Subjects

We considered consecutive subjects referred for weight control during a two-year period for enrollment in the study if they were more than 20 years of age, had a body-mass index (calculated as the weight in kilograms divided by the square of the height in meters) greater than 27, and had no major illnesses. Subjects taking medications that influence energy expenditure were excluded, except for those with a history of thyroid disease who were euthyroid with or without treatment. The 224 subjects who met these criteria were screened for a history of diet resistance, arbitrarily defined as a current intake of less than 1200 kcal per day as reported on three-day records of food consumption; weight stability (within a range of 3 kg) for the previous six months; and a history of failure to lose weight while following a hypocaloric diet. The 16 subjects who met these criteria were considered for entry into the diet-resistant group (group 1); the remaining 208 subjects were assigned to the control group (group 2).

Protocol

Each potential subject in group 1 was instructed by a dietitian and was shown a standard educational videotape about keeping daily records of food intake and physical activity.11 , 12 The subject was enrolled in group 1 if the average reported daily caloric intake for seven subsequent consecutive days was less than 1200 kcal, with continued weight stability. The 10 subjects who met this criterion completed a medical and nutritional history and underwent physical examination, metabolic testing, body-composition analysis, psychological evaluation, assessment of food-portion size, and testing of ability to recall foods eaten after 24 hours.

Of the 208 subjects assigned to group 2, 80 who agreed to participate in additional evaluations completed a medical and nutritional history and underwent a physical examination. Six overlapping subgroups of these group 2 subjects underwent metabolic testing, body-composition analysis, psychological evaluation, and assessment of food-portion size and 24-hour recall. The study protocol was approved by the institutional review board of St. Luke's–Roosevelt Hospital, and informed consent was obtained from all the study subjects.

Self-Reported Food Intake and Physical Activity

The 10 subjects in group 1 and 6 of the subjects in group 2 were evaluated with regard to self-reported food intake, physical activity, body composition, and total energy expenditure for 14 days. The subjects recorded their daily food intake to the nearest ounce or number of items, and these data were then converted to calories with Nutri-Calc Plus software (version 1.10, Camde, Tempe, Ariz.).11 Physical activity was recorded at 15-minute intervals; from these records we estimated the number of calories expended in physical activity by multiplying the total time spent engaged in each of 10 categories of activity by the energy cost of the activity.12

Metabolic Testing

The resting metabolic rate, the thermic effect of food,13 , 14 the thermic response (measured as oxygen consumption) to a standard exercise test, and the total energy expenditure were measured in all the subjects in group 1. A regression line for resting metabolic rate in relation to fat-free body mass was calculated for 75 subjects in group 2.15 The difference from this regression line was then calculated for subjects in group 1 as the observed resting metabolic rate minus the predicted rate. A resting metabolic rate more than 15 percent below the predicted rate was considered abnormally low.16

The resting metabolic rate was evaluated after the subject fasted overnight and remained prone for 30 minutes. Respiratory gas was collected for 20 minutes and its oxygen and carbon dioxide content analyzed during the last 15 minutes of this period with paramagnetic and infrared analyzers (Beckman OM-11 and LB-2, Sensor-Medics, Anaheim, Calif.), respectively. Measures of oxygen consumption and carbon dioxide production were used to calculate the resting metabolic rate.17

The thermic effect of food, which is the postprandial rise in energy expenditure, was measured for three hours after the resting subject consumed a 710-kcal liquid meal (Ensure Plus, Ross Laboratories, Columbus, Ohio).13 , 14 Gas exchange was measured for 10 of every 30 minutes, and the thermic effect of food was calculated as the integrated energy expenditure 3 hours after a meal minus the resting metabolic rate; the results were expressed as a percentage of the number of calories in the ingested meal.

Oxygen consumption in response to exercise, which is an indication of the energy expended during physical activity, was measured by monitoring gas exchange at rest and during the last two minutes of a five-minute period at three workloads on a treadmill. The thermic response to exercise was measured by calculating the regression equation for oxygen consumption per kilogram of body weight in relation to the workload for each group.18 The slopes and intercepts of the two groups were then compared. Ten subjects in group 2 completed the studies of the thermic effect of food and the exercise studies.

Total daily energy expenditure was measured for 14 days with doubly labeled water while the subjects maintained their usual food intake. The method, which is accurate to within a range of 5 percent in adults under free-living conditions, is based on the calculation of carbon dioxide production from the differential disappearance rates of two stable isotopes of water.19 20 21 Bioimpedance analysis (Valhalla Scientific 1990B, San Diego, Calif.) was used to estimate the total amount of water in each subject's body before the doubly labeled water was administered.22 The subjects then received 0.25 g of [18O]water (either 7 percent [18O]water from EG&G Mound Laboratories, Miamisburg, Ohio, or 10 percent [18O]water from Icon Laboratories, Summit, N.J.) per kilogram of total body water and 0.2 g of 99.9 percent [2H]water (Icon and Isotec, Miamisburg, Ohio) per kilogram of total body water on day 0. Urine was collected daily from day 0 through day 14, as described elsewhere.19

The enrichment of urine with hydrogen-2 and oxygen-18 was measured on days 0, 1, 2, 13, and 14 by isotope-ratio mass spectrometry.19 The rates of disappearance of the hydrogen-2 and oxygen-18 tracers from body water over the 14-day period were determined by an analysis of the regression of the logarithm of tracer enrichment against time. Rates of daily water turnover and carbon dioxide production were calculated from the product of total body water and the disappearance rates of hydrogen-2 and oxygen-18, with correction for isotope fractionation.23 Daily oxygen consumption was determined by dividing carbon dioxide production by an assumed respiratory quotient20 of 0.85; total energy expenditure was then calculated from oxygen consumption and carbon dioxide production.24 A regression equation relating total energy expenditure to body composition was calculated for 16 subjects in group 2.15 , 25 Using this equation, we calculated the difference between the observed and the predicted total energy expenditures for the subjects in group 1.

Analysis of Body Composition

The subjects in groups 1 and 2 who had resting studies of the metabolic rate also had measurements of total body fat and metabolically active fat-free body mass by hydrodensitometry.26 27 28 Body composition was also determined by hydrodensitometry before and after the period when doubly labeled water was used, and the results were used to estimate changes in energy stores.19

Behavioral and Psychological Testing

All the subjects in group 1 were evaluated with the following tests: the Beck Depression Inventory, a self-administered test designed to screen for the presence and severity of depression29; the Minnesota Multiphasic Personality Inventory (MMPI), a self-administered questionnaire that examines a wide range of behavioral characteristics and psychological functions30; the Structured Clinical Interview for Diagnosis (SCID), based on the Diagnostic and Statistical Manual of Mental Disorders (third edition, revised)31 and designed to diagnose Axis I (major psychiatric illness) and Axis II (disorders of character or personality) psychiatric disorders32; and the Eating Inventory, a self-administered questionnaire that evaluates cognitive restraint (conscious attempts to limit food intake), disinhibition (tendency to lose control of a diet), and hunger.33 The Beck Depression Inventory, the MMPI, the SCID, and the Eating Inventory were also completed by 57, 30, 56, and 47 subjects in group 2, respectively.

Accuracy of Estimates of Portion Size and Meal Recall

Errors in estimating the size of meal portions may cause food intake to be misreported. We therefore tested the accuracy of estimates of portion size by the subjects in group 1 and by 10 of the subjects in group 2.34 The subjects were asked to estimate the overall size (the linear dimensions and the volume or weight) of various standard foods. The results were expressed as a percentage of the actual weight or volume.

We used a test meal to evaluate the accuracy of the subjects' reports of their food intake 24 hours after they ingested food under standardized conditions.35 While fasting, the subjects in group 1 and 10 of the subjects in group 2 were given a lunch composed of a variety of foods and instructed to eat until they felt 80 percent full, with a time limit of 45 minutes. The next day, an investigator contacted each subject by telephone and inquired about the foods he or she had eaten during the previous day, and about the amounts eaten. The results of the subject's attempt to recall the test meal were then compared with the weight of the actual foods eaten.35

Evaluation of Hypotheses

The hypothesis that low energy expenditure is the mechanism of failure to lose weight was examined by evaluating the resting metabolic rate, the thermic effect of food, the thermic response to exercise, and the total energy expenditure in the two groups. The second hypothesis, underreporting of caloric intake and overreporting of physical activity, was tested by combining the results of records of food and activity kept simultaneously during the 14-day study with doubly labeled water. An average daily self-reported energy intake was calculated from the food records, and an average daily total energy expenditure was estimated from the study with doubly labeled water. Changes in energy stores were calculated on the basis of the difference in fat and fat-free body mass from day 0 to day 14.6 , 19 Actual caloric intake was calculated as the difference between total energy expenditure and stored energy. Self-reported caloric intake was expressed as a percentage of actual intake, with overreporting and underreporting indicated by positive and negative values, respectively. Actual energy expended in physical activities was calculated as the total energy expenditure minus the sum of the resting metabolic rate and the thermic effect of food.36 The daily thermic effect of food was calculated as the thermic effect of the test meal (expressed as a percentage) multiplied by the daily energy intake as estimated from the study using doubly labeled water. The actual energy expended in physical activity (kilocalories per day) was then compared with the amount of energy the subject reported expending in physical activities.

Statistical Analysis

Student's t-test for unpaired observations was used for comparisons of continuous variables between groups, the chi-square test was used for comparisons of categorical variables between groups, Pearson's product-moment correlation coefficient was used to measure association, and stepwise multiple linear regression was used to develop the equations relating resting metabolic rate and total energy expenditure to body composition (SAS version 5 software, SAS Institute, Cary, N.C.). Results are expressed as means ±SD, and P values below 0.05 were considered to indicate statistical significance.