Body weight can be affected by the content of fat and carbohydrate in the diet. On average, people will lose a modest (< 5 kg) amount of weight when switched from a high fat diet to a low fat, high carbohydrate diet. Determining mechanisms whereby changing the makeup of the diet can change one's body weight will be important in understanding why body weight in the US population is trending upward recently and what health care providers can recommend to reverse this trend. Previous studies have shown that increasing the carbohydrate and lowering the fat content in the diet leads to a change in the appearance of the hormone leptin in the blood over 24 hours. Leptin is an important signal from the fat cell to the brain that leads to a reduction in appetite and weight loss. A previous study found that after keeping people's weight stable, that the greater rise in leptin over the day on a low fat-high carbohydrate diet compared to a high fat diet predicted the reduction in calories they ate over a subsequent 12 weeks when their weight was allowed to freely fluctuate. Recent studies have also provided evidence that limiting fat and increasing the amount of protein in the diet also leads to modest weight loss. It is therefore proposed to test whether low fat, high protein diets also result a change in leptin secretion, and if this change predicts a reduction in appetite when they are allowed to eat freely.

The role of leptin in regulating body fat mass in humans is incompletely understood. Although complete loss of leptin signaling results in morbid obesity, there is an inconsistent association between more subtle changes in leptin levels and changes in body composition. Administration of recombinant leptin to human volunteers also results in a variable loss of fat mass. Therapeutic high carbohydrate diets generally lead to decreased caloric intake and weight loss compared with high fat diets. The mechanism of this decrease in appetite is, however, unknown. In preliminary data, the invesigators have shown that compared to high fat feeding, isocaloric high carbohydrate feeding over 2 weeks leads to increased leptin excursion during 24 hours. In addition, this change in leptin signaling predicts subsequent reduction in daily caloric intake with ad-lib high carbohydrate feeding. It has recently been reported that an increase in dietary protein also leads to modest spontaneous weight loss in ad-lib feeding subjects. The current proposal is to therefore determine whether prolonged high protein feeding leads to a sustained increase in the integrated daily leptin level and whether this increase predicts a subsequent decrease in caloric intake in human volunteers. Eligible subjects will consume a control protein diet (15%, low protein) followed by a high protein diet (30% protein) for 2 weeks each while maintaining weight stability. At the end of each 2-week feeding phase, subjects will be admitted to the inpatient GCRC for frequent sampling for insulin and leptin levels over 24 hours. Immediately following the second CRC inpatient visit, subjects will continue to consume the high protein diet ad-libitum for another 12 weeks, during which time they will be followed for changes in their caloric intake and body weight. Because of limitations in metabolic kitchen resources, if this study were to be conducted solely at OHSU, it would require recruitment and study of two groups of subjects over sequential time periods. This results in delay of acquisition of data, completion of the study, and the potential introduction of seasonal variation as a study confounder. Therefore, a two-site study is proposed utilizing the metabolic kitchen resources of OHSU and the University of Washington GCRC's jointly. Instead of two groups of subjects being recruited and studied sequentially at one site, subjects will be recruited at both sites and studied in parallel, thus allowing the completion of the protocol in half the usual amount of time and without additional study confounders.

It is hypothesized that switching human volunteers from a 15% protein diet to an isocaloric high (30%) protein diet will cause a significant increase in the area under the diurnal plasma leptin versus time curve (AUC-leptin) and the insulin versus time curve (AUC-insulin), that these increases will be sustained over 2 weeks of isocaloric high protein feeding, and that the elevation in AUC-leptin will predict the extent to which caloric intake decreases when subjects are switched from an isocaloric to an ad libitum high protein diet.

Specific Aim 1: To determine whether an isocaloric increase in dietary protein content from 15% to 30% causes a significant increase in AUC-leptin and AUC-insulin that is sustained for two weeks.

Specific Aim 2: To determine whether the increase in AUC-leptin on a 30% protein diet predicts a subsequent decrease in ad libitum caloric intake and weight loss.

Inclusion Criteria:

• Ability to provide informed written consent
• Age between 18 and 65 years
• Willingness to consume only food prepared by the CRC for 6 weeks
• Body mass index between 22 and 28 kg/m2
• Weight stable to within 2 kg for 3 months preceding study, and at lifetime maximal weight

Exclusion Criteria:

• Diabetes mellitus
• Renal disease
• Other chronic medical or psychiatric illness
• Pregnancy or female subject unwilling to use contraception
• Use of tobacco products
• Regular intense exercise (>30 minutes of aerobics, 3x / week)
• Vegetarian or extreme dietary preferences (< 20% or > 40% fat diet, > 40% protein diet)
• Use of anabolic steroids, glucocorticoids, or lipid-lowering agents
• Alcohol consumption >2 drinks / day