Guyton and Hall Textbook of Medical Physiology, 12th Ed


Dietary Balances; Regulation of Feeding; Obesity and Starvation; Vitamins and Minerals

imageEnergy Intake and Output Are Balanced Under Steady-State Conditions

Intake of carbohydrates, fats, and proteins provides energy that can be used to perform various body functions or stored for later use. Stability of body weight and composition over long periods requires that a person’s energy intake and energy expenditure be balanced. When a person is overfed and energy intake persistently exceeds expenditure, most of the excess energy is stored as fat, and body weight increases; conversely, loss of body mass and starvation occur when energy intake is insufficient to meet the body’s metabolic needs.

Because different foods contain different proportions of proteins, carbohydrates, fats, minerals, and vitamins, appropriate balances must also be maintained among these constituents so that all segments of the body’s metabolic systems can be supplied with the requisite materials. This chapter discusses the mechanisms by which food intake is regulated in accordance with the body’s metabolic needs and some of the problems of maintaining balance among the different types of foods.

Dietary Balances

Energy Available in Foods

The energy liberated from each gram of carbohydrate as it is oxidized to carbon dioxide and water is 4.1 Calories (1 Calorie equals 1 kilocalorie), and that liberated from fat is 9.3 Calories. The energy liberated from metabolism of the average dietary protein as each gram is oxidized to carbon dioxide, water, and urea is 4.35 Calories. Also, these substances vary in the average percentages that are absorbed from the gastrointestinal tract: about 98 percent of carbohydrate, 95 percent of fat, and 92 percent of protein. Therefore, the average physiologically available energy in each gram of these three foodstuffs is as follows:









Average Americans receive about 15 percent of their energy from protein, 40 percent from fat, and 45 percent from carbohydrate. In most non-Western countries, the quantity of energy derived from carbohydrates far exceeds that derived from both proteins and fats. Indeed, in some parts of the world where meat is scarce, the energy received from fats and proteins combined may be no greater than 15 to 20 percent.

Table 71-1 gives the compositions of selected foods, demonstrating especially the high proportions of fat and protein in meat products and the high proportion of carbohydrate in most vegetable and grain products. Fat is deceptive in the diet because it usually exists as nearly 100 percent fat, whereas both proteins and carbohydrates are mixed in watery media so that each of these normally represents less than 25 percent of the weight. Therefore, the fat of one pat of butter mixed with an entire helping of potato sometimes contains as much energy as the potato itself.

Table 71-1 Protein, Fat, and Carbohydrate Content of Different Foods


Average Daily Requirement for Protein Is 30 to 50 Grams

Twenty to 30 grams of the body proteins are degraded and used to produce other body chemicals daily. Therefore, all cells must continue to form new proteins to take the place of those that are being destroyed, and a supply of protein is necessary in the diet for this purpose. An average person can maintain normal stores of protein, provided the daily intake is above 30 to 50 grams.

Some proteins have inadequate quantities of certain essential amino acids and therefore cannot be used to replace the degraded proteins. Such proteins are called partial proteins, and when they are present in large quantities in the diet, the daily protein requirement is much greater than normal. In general, proteins derived from animal foodstuffs are more complete than are proteins derived from vegetable and grain sources. For example, the protein of corn has almost no tryptophan, one of the essential amino acids. Therefore, individuals in low-income countries who consume cornmeal as the principal source of protein sometimes develop the protein-deficiency syndrome called kwashiorkor, which consists of failure to grow, lethargy, depressed mentality, and edema caused by low plasma protein concentration.

Carbohydrates and Fats Act as “Protein Sparers.”

When the diet contains an abundance of carbohydrates and fats, almost all the body’s energy is derived from these two substances, and little is derived from proteins.

Therefore, both carbohydrates and fats are said to be protein sparers. Conversely, in starvation, after the carbohydrates and fats have been depleted, the body’s protein stores are consumed rapidly for energy, sometimes at rates approaching several hundred grams per day rather than the normal daily rate of 30 to 50 grams.

Methods for Determining Metabolic Utilization of Carbohydrates, Fats, and Proteins

“Respiratory Quotient” Is the Ratio of CO2 Production to O2 Utilization and Can Be Used to Estimate Fat and Carbohydrate Utilization

When carbohydrates are metabolized with oxygen, exactly one carbon dioxide molecule is formed for each molecule of oxygen consumed. This ratio of carbon dioxide output to oxygen usage is called the respiratory quotient, so the respiratory quotient for carbohydrates is 1.0.

When fat is oxidized in the body’s cells, an average of 70 carbon dioxide molecules are formed for each 100 molecules of oxygen consumed. The respiratory quotient for the metabolism of fat therefore averages 0.70. When proteins are oxidized by the cells, the average respiratory quotient is 0.80. The reason that the respiratory quotients for fats and proteins are lower than those for carbohydrates is that a portion of the oxygen metabolized with these foods is required to combine with the excess hydrogen atoms present in their molecules, so less carbon dioxide is formed in relation to the oxygen used.

Now let us see how one can make use of the respiratory quotient to determine the relative utilization of different foods by the body. First, it will be recalled from Chapter 39 that the output of carbon dioxide by the lungs divided by the uptake of oxygen during the same period is called the respiratory exchange ratio. Over a period of 1 hour or more, the respiratory exchange ratio exactly equals the average respiratory quotient of the metabolic reactions throughout the body. If a person has a respiratory quotient of 1.0, he or she is metabolizing almost entirely carbohydrates, because the respiratory quotients for both fat and protein metabolism are considerably less than 1.0. Likewise, when the respiratory quotient is about 0.70, the body is metabolizing almost entirely fats, to the exclusion of carbohydrates and proteins. And, finally, if we ignore the normally small amount of protein metabolism, respiratory quotients between 0.70 and 1.0 describe the approximate ratios of carbohydrate to fat metabolism. To be more exact, one can first determine the protein utilization by measuring nitrogen excretion as discussed in the next section. Then, using the appropriate mathematical formula, one can calculate almost exactly the utilization of the three foodstuffs.

Some of the important findings from studies of respiratory quotients are the following:

1. Immediately after a meal, almost all the food that is metabolized is carbohydrates, so the respiratory quotient at that time approaches 1.0.

2. About 8 to 10 hours after a meal, the body has already used up most of its readily available carbohydrates, and the respiratory quotient approaches that for fat metabolism, about 0.70.

3. In untreated diabetes mellitus, little carbohydrate can be used by the body’s cells under any conditions because insulin is required for this. Therefore, when diabetes is severe, most of the time the respiratory quotient remains near that for fat metabolism, 0.70.

Nitrogen Excretion Can Be Used to Assess Protein Metabolism

The average protein contains about 16 percent nitrogen. During metabolism of the protein, about 90 percent of this nitrogen is excreted in the urine in the form of urea, uric acid, creatinine, and other nitrogen products. The remaining 10 percent is excreted in the feces. Therefore, the rate of protein breakdown in the body can be estimated by measuring the amount of nitrogen in the urine, then adding 10 percent for the nitrogen excreted in the feces, and multiplying by 6.25 (i.e., 100/16) to determine the total amount of protein metabolism in grams per day. Thus, excretion of 8 grams of nitrogen in the urine each day means that there has been about 55 grams of protein breakdown. If the daily intake of protein is less than the daily breakdown of protein, the person is said to have a negative nitrogen balance, which means that his or her body stores of protein are decreasing daily.

Regulation of Food Intake and Energy Storage

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 percent 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 physiological 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 physiological conditions, as well as in obesity and starvation.

Neural Centers Regulate Food Intake

The sensation of hunger is associated with a craving for food and several other physiological effects, such as rhythmical contractions of the stomach and restlessness, which cause the person to seek 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 weighing as much 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 hypothalamic nuclei 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.


Figure 71-1 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), cholecystokinin (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.

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.

Table 71-2 Neurotransmitters and Hormones That Influence Feeding and Satiety Centers in the Hypothalamus

Decrease Feeding (Anorexigenic)

Increase Feeding (Orexigenic)

α-Melanocyte-stimulating hormone (α-MSH)

Neuropeptide Y (NPY)


Agouti-related protein (AGRP)


Melanin-concentrating hormone (MCH)


Orexins A and B

Corticotropin-releasing hormone



Galanin (GAL)

Cholecystokinin (CCK)

Amino acids (glutamate and γ-aminobutyric acid)

Glucagon-like peptide (GLP)


Cocaine- and amphetamine-regulated transcript (CART)


Peptide YY (PYY)


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) pro-opiomelanocortin (POMC) neurons that produce α-melanocyte-stimulating hormone (α-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. As discussed later, these neurons appear to be the major targets for several hormones that regulate appetite, including leptininsulincholecystokinin (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.


Figure 71-2 Control of energy balance by two types of neurons of the arcuate nuclei: (1) pro-opiomelanocortin (POMC) neurons that release α-melanocyte-stimulating hormone (α-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. α-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; Y1R, neuropeptide Y1 receptor.

(Redrawn from Barsh GS, Schwartz MW: Nature Rev Genetics 3:589, 2002.)

The POMC neurons release α-MSH, which then acts on melanocortin receptors found especially in neurons of the paraventricular nuclei. Although there are at least five subtypes of melanocortin receptors (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 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 monogenic (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, cancer tumors, or uremia.

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 α-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 increased food intake 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 mesencephalon, 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.

Factors That Regulate Quantity of Food Intake

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.

Short-Term Regulation of Food Intake

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 (see Figure 71-1).

Gastrointestinal Hormonal Factors Suppress Feeding

Cholecystokinin (CCK), released mainly in response to fat and proteins entering the duodenum, enters the blood and acts as a hormone to influence several gastrointestinal functions such as gallbladder contraction, gastric emptying, gut motility, and gastric acid secretion as discussed in Chapters Chapters 6263, and 64. However, CCK also activates receptors on local sensory nerves in the duodenum, sending messages to the brain via the vagus nerve that contribute to satiation and meal cessation. The effect of CCK is short-lived and chronic administration of CCK by itself has no major effect on body weight. Therefore, CCK functions mainly to prevent overeating during meals but may not play a major role in the frequency of meals or the total energy consumed.

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 (GLP), 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 Figure 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.

Neurophysiological studies of function in specific areas of the brain also support the glucostatic, aminostatic, 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 glucosensitive 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?

Studies in humans and in experimental animals indicate 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 hypothalamic 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 α-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 is 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 postreceptor 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.


Obesity can be defined as an excess of body fat. A surrogate marker for body fat content is the body mass index (BMI), which is calculated as:


In clinical terms, a BMI between 25 and 29.9 kg/m2 is called overweight, and a BMI greater than 30 kg/m2 is called obese. BMI is not a direct estimate of adiposity and does not take into account the fact that some individuals have a high BMI due to a large muscle mass. A better way to define obesity is to actually measure the percentage of total body fat. Obesity is usually defined as 25 percent or greater total body fat in men and 35 percent or greater in women. Although percentage of body fat can be estimated with various methods, such as measuring skin-fold thickness, bioelectrical impedance, or underwater weighing, these methods are rarely used in clinical practice, where BMI is commonly used to assess obesity.

The prevalence of obesity in children and adults in the United States and in many other industrialized countries is rapidly increasing, rising by more than 30 percent over the past decade. Approximately 65 percent of adults in the United States are overweight, and nearly 33 percent of adults are obese.

Obesity Results from Greater Energy Intake Than Energy Expenditure

When greater quantities of energy (in the form of food) enter the body than are expended, the body weight increases, and most of the excess energy is stored as fat. Therefore, excessive adiposity (obesity) is caused by energy intake in excess of energy output. For each 9.3 Calories of excess energy that enter the body, approximately 1 gram of fat is stored.

Fat is stored mainly in adipocytes in subcutaneous tissue and in the intraperitoneal cavity, although the liver and other tissues of the body often accumulate significant amounts of lipids in obese persons. The metabolic processes involved in fat storage were discussed in Chapter 68.

It was previously believed that the number of adipocytes could increase substantially only during infancy and childhood and that excess energy intake in children led to hyperplastic obesity, associated with increased numbers of adipocytes and only small increases in adipocyte size. In contrast, obesity developing in adults was thought to increase only adipocyte size, resulting in hypertrophic obesity. Recent studies, however, have shown that new adipocytes can differentiate from fibroblast-like preadipocytes at any period of life and that the development of obesity in adults is accompanied by increased numbers, as well as increased size, of adipocytes. An extremely obese person may have as many as four times as many adipocytes, each containing twice as much lipid, as a lean person.

Once a person has become obese and a stable weight is obtained, energy intake once again equals energy output. For a person to lose weight, energy intake must be less than energy expenditure.

Decreased Physical Activity and Abnormal Feeding Regulation as Causes of Obesity

The causes of obesity are complex. Although genes play an important role in programming the powerful physiological mechanisms that regulate food intake and energy metabolism, lifestyle and environmental factors may play the dominant role in many obese people. The rapid increase in the prevalence of obesity in the past 20 to 30 years emphasizes the important role of lifestyle and environmental factors because genetic changes could not have occurred so rapidly.

Sedentary Lifestyle Is a Major Cause of Obesity

Regular physical activity and physical training are known to increase muscle mass and decrease body fat mass, whereas inadequate physical activity is typically associated with decreased muscle mass and increased adiposity. For example, studies have shown a close association between sedentary behaviors, such as prolonged television watching, and obesity.

About 25 to 30 percent of the energy used each day by the average person goes into muscular activity, and in a laborer, as much as 60 to 70 percent is used in this way. In obese people, increased physical activity usually increases energy expenditure more than food intake, resulting in significant weight loss. Even a single episode of strenuous exercise may increase basal energy expenditure for several hours after the physical activity is stopped. Because muscular activity is by far the most important means by which energy is expended in the body, increased physical activity is often an effective means of reducing fat stores.

Abnormal Feeding Behavior Is an Important Cause of Obesity

Although powerful physiological mechanisms regulate food intake, there are also important environmental and psychological factors that can cause abnormal feeding behavior, excessive energy intake, and obesity.

Environmental, Social, and Psychological Factors Contribute to Abnormal Feeding

As discussed previously, the importance of environmental factors is evident from the rapid increase in the prevalence of obesity in most industrialized countries, which has coincided with an abundance of high-energy foods (especially fatty foods) and sedentary lifestyles.

Psychological factors may contribute to obesity in some people. For example, people often gain large amounts of weight during or after stressful situations, such as the death of a parent, a severe illness, or even mental depression. It seems that eating can be a means of releasing tension.

Childhood Overnutrition as a Possible Cause of Obesity

One factor that may contribute to obesity is the prevalent idea that healthy eating habits require three meals a day and that each meal must be filling. Many young children are forced into this habit by overly solicitous parents, and the children continue to practice it throughout life.

The rate of formation of new fat cells is especially rapid in the first few years of life, and the greater the rate of fat storage, the greater the number of fat cells. The number of fat cells in obese children is often as much as three times that in normal children. Therefore, it has been suggested that overnutrition of children—especially in infancy and, to a lesser extent, during the later years of childhood—can lead to a lifetime of obesity.

Neurogenic Abnormalities as a Cause of Obesity

We previously pointed out that lesions in the ventromedial nuclei of the hypothalamus cause an animal to eat excessively and become obese. People with hypophysial tumors that encroach on the hypothalamus often develop progressive obesity, demonstrating that obesity in human beings, too, can result from damage to the hypothalamus.

Although hypothalamic damage is almost never found in obese people, it is possible that the functional organization of the hypothalamic or other neurogenic feeding centers in obese individuals is different from that in nonobese persons. Also, there may be abnormalities of neurotransmitters or receptor mechanisms in the neural pathways of the hypothalamus that control feeding. In support of this theory, an obese person who has reduced to normal weight by strict dietary measures usually develops intense hunger that is demonstrably far greater than that of a normal person. This indicates that the “set-point” of an obese person’s feeding control system is at a much higher level of nutrient storage than that of a nonobese person.

Studies in experimental animals also indicate that when food intake is restricted in obese animals, there are marked neurotransmitter changes in the hypothalamus that greatly increase hunger and oppose weight loss. Some of these changes include increased formation of orexigenic neurotransmitters such as NPY and decreased formation of anorexic substances such as leptin and α-MSH.

Genetic Factors as a Cause of Obesity

Obesity definitely runs in families. Yet it has been difficult to determine the precise role of genetics in contributing to obesity because family members generally share many of the same eating habits and physical activity patterns. Current evidence, however, suggests that 20 to 25 percent of cases of obesity may be caused by genetic factors.

Genes can contribute to obesity by causing abnormalities of (1) one or more of the pathways that regulate the feeding centers and (2) energy expenditure and fat storage. Three of the monogenic (single-gene) causes of obesity are (1) mutations of MCR-4, the most common monogenic form of obesity discovered thus far; (2) congenital leptin deficiency caused by mutations of the leptin gene, which are very rare; and (3) mutations of the leptin receptor, also very rare. All these monogenic forms of obesity account for only a very small percentage of obesity. It is likely that many gene variations interact with environmental factors to influence the amount and distribution of body fat.

Treatment of Obesity

Treatment of obesity depends on decreasing energy input below energy expenditure and creating a sustained negative energy balance until the desired weight loss is achieved. In other words, this means either reducing energy intake or increasing energy expenditure. The current National Institutes of Health (NIH) guidelines recommend a decrease in caloric intake of 500 kilocalories per day for overweight and moderately obese persons (BMI > 25 but < 35 kg/m2) to achieve a weight loss of approximately 1 pound each week. A more aggressive energy deficit of 500 to 1000 kilocalories per day is recommended for persons with BMIs greater than 35 kg/m2. Typically, such an energy deficit, if it can be achieved and sustained, will cause a weight loss of about 1 to 2 pounds per week, or about a 10 percent weight loss after 6 months. For most people attempting to lose weight, increasing physical activity is also an important component of successful long-term weight loss.

To decrease energy intake, most reducing diets are designed to contain large quantities of “bulk,” which is generally made up of non-nutritive cellulose substances. This bulk distends the stomach and thereby partially appeases hunger. In experimental animals, such a procedure simply makes the animal increase its food intake even more, but human beings can often fool themselves because their food intake is sometimes controlled as much by habit as by hunger. As pointed out later in connection with starvation, it is important to prevent vitamin deficiencies during the dieting period.

Various drugs for decreasing the degree of hunger have been used in the treatment of obesity. The most widely used drugs are amphetamines (or amphetamine derivatives), which directly inhibit the feeding centers in the brain. One drug for treating obesity is sibutramine, a sympathomimetic that reduces food intake and increases energy expenditure. The danger in using these drugs is that they simultaneously overexcite the sympathetic nervous system and raise the blood pressure. Also, a person soon adapts to the drug, so weight reduction is usually no greater than 5 to 10 percent.

Another group of drugs works by altering lipid metabolism. For example, orlistat, a lipase inhibitor, reduces the intestinal digestion of fat. This causes a portion of the ingested fat to be lost in the feces and therefore reduces energy absorption. However, fecal fat loss may cause unpleasant gastrointestinal side effects, as well as loss of fat-soluble vitamins in the feces.

Significant weight loss can be achieved in many obese persons with increased physical activity. The more exercise one gets, the greater the daily energy expenditure and the more rapidly the obesity disappears. Therefore, forced exercise is often an essential part of treatment. The current clinical guidelines for the treatment of obesity recommend that the first step be lifestyle modifications that include increased physical activity combined with a reduction in caloric intake. For morbidly obese patients with BMIs greater than 40, or for patients with BMIs greater than 35 and conditions such as hypertension or type II diabetes that predispose them to other serious diseases, various surgical procedures can be used to decrease the fat mass of the body or to decrease the amount of food that can be eaten at each meal.

Two of the most common surgical procedures used in the United States to treat morbid obesity are gastric bypass surgery and gastric banding surgery. Gastric bypass surgery involves construction of a small pouch in the proximal part of the stomach that is then connected to the jejunum with a section of small bowel of varying lengths; the pouch is separated from the remaining part of the stomach with staples. Gastric banding surgery involves placing an adjustable band around the stomach near its upper end; this also creates a small stomach pouch that restricts the amount of food that can be eaten at each meal. Although these surgical procedures generally produce substantial weight loss in obese patients, they are major operations, and their long-term effects on overall health and mortality are still uncertain.

Inanition, Anorexia, and Cachexia

Inanition is the opposite of obesity and is characterized by extreme weight loss. It can be caused by inadequate availability of food or by pathophysiological conditions that greatly decrease the desire for food, including psychogenic disturbances, hypothalamic abnormalities, and factors released from peripheral tissues. In many instances, especially in those with serious diseases such as cancer, the reduced desire for food may be associated with increased energy expenditure, causing serious weight loss.

Anorexia can be defined as a reduction in food intake caused primarily by diminished appetite, as opposed to the literal definition of “not eating.” This definition emphasizes the important role of central neural mechanisms in the pathophysiology of anorexia in diseases such as cancer, when other common problems, such as pain and nausea, may also cause a person to consume less food. Anorexia nervosa is an abnormal psychic state in which a person loses all desire for food and even becomes nauseated by food; as a result, severe inanition occurs.

Cachexia is a metabolic disorder of increased energy expenditure leading to weight loss greater than that caused by reduced food intake alone. Anorexia and cachexia often occur together in many types of cancer or in the “wasting syndrome” observed in patients with acquired immunodeficiency syndrome (AIDS) and chronic inflammatory disorders. Almost all types of cancer cause both anorexia and cachexia, and more than half of cancer patients develop anorexia-cachexia syndrome during the course of their disease.

Central neural and peripheral factors are believed to contribute to cancer-induced anorexia and cachexia. Several inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, interleukin-1β, and a proteolysis-inducing factor, have been shown to cause anorexia and cachexia. Most of these inflammatory cytokines appear to mediate anorexia by activation of the melanocortin system in the hypothalamus. The precise mechanisms by which cytokines or tumor products interact with the melanocortin pathway to decrease food intake are still unclear, but blockade of the hypothalamic melanocortin receptors appears to almost completely prevent their anorexic and cachectic effects in experimental animals. Additional research, however, is necessary to better understand the pathophysiological mechanisms of anorexia and cachexia in cancer patients and to develop therapeutic agents to improve their nutritional status and survival.


Depletion of Food Stores in the Body Tissues During Starvation

Even though the tissues preferentially use carbohydrate for energy over both fat and protein, the quantity of carbohydrate normally stored in the entire body is only a few hundred grams (mainly glycogen in the liver and muscles), and it can supply the energy required for body functions for perhaps half a day. Therefore, except for the first few hours of starvation, the major effects are progressive depletion of tissue fat and protein. Because fat is the prime source of energy (100 times as much fat energy is stored in the normal person as carbohydrate energy), the rate of fat depletion continues unabated, as shown in Figure 71-3, until most of the fat stores in the body are gone.


Figure 71-3 Effect of starvation on the food stores of the body.

Protein undergoes three phases of depletion: rapid depletion at first, then greatly slowed depletion, and, finally, rapid depletion again shortly before death. The initial rapid depletion is caused by the use of easily mobilized protein for direct metabolism or for conversion to glucose and then metabolism of glucose mainly by the brain. After the readily mobilized protein stores have been depleted during the early phase of starvation, the remaining protein is not so easily removed. At this time, the rate of gluconeogenesis decreases to one-third to one-fifth its previous rate, and the rate of depletion of protein becomes greatly decreased. The lessened availability of glucose then initiates a series of events that leads to excessive fat utilization and conversion of some of the fat breakdown products to ketone bodies, producing the state of ketosis, which is discussed in Chapter 68. The ketone bodies, like glucose, can cross the blood-brain barrier and can be used by the brain cells for energy. Therefore, about two thirds of the brain’s energy is now derived from these ketone bodies, principally from beta-hydroxybutyrate. This sequence of events leads to at least partial preservation of the protein stores of the body.

There finally comes a time when the fat stores are almost depleted, and the only remaining source of energy is protein. At that time, the protein stores once again enter a stage of rapid depletion. Because proteins are also essential for the maintenance of cellular function, death ordinarily ensues when the proteins of the body have been depleted to about half their normal level.

Vitamin Deficiencies in Starvation

The stores of some of the vitamins, especially the water-soluble vitamins—the vitamin B group and vitamin C—do not last long during starvation. Consequently, after a week or more of starvation, mild vitamin deficiencies usually begin to appear, and after several weeks, severe vitamin deficiencies can occur. These deficiencies can add to the debility that leads to death.


Daily Requirements of Vitamins

A vitamin is an organic compound needed in small quantities for normal metabolism that cannot be manufactured in the cells of the body. Lack of vitamins in the diet can cause important metabolic deficits. Table 71-3 lists the amounts of important vitamins required daily by the average person. These requirements vary considerably, depending on such factors as body size, rate of growth, amount of exercise, and pregnancy.

Table 71-3 Required Daily Amounts of Vitamins




5000 IU


1.5 mg


1.8 mg


20 mg

Ascorbic acid

45 mg


400 IU


15 IU


70 μg

Folic acid

0.4 mg


3 μg


2 mg

Pantothenic acid


Storage of Vitamins in the Body

Vitamins are stored to a slight extent in all cells. Some vitamins are stored to a major extent in the liver. For instance, the quantity of vitamin A stored in the liver may be sufficient to maintain a person for 5 to 10 months without any intake of vitamin A. The quantity of vitamin D stored in the liver is usually sufficient to maintain a person for 2 to 4 months without any additional intake of vitamin D.

The storage of most water-soluble vitamins is relatively slight. This applies especially to most vitamin B compounds. When a person’s diet is deficient in vitamin B compounds, clinical symptoms of the deficiency can sometimes be recognized within a few days (except for vitamin B12, which can last in the liver in a bound form for a year or longer). Absence of vitamin C, another water-soluble vitamin, can cause symptoms within a few weeks and can cause death from scurvy in 20 to 30 weeks.

Vitamin A

Vitamin A occurs in animal tissues as retinol. This vitamin does not occur in foods of vegetable origin, but provitamins for the formation of vitamin A do occur in abundance in many vegetable foods. These are the yellow and red carotenoid pigments, which, because their chemical structures are similar to that of vitamin A, can be changed into vitamin A in the liver.

Vitamin A Deficiency Causes “Night Blindness” and Abnormal Epithelial Cell Growth

One basic function of vitamin A is its use in the formation of the retinal pigments of the eye, which is discussed in Chapter 50. Vitamin A is needed to form the visual pigments and, therefore, to prevent night blindness.

Vitamin A is also necessary for normal growth of most cells of the body and especially for normal growth and proliferation of the different types of epithelial cells. When vitamin A is lacking, the epithelial structures of the body tend to become stratified and keratinized. Vitamin A deficiency manifests itself by (1) scaliness of the skin and sometimes acne; (2) failure of growth of young animals, including cessation of skeletal growth; (3) failure of reproduction, associated especially with atrophy of the germinal epithelium of the testes and sometimes with interruption of the female sexual cycle; and (4) keratinization of the cornea, with resultant corneal opacity and blindness.

In vitamin A deficiency, the damaged epithelial structures often become infected (e.g., conjunctivae of the eyes, linings of the urinary tract, and respiratory passages). Vitamin A has been called an “anti-infection” vitamin.

Thiamine (Vitamin B1)

Thiamine operates in the metabolic systems of the body principally as thiamine pyrophosphate; this compound functions as a cocarboxylase, operating mainly in conjunction with a protein decarboxylase for decarboxylation of pyruvic acid and other α-keto acids, as discussed in Chapter 67.

Thiamine deficiency (beriberi) causes decreased utilization of pyruvic acid and some amino acids by the tissues, but increased utilization of fats. Thus, thiamine is specifically needed for the final metabolism of carbohydrates and many amino acids. The decreased utilization of these nutrients is responsible for many debilities associated with thiamine deficiency.

Thiamine Deficiency Causes Lesions of the Central and Peripheral Nervous Systems

The central nervous system normally depends almost entirely on the metabolism of carbohydrates for its energy. In thiamine deficiency, the utilization of glucose by nervous tissue may be decreased 50 to 60 percent and is replaced by the utilization of ketone bodies derived from fat metabolism. The neuronal cells of the central nervous system frequently show chromatolysis and swelling during thiamine deficiency, changes that are characteristic of neuronal cells with poor nutrition. These changes can disrupt communication in many portions of the central nervous system.

Thiamine deficiency can cause degeneration of myelin sheaths of nerve fibers in both the peripheral nerves and the central nervous system. Lesions in the peripheral nerves frequently cause them to become extremely irritable, resulting in “polyneuritis,” characterized by pain radiating along the course of one or many peripheral nerves. Also, fiber tracts in the cord can degenerate to such an extent that paralysisoccasionally results; even in the absence of paralysis, the muscles atrophy, resulting in severe weakness.

Thiamine Deficiency Weakens the Heart and Causes Peripheral Vasodilation

A person with severe thiamine deficiency eventually develops cardiac failure because of weakened cardiac muscle. Further, the venous return of blood to the heart may be increased to as much as two times normal. This occurs because thiamine deficiency causes peripheral vasodilation throughout the circulatory system, presumably as a result of decreased release of metabolic energy in the tissues, leading to local vascular dilation. The cardiac effects of thiamine deficiency are due partly to high blood flow into the heart and partly to primary weakness of the cardiac muscle. Peripheral edema and ascites also occur to a major extent in some people with thiamine deficiency, mainly because of cardiac failure.

Thiamine Deficiency Causes Gastrointestinal Tract Disturbances

Among the gastrointestinal symptoms of thiamine deficiency are indigestion, severe constipation, anorexia, gastric atony, and hypochlorhydria. All these effects presumably result from failure of the smooth muscle and glands of the gastrointestinal tract to derive sufficient energy from carbohydrate metabolism.

The overall picture of thiamine deficiency, including polyneuritis, cardiovascular symptoms, and gastrointestinal disorders, is frequently referred to as beriberi—especially when the cardiovascular symptoms predominate.


Niacin, also called nicotinic acid, functions in the body as coenzymes in the form of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes are hydrogen acceptors; they combine with hydrogen atoms as they are removed from food substrates by many types of dehydrogenases. The typical operation of both these coenzymes is presented in Chapter 67. When a deficiency of niacin exists, the normal rate of dehydrogenation cannot be maintained; therefore, oxidative delivery of energy from the foodstuffs to the functioning elements of all cells cannot occur at normal rates.

In the early stages of niacin deficiency, simple physiological changes such as muscle weakness and poor glandular secretion may occur, but in severe niacin deficiency, actual tissue death ensues. Pathological lesions appear in many parts of the central nervous system, and permanent dementia or many types of psychoses may result. Also, the skin develops a cracked, pigmented scaliness in areas that are exposed to mechanical irritation or sun irradiation; thus, it appears that in persons with niacin deficiency, the skin is unable to repair irritative damage.

Niacin deficiency causes intense irritation and inflammation of the mucous membranes of the mouth and other portions of the gastrointestinal tract, resulting in many digestive abnormalities that can lead to widespread gastrointestinal hemorrhage in severe cases. It is possible that this results from generalized depression of metabolism in the gastrointestinal epithelium and failure of appropriate epithelial repair.

The clinical entity called pellagra and the canine disease called black tongue are caused mainly by niacin deficiency. Pellagra is greatly exacerbated in people on a corn diet because corn is deficient in the amino acid tryptophan, which can be converted in limited quantities to niacin in the body.

Riboflavin (Vitamin B2)

Riboflavin normally combines in the tissues with phosphoric acid to form two coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). They operate as hydrogen carriers in important oxidative systems of the mitochondria. NAD, operating in association with specific dehydrogenases, usually accepts hydrogen removed from various food substrates and then passes the hydrogen to FMN or FAD; finally, the hydrogen is released as an ion into the mitochondrial matrix to become oxidized by oxygen (described in Chapter 67).

Deficiency of riboflavin in experimental animals causes severe dermatitis, vomiting, diarrhea, muscle spasticity that finally becomes muscle weakness, coma and decline in body temperature, and then death. Thus, severe riboflavin deficiency can cause many of the same effects as a lack of niacin in the diet; presumably, the debilities that result in each instance are due to generally depressed oxidative processes within the cells.

In the human being, there are no known cases of riboflavin deficiency severe enough to cause the marked debilities noted in experimental animals, but mild riboflavin deficiency is probably common. Such deficiency causes digestive disturbances, burning sensations of the skin and eyes, cracking at the corners of the mouth, headaches, mental depression, forgetfulness, and so on.

Although the manifestations of riboflavin deficiency are usually relatively mild, this deficiency frequently occurs in association with deficiency of thiamine, niacin, or both. Many deficiency syndromes, including pellagra, beriberi, sprue, and kwashiorkor, are probably due to a combined deficiency of a number of vitamins, as well as other aspects of malnutrition.

Vitamin B12

Several cobalamin compounds that possess the common prosthetic group shown next exhibit so-called vitamin B12 activity. Note that this prosthetic group contains cobalt, which has bonds similar to those of iron in the hemoglobin molecule. It is likely that the cobalt atom functions in much the same way that the iron atom functions to combine reversibly with other substances.

Vitamin B12 Deficiency Causes Pernicious Anemia

Vitamin B12 performs several metabolic functions, acting as a hydrogen acceptor coenzyme. Its most important function is to act as a coenzyme for reducing ribonucleotides to deoxyribonucleotides, a step that is necessary in the replication of genes. This could explain the major functions of vitamin B12: (1) promotion of growth and (2) promotion of red blood cell formation and maturation. This red cell function is described in detail in Chapter 32 in relation to pernicious anemia, a type of anemia caused by failure of red blood cell maturation when vitamin B12 is deficient.

Vitamin B12 Deficiency Causes Demyelination of the Large Nerve Fibers of the Spinal Cord

The demyelination of nerve fibers in people with vitamin B12 deficiency occurs especially in the posterior columns, and occasionally the lateral columns, of the spinal cord. As a result, many people with pernicious anemia have loss of peripheral sensation and, in severe cases, even become paralyzed.

The usual cause of vitamin B12 deficiency is not lack of this vitamin in the food but deficiency of formation of intrinsic factor, which is normally secreted by the parietal cells of the gastric glands and is essential for absorption of vitamin B12 by the ileal mucosa. This is discussed in Chapters 32 and 66.

Folic Acid (Pteroylglutamic Acid)

Several pteroylglutamic acids exhibit the “folic acid effect.” Folic acid functions as a carrier of hydroxymethyl and formyl groups. Perhaps its most important use in the body is in the synthesis of purines and thymine, which are required for formation of DNA. Therefore, folic acid, like vitamin B12, is required for replication of the cellular genes. This may explain one of the most important functions of folic acid—to promote growth. Indeed, when it is absent from the diet, an animal grows very little.

Folic acid is an even more potent growth promoter than vitamin B12 and, like vitamin B12, is important for the maturation of red blood cells, as discussed in Chapter 32. However, vitamin B12 and folic acid each perform specific and different chemical functions in promoting growth and maturation of red blood cells. One of the significant effects of folic acid deficiency is the development of macrocytic anemia, almost identical to that which occurs in pernicious anemia. This often can be treated effectively with folic acid alone.

Pyridoxine (Vitamin B6)

Pyridoxine exists in the form of pyridoxal phosphate in the cells and functions as a coenzyme for many chemical reactions related to amino acid and protein metabolism. Its most important role is that of coenzyme in the transamination process for the synthesis of amino acids. As a result, pyridoxine plays many key roles in metabolism, especially protein metabolism. Also, it is believed to act in the transport of some amino acids across cell membranes.

Dietary lack of pyridoxine in lower animals can cause dermatitis, decreased rate of growth, development of fatty liver, anemia, and evidence of mental deterioration. Rarely, in children, pyridoxine deficiency has been known to cause seizures, dermatitis, and gastrointestinal disturbances such as nausea and vomiting.

Pantothenic Acid

Pantothenic acid is mainly incorporated in the body into coenzyme A (CoA), which has many metabolic roles in the cells. Two of these discussed at length in Chapters 67 and 68 are (1) conversion of decarboxylated pyruvic acid into acetyl-CoA before its entry into the citric acid cycle and (2) degradation of fatty acid molecules into multiple molecules of acetyl-CoA. Thus, lack of pantothenic acid can lead to depressed metabolism of both carbohydrates and fats.

Deficiency of pantothenic acid in lower animals can cause retarded growth, failure of reproduction, graying of the hair, dermatitis, fatty liver, and hemorrhagic adrenocortical necrosis. In the human being, no definite deficiency syndrome has been proved, presumably because of the wide occurrence of this vitamin in almost all foods and because small amounts can probably be synthesized in the body. This does not mean that pantothenic acid is not of value in the metabolic systems of the body; indeed, it is perhaps as necessary as any other vitamin.

Ascorbic Acid (Vitamin C)

Ascorbic Acid Deficiency Weakens Collagen Fibers Throughout the Body

Ascorbic acid is essential for activating the enzyme prolyl hydroxylase, which promotes the hydroxylation step in the formation of hydroxyproline, an integral constituent of collagen. Without ascorbic acid, the collagen fibers that are formed in virtually all tissues of the body are defective and weak. Therefore, this vitamin is essential for the growth and strength of the fibers in subcutaneous tissue, cartilage, bone, and teeth.

Ascorbic Acid Deficiency Causes Scurvy

Deficiency of ascorbic acid for 20 to 30 weeks, which occurred frequently during long ship voyages in the past, causes scurvy. One of the most important effects of scurvy is failure of wounds to heal. This is caused by failure of the cells to deposit collagen fibrils and intercellular cement substances. As a result, healing of a wound may require several months instead of the several days ordinarily necessary.

Lack of ascorbic acid also causes cessation of bone growth. The cells of the growing epiphyses continue to proliferate, but no new collagen is laid down between the cells, and the bones fracture easily at the point of growth because of failure to ossify. Also, when an already ossified bone fractures in a person with ascorbic acid deficiency, the osteoblasts cannot form new bone matrix. Consequently, the fractured bone does not heal.

The blood vessel walls become extremely fragile in scurvy because of (1) failure of the endothelial cells to be cemented together properly and (2) failure to form the collagen fibrils normally present in vessel walls. The capillaries are especially likely to rupture, and as a result, many small petechial hemorrhages occur throughout the body. The hemorrhages beneath the skin cause purpuric blotches, sometimes over the entire body. To test for ascorbic acid deficiency, one can produce such petechial hemorrhages by inflating a blood pressure cuff over the upper arm; this occludes the venous return of blood, the capillary pressure rises, and red blotches occur on the forearm if the ascorbic acid deficiency is sufficiently severe.

In extreme scurvy, the muscle cells sometimes fragment; lesions of the gums occur, with loosening of the teeth; infections of the mouth develop; and vomiting of blood, bloody stools, and cerebral hemorrhage can all occur. Finally, high fever often develops before death.

Vitamin D

Vitamin D increases calcium absorption from the gastrointestinal tract and helps control calcium deposition in the bone. The mechanism by which vitamin D increases calcium absorption is mainly to promote active transport of calcium through the epithelium of the ileum. In particular, it increases the formation of a calcium-binding protein in the intestinal epithelial cells that aids in calcium absorption. The specific functions of vitamin D in relation to overall body calcium metabolism and bone formation are presented in Chapter 79.

Vitamin E

Several related compounds exhibit so-called vitamin E activity. Only rare instances of proved vitamin E deficiency have occurred in human beings. In experimental animals, lack of vitamin E can cause degeneration of the germinal epithelium in the testis and, therefore, can cause male sterility. Lack of vitamin E can also cause resorption of a fetus after conception in the female. Because of these effects of vitamin E deficiency, vitamin E is sometimes called the “antisterility vitamin.” Deficiency of vitamin E prevents normal growth and sometimes causes degeneration of the renal tubular cells and the muscle cells.

Vitamin E is believed to play a protective role in the prevention of oxidation of unsaturated fats. In the absence of vitamin E, the quantity of unsaturated fats in the cells becomes diminished, causing abnormal structure and function of such cellular organelles as the mitochondria, the lysosomes, and even the cell membrane.

Vitamin K

Vitamin K is an essential co-factor to a liver enzyme that adds a carboxyl group to factors II (prothrombin), VII (proconvertin), IX, and X, all of which are important in blood coagulation. Without this carboxylation these coagulation factors are inactive. Therefore, when vitamin K deficiency occurs, blood clotting is retarded. The function of this vitamin and its relation to some of the anticoagulants, such as dicumarol, are presented in greater detail in Chapter 36.

Several compounds, both natural and synthetic, exhibit vitamin K activity. Because vitamin K is synthesized by bacteria in the colon, it is rare for a person to have a bleeding tendency because of vitamin K deficiency in the diet. However, when the bacteria of the colon are destroyed by the administration of large quantities of antibiotic drugs, vitamin K deficiency occurs rapidly because of the paucity of this compound in the normal diet.

Mineral Metabolism

The functions of many of the minerals, such as sodium, potassium, and chloride, are presented at appropriate points in the text. Only specific functions of minerals not covered elsewhere are mentioned here. The body content of the most important minerals is listed in Table 71-4, and the daily requirements of these are given in Table 71-5.

Table 71-4 Average Content of a 70-Kilogram Man


Amount (grams)



























Table 71-5 Average Required Daily Amounts of Minerals for Adults




3.0 g


1.0 g


3.5 g


1.2 g


1.2 g


18.0 mg


150.0 μg


0.4 g








15 mg


Magnesium is about one sixth as plentiful in cells as potassium. Magnesium is required as a catalyst for many intracellular enzymatic reactions, particularly those related to carbohydrate metabolism.

The extracellular fluid magnesium concentration is slight, only 1.8 to 2.5 mEq/L. Increased extracellular concentration of magnesium depresses nervous system activity, as well as skeletal muscle contraction. This latter effect can be blocked by the administration of calcium. Low magnesium concentration causes increased irritability of the nervous system, peripheral vasodilation, and cardiac arrhythmias, especially after acute myocardial infarction.


Calcium is present in the body mainly in the form of calcium phosphate in the bone. This subject is discussed in detail in Chapter 79, as is the calcium content of extracellular fluid. Excess quantities of calcium ions in extracellular fluid can cause the heart to stop in systole and can act as a mental depressant. At the other extreme, low levels of calcium can cause spontaneous discharge of nerve fibers, resulting in tetany, as discussed in Chapter 79.


Phosphate is the major anion of intracellular fluid. Phosphates have the ability to combine reversibly with many coenzyme systems and with multiple other compounds that are necessary for the operation of metabolic processes. Many important reactions of phosphates have been catalogued at other points in this text, especially in relation to the functions of adenosine triphosphate, adenosine diphosphate, phosphocreatine, and so forth. Also, bone contains a tremendous amount of calcium phosphate, which is discussed in Chapter 79.


The function of iron in the body, especially in relation to the formation of hemoglobin, is discussed in Chapter 32Two thirds of the iron in the body is in the form of hemoglobin, although smaller quantities are present in other forms, especially in the liver and the bone marrow. Electron carriers containing iron (especially the cytochromes) are present in the mitochondria of all cells of the body and are essential for most of the oxidation that occurs in the cells. Therefore, iron is absolutely essential for both the transport of oxygen to the tissues and the operation of oxidative systems within the tissue cells, without which life would cease within a few seconds.

Important Trace Elements in the Body

A few elements are present in the body in such small quantities that they are called trace elements. The amounts of these elements in foods are also usually minute. Yet without any one of them, a specific deficiency syndrome is likely to develop. Three of the most important are iodine, zinc, and fluorine.


The best known of the trace elements is iodine. This element is discussed in Chapter 76 in connection with the formation and function of thyroid hormone; as shown in Table 71-4, the entire body contains an average of only 14 milligrams. Iodine is essential for the formation of thyroxine and triiodothyronine, the two thyroid hormones that are essential for maintenance of normal metabolic rates in all cells of the body.


Zinc is an integral part of many enzymes, one of the most important of which is carbonic anhydrase, present in especially high concentration in the red blood cells. This enzyme is responsible for rapid combination of carbon dioxide with water in the red blood cells of the peripheral capillary blood and for rapid release of carbon dioxide from the pulmonary capillary blood into the alveoli. Carbonic anhydrase is also present to a major extent in the gastrointestinal mucosa, the tubules of the kidney, and the epithelial cells of many glands of the body. Consequently, zinc in small quantities is essential for the performance of many reactions related to carbon dioxide metabolism.

Zinc is also a component of lactic dehydrogenase and is therefore important for the interconversions between pyruvic acid and lactic acid. Finally, zinc is a component of some peptidases and is important for the digestion of proteins in the gastrointestinal tract.


Fluorine does not seem to be a necessary element for metabolism, but the presence of a small quantity of fluorine in the body during the period of life when the teeth are being formed subsequently protects against caries. Fluorine does not make the teeth stronger but has a poorly understood effect in suppressing the cariogenic process. It has been suggested that fluorine is deposited in the hydroxyapatite crystals of the tooth enamel and combines with and therefore blocks the functions of various trace metals that are necessary for activation of the bacterial enzymes that cause caries. Therefore, when fluorine is present, the enzymes remain inactive and cause no caries.

Excessive intake of fluorine causes fluorosis, which manifests in its mild state by mottled teeth and in its more severe state by enlarged bones. It has been postulated that in this condition, fluorine combines with trace metals in some of the metabolic enzymes, including the phosphatases, so that various metabolic systems become partially inactivated. According to this theory, the mottled teeth and enlarged bones are due to abnormal enzyme systems in the odontoblasts and osteoblasts. Even though the mottled teeth are highly resistant to the development of caries, the structural strength of these teeth may be considerably lessened by the mottling process.


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