Modifiers of Metabolism: Overnutrition, Undernutrition, and Disease States

Human energy expenditure can be divided into three components: basal or resting metabolic rate (RMR), the thermic effect of food (TEF), and the thermic effect of activity (TEA). The stoichiometric relationships between oxygen consumption and the heat release that occurs with biologic substrate oxidations are similar to those seen in chemical combustion. As a result, the rate of energy expenditure and substrate oxidation can be determined by measuring heat losses (direct calorimetry) or by measuring oxygen consumption and carbon dioxide production.

RMR has been operationally defined as the calories expended per unit time by a relaxed person who is in a thermoneutral environment and who has been fasting for 12 to 18 hours. The RMR defines that energy which is necessary for the basic maintenance of the body. This includes energy utilized for the movement of the heart and respiratory muscles, for maintenance of ionic gradients between cells and the body fluids, for synthesis of new protein, and for the maintenance of body temperature. The TEF is defined as the elevation of metabolic rate occurring after food ingestion. It includes the cost of the absorption, metabolism, and storage of the food within the body. The TEA is the energy expended with activity and exercise.


The increase of caloric intake over expenditure leads to the accretion of fat and an increase in weight. The increase in fat is accompanied by a proportional increase in lean body mass. Thus, for every pound of excess weight added to the body, about two-thirds is fat and one-third is lean. Although the predominant increase in fat-free mass (FFM) is in muscle, other organs are also involved. It has been shown that the RMR is related to the FFM. As a result, as individuals gain weight, they increase their RMR.

On the other hand, what happens to the TEF is more complex. Some studies in obese persons have shown a decrease in TEF whereas others have not. This is most likely related to the insulin sensitivity of the subjects. The more insulin resistant an obese individual is, the more trouble he/she will have in glucose oxidation and disposal, so that postprandial thermogenesis will be decreased. Obese individuals with normal glucose tolerance will have normal TEF, whereas those with impaired glucose tolerance will tend to have decreased TEF.

The TEA is increased in obese individuals per unit of activity. That is, for a given activity, obese persons expend more energy because they are carrying around a greater weight. However, obese persons tend to be very sedentary, so that they actually are likely to spend fewer minutes per day in any type of activity.

Overall, in either room calorimeters or using doubly labeled water in the free-living state, obese persons expend more total 24-hour energy than age- and sex-matched nonathletic normal weight persons.


The best known study of metabolism during starvation was conducted by Ancel Keys and his coworkers at the University of Minnesota in the late 1940’s. They studied 32 young male volunteers, who were placed on a diet that provided about two-thirds of their usual calories for 24 weeks. The young men lost more than 70 percent of their fat and about 24 percent of their FFM. The RMR of these volunteers decreased by 40 percent after the 24 weeks of starvation. This decreased RMR can be ascribed primarily to the decrease in lean body mass (LBM). However, the RMR also decreased if expressed per unit of remaining lean tissue, suggesting that other hormonal changes had an important impact. The TEF also decreased, partly because smaller meals were being eaten by the subjects, although the influence of hormonal changes could also have played a role. In addition, TEA decreased, both because the men moved about much less and were moving a much lighter total body, requiring less work and caloric output.

This study has been replicated (less elegantly) in many other studies around the world on undernourished populations. A great deal of information also exists on obese individuals placed on hypocaloric diets for weight loss. Even at weights that are above the normal, hypocaloric diets will induce a drop in RMR. This seems to be in proportion to the loss in LBM. In addition, there is an important drop in nonresting energy expenditure.


One of the first manifestations of cancer is loss of weight. This has been primarily ascribed to a loss of appetite and decreased food intake. The net effect of such a hypocaloric diet is to lower energy expenditure. Despite the decreased energy expenditure, energy balance is not maintained. As the imbalance continues or exacerbates, severe undernutrition, called cancer cachexia, can result. Some studies have suggested that cancer patients have an increased RMR. These studies have often expressed RMR as kcal/kg of weight and compared the cancer patients with normal weight patients. Clearly, however, as already mentioned above in the Minnesota study, as one loses weight, one loses more fat than LBM. Since the kcal/kg of fat are much lower than the kcal/kg of LBM, losing proportionally greater fat will leave an individual with a higher kcal/kg of total weight. Overall, the available evidence suggests that an increased RMR contributes very little to the loss of weight in cancer patients, whereas decrease in food intake is key.


Infections are often manifested by fever. Fever is an elevation of body temperature above normal to more than 37.5°C and is a marker of inflammation. The infection may be obvious, with pain, redness, and inflammation at a site, or it may be a fever of unknown origin, such as bacterial endocarditis. In humans, for each temperature increment of 0.6°C (1°F), RMR increases by approximately 10 percent. Thus, a considerable increase of energy expenditure can occur with even a mild elevation of temperature. Cytokines such as tumor necrosis factor, IL-6, and IL-1 have been implicated in this process, probably working through prostaglandins, and re-setting the hypothalamic thermoregulatory center.


There have been a number of studies suggesting that RMR is elevated in patients with AIDS, and that this may contribute to their weight loss and eventual demise. The issue is complicated, as with cancer, in that appetite is also decreased. Also, gastrointestinal symptoms are very prominent in many patients. Studies to date have generally observed an increase of about 10 percent in RMR in relation to the LBM, with a great deal of variation. This is probably explained as an infection effect, discussed above. However, studies of total energy expenditure using doubly labeled water suggest that 24-hour energy expenditure is decreased, related to the fact that these patients feel very ill and as a result are very inactive.

Anorexia Nervosa

The weight loss that occurs in anorexia nervosa because of the patients’ unwillingness to eat appropriate amounts of calories leads to a decrease in RMR, similar to that which occurs in any other starved individual. However, anorexia nervosa patients are generally overactive, so that their 24-hour energy expenditure tends to be higher than one would predict on the basis of their RMR.

Rheumatoid Arthritis

Rheumatoid arthritis is an inflammatory disease in which cytokine production is increased. A recent study has reported that RMR is 12 percent higher in this disease than would be predicted. This is probably modulated by increased levels of IL-I beta and TNF-alpha. In contrast, TEA is much lower because general activity and certainly exercise is greatly decreased in patients with the disease.

Surgery and Trauma

Energy expenditure is increased in response to surgery and trauma. The stress that occurs leads to increased levels of catecholamines, cortisol, and glucagon. These, particularly catecholamines, are thermogenic hormones. Also, some cytokine effects lead to fever and anorexia. Energy expenditure tends to be increased proportionate to the degree of injury. A catabolic response occurs that can rapidly deplete muscle mass, again mediated by hormonal response to injury.

Pulmonary Disease

Patients with chronic obstructive pulmonary disease and emphysema tend to be very thin. Studies that have been published on their RMR suggest that it is elevated. This has been ascribed to the increased energy cost of breathing. TEA is decreased in these patients because of their difficulty breathing. Therefore, generally, their total 24-hour energy expenditure may be low, normal, or high, depending on the balance between these two conditions.

Diabetes Mellitus

When diabetes is out of control, with high fasting and postprandial blood glucose levels, energy expenditure is increased above the predicted level for the individual because of an increased RMR. Such an increased RMR has been ascribed primarily to the protein catabolism that occurs in this condition. The protein that is broken down needs to be replaced so that protein synthesis can be increased. This increased protein turnover is metabolically costly and raises the energy expenditure, which returns to normal with diet and drug therapy, as glucose metabolism comes under control.


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Written by F. Xavier Pi-Sunyer MD MPH

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