-concentrating hormone (MCH) Orexins A and B Endorphins Galanin (GAL)
Amino acids (glutamate and g-aminobutyric acid)
Neurons of PVN
To nucleus tractus solitarius (NTS) •Sympathetic activity •Energy expenditure
Control of energy balance by two types of neurons of the arcuate nuclei: (1) proopiomelanocortin (POMC) neurons that release a-melanocyte-stimulating hormone (a-MSH) and cocaine- and amphetamine-regulated transcript (CART), decreasing food intake and increasing energy expenditure; and (2) neurons that produce agouti-related protein (AGRP) and neuropeptide Y (NPY), increasing food intake and reducing energy expenditure. a-MSH released by POMC neurons stimulates melanocortin receptors (MCR-3 and MCR-4) in the paraventricular nuclei (PVN), which then activate neuronal pathways that project to the nucleus tractus solitarius (NTS) and increase sympathetic activity and energy expenditure. AGRP acts as an antagonist of MCR-4. Insulin, leptin, and cholecystokinin (CCK) are hormones that inhibit AGRP-NPY neurons and stimulate adjacent POMC-CART neurons, thereby reducing food intake. Ghrelin, a hormone secreted from the stomach, activates AGRP-NPY neurons and stimulates food intake. LepR, leptin receptor; YiR, neuropeptide Y1 receptor. (Redrawn from Barsh GS, Schwartz MW: Nature Rev Genetics 3:589, 2002).
be mediated, at least in part, by activation of neuronal pathways that project from the paraventricular nuclei to the nucleus tractus solitarius and stimulate sympathetic nervous system activity.
The hypothalamic melanocortin system plays a powerful role in regulating energy stores of the body, and defective signaling of the melanocortin pathway is associated with extreme obesity. In fact, mutations of MCR-4 represent the most common known mono-genic (single-gene) cause of human obesity, and some studies suggest that MCR-4 mutations may account for as much as 5 to 6 percent of early-onset severe obesity in children. In contrast, excessive activation of the melanocortin system reduces appetite. Some studies suggest that this activation may play a role in causing the anorexia associated with severe infections or cancer tumors.
AGRP released from the orexigenic neurons of the hypothalamus is a natural antagonist of MCR-3 and MCR-4 and probably increases feeding by inhibiting the effects of a-MSH to stimulate melanocortin receptors (see Figure 71-2). Although the role of AGRP in normal physiologic control of food intake is unclear, excessive formation of AGRP in mice and humans, due to gene mutations, is associated with excessive feeding and obesity.
NPY is also released from orexigenic neurons of the arcuate nuclei. When energy stores of the body are low, orexigenic neurons are activated to release NPY, which stimulates appetite. At the same time, firing of the POMC neurons is reduced, thereby decreasing the activity of the melanocortin pathway and further stimulating appetite.
Neural Centers That Influence the Mechanical Process of
Feeding. Another aspect of feeding is the mechanical act of the feeding process itself. If the brain is sectioned below the hypothalamus but above the mesen-cephalon, the animal can still perform the basic mechanical features of the feeding process. It can salivate, lick its lips, chew food, and swallow. Therefore, the actual mechanics of feeding are controlled by centers in the brain stem. The function of the other centers in feeding, then, is to control the quantity of food intake and to excite these centers of feeding mechanics to activity.
Neural centers higher than the hypothalamus also play important roles in the control of feeding, particularly in the control of appetite. These centers include the amygdala and the prefrontal cortex, which are closely coupled with the hypothalamus. It will be recalled from the discussion of the sense of smell in Chapter 53 that portions of the amygdala are a major part of the olfactory nervous system. Destructive lesions in the amygdala have demonstrated that some of its areas increase feeding, whereas others inhibit feeding. In addition, stimulation of some areas of the amygdala elicits the mechanical act of feeding. An important effect of destruction of the amygdala on both sides of the brain is a "psychic blindness" in the choice of foods. In other words, the animal (and presumably the human being as well) loses or at least partially loses the appetite control that determines the type and quality of food it eats.
Regulation of the quantity of food intake can be divided into short-term regulation, which is concerned primarily with preventing overeating at each meal, and long-term regulation, which is concerned primarily with maintenance of normal quantities of energy stores in the body.
When a person is driven by hunger to eat voraciously and rapidly, what turns off the eating when he or she has eaten enough? There has not been enough time for changes in the body's energy stores to occur, and it takes hours for enough nutritional factors to be absorbed into the blood to cause the necessary inhibition of eating. Yet it is important that the person not overeat and that he or she eat an amount of food that approximates nutritional needs. The following are several types of rapid feedback signals that are important for these purposes.
Gastrointestinal Filling Inhibits Feeding. When the gastrointestinal tract becomes distended, especially the stomach and the duodenum, stretch inhibitory signals are transmitted mainly by way of the vagi to suppress the feeding center, thereby reducing the desire for food (Fig. 71-1).
Gastrointestinal Hormonal Factors Suppress Feeding. Chole-cystokinin is released mainly in response to fat entering the duodenum and has a direct effect on the feeding centers to reduce subsequent eating. Studies in experimental animals suggest that CCK may decrease feeding mainly by activation of the melanocortin pathway in the hypothalamus.
Peptide YY (PYY) is secreted from the entire gastrointestinal tract, but especially from the ileum and colon. Food intake stimulates release of PYY, with blood concentrations rising to peak levels 1 to 2 hours after ingesting a meal. These peak levels of PYY are influenced by the number of calories ingested and the composition of the food, with higher levels of PYY observed after meals with a high fat content. Although injections of PYY into mice have been shown to decrease food intake for 12 hours or more, the importance of this gastrointestinal hormone in regulating appetite in humans is still unclear.
For reasons that are not entirely understood, the presence of food in the intestines stimulates them to secrete glucagon-like peptide, which in turn enhances glucose-dependent insulin production and secretion from the pancreas. Glucagon-like peptide and insulin both tend to suppress appetite. Thus, eating a meal stimulates the release of several gastrointestinal hormones that may induce satiety and reduce further intake of food (see Fig. 71-1).
Ghrelin—a Gastrointestinal Hormone—Increases Feeding.
Ghrelin is a hormone released mainly by the oxyntic cells of the stomach but also, to a much less extent, by the intestine. Blood levels of ghrelin rise during fasting, peak just before eating, and then fall rapidly after a meal, suggesting a possible role in stimulating feeding. Also, administration of ghrelin increases food intake in experimental animals, further supporting the possibility that it may be an orexigenic hormone. However, its physiologic role in humans is still uncertain.
Oral Receptors Meter Food Intake. When an animal with an esophageal fistula is fed large quantities of food, even though this food is immediately lost again to the exterior, the degree of hunger is decreased after a reasonable quantity of food has passed through the mouth. This effect occurs despite the fact that the gastrointestinal tract does not become the least bit filled. Therefore, it is postulated that various "oral factors" related to feeding, such as chewing, salivation, swallowing, and tasting, "meter" the food as it passes through the mouth, and after a certain amount has passed, the hypothalamic feeding center becomes inhibited. However, the inhibition caused by this metering mechanism is considerably less intense and of shorter duration, usually lasting for only 20 to 40 minutes, than is the inhibition caused by gastrointestinal filling.
Intermediate and Long-Term Regulation of Food Intake
An animal that has been starved for a long time and is then presented with unlimited food eats a far greater quantity than does an animal that has been on a regular diet. Conversely, an animal that has been force-fed for several weeks eats very little when allowed to eat according to its own desires. Thus, the feeding control mechanism of the body is geared to the nutritional status of the body.
Effect of Blood Concentrations of Glucose, Amino Acids, and Lipids on Hunger and Feeding. It has long been known that a decrease in blood glucose concentration causes hunger, which has led to the so-called glucostatic theory of hunger and feeding regulation. Similar studies have demonstrated the same effect for blood amino acid concentration and blood concentration of breakdown products of lipids such as the keto acids and some fatty acids, leading to the aminostatic and lipostatic theories of regulation. That is, when the availability of any of the three major types of food decreases, the desire for feeding is increased, eventually returning the blood metabolite concentrations back toward normal.
Neurophysiologic studies of function in specific areas of the brain also support the glucostatic, amino-static, and lipostatic theories, by the following observations: (1) A rise in blood glucose level increases the rate of firing of glucoreceptor neurons in the satiety center in the ventromedial and paraventricular nuclei of the hypothalamus. (2) The same increase in blood glucose level simultaneously decreases the firing of glu-cosensitive neurons in the hunger center of the lateral hypothalamus. In addition, some amino acids and lipid substances affect the rates of firing of these same neurons or other closely associated neurons.
Temperature Regulation and Food Intake. When an animal is exposed to cold, it tends to increase feeding; when it is exposed to heat, it tends to decrease its caloric intake. This is caused by interaction within the hypothalamus between the temperature-regulating system (see Chapter 73) and the food intake-regulating system. This is important, because increased food intake in a cold animal (1) increases its metabolic rate and (2) provides increased fat for insulation, both of which tend to correct the cold state.
Feedback Signals from Adipose Tissue Regulate Food Intake.
Most of the stored energy in the body consists of fat, the amount of which can vary considerably in different individuals. What regulates this energy reserve, and why is there so much variability among individuals?
Recent studies suggest that the hypothalamus senses energy storage through the actions of leptin, a peptide hormone released from adipocytes. When the amount of adipose tissue increases (signaling excess energy storage), the adipocytes produce increased amounts of leptin, which is released into the blood. Leptin then circulates to the brain, where it moves across the blood-brain barrier by facilitated diffusion and occupies leptin receptors at multiple sites in the hypothalamus, especially the POMC neurons of the arcuate nuclei and neurons of the paraventricular nuclei.
Stimulation of leptin receptors in these hypothala-mic nuclei initiates multiple actions that decrease fat storage, including (1) decreased production in the hypothalamus of appetite stimulators, such as NPY and AGRP; (2) activation of POMC neurons, causing release of a-MSH and activation of melanocortin receptors; (3) increased production in the hypothalamus of substances, such as corticotropin-releasing hormone, that decrease food intake; (4) increased sympathetic nerve activity (through neural projections from the hypothalamus to the vasomotor centers), which increases metabolic rate and energy expenditure; and (5) decreased insulin secretion by the pancreatic beta cells, which decreases energy storage. Thus, leptin may be an important means by which the adipose tissue signals the brain that enough energy has been stored and that intake of food is no longer necessary.
In mice or humans with mutations that render their fat cells unable to produce leptin or mutations that cause defective leptin receptors in the hypothalamus, marked hyperphagia and morbid obesity occur. In most obese humans, however, there does not appear to be a deficiency of leptin production, because plasma leptin levels increase in proportion with increasing adiposity. Therefore, some physiologists believe that obesity may be associated with leptin resistance; that is, leptin receptors or post-receptor signaling pathways normally activated by leptin may be defective in obese people, who continue to eat despite very high levels of leptin.
Another explanation for the failure of leptin to prevent increasing adiposity in obese individuals is that there are many redundant systems that control feeding behavior, as well as social and cultural factors that can cause continued excess food intake even in the presence of high levels of leptin.
Summary of Long-Term Regulation. Even though our information on the different feedback factors in long-term feeding regulation is imprecise, we can make the following general statement: When the energy stores of the body fall below normal, the feeding centers of the hypothalamus and other areas of the brain become highly active, and the person exhibits increased hunger as well as searching for food; conversely, when the energy stores (mainly the fat stores) are already abundant, the person usually loses the sensation of hunger and develops a state of satiety.
Importance of Having Both Long- and Short-Term Regulatory Systems for Feeding
The long-term regulatory system for feeding, which includes all the nutritional energy feedback mechanisms, helps maintain constant stores of nutrients in the tissues, preventing them from becoming too low or too high. The short-term regulatory stimuli serve two other purposes. First, they tend to make the person eat smaller quantities at each eating session, thus allowing food to pass through the gastrointestinal tract at a steadier pace, so that its digestive and absorptive mechanisms can work at optimal rates rather than becoming periodically overburdened. Second, they help prevent the person from eating amounts at each meal that would be too much for the metabolic storage systems once all the food has been absorbed.
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