application) Obesity is a well-established risk factor for the development of type-2 diabetes, hyperlipidemia, and hypertension. The prevalence of obesity has increased progressively over the past two decades. Available evidence suggests that dietary intake of fructose has also increased. Whereas glucose stimulates insulin and leptin production, fructose does not. Both insulin and leptin act as long-term peripheral signals of energy status to the central nervous system (CNS), and are involved in the regulation of food intake and energy expenditure. We have found that meals with a high fat content and a low amount of glucose-containing carbohydrate lead to lower circulating leptin levels over a 24-hour period than do low fat, high carbohydrate meals. Since fructose administration does not stimulate either leptin or insulin, we hypothesize that energy (calories) consumed as fructose essentially are unrecognized by the CNS and the appropriate adjustments of appetite and energy expenditure do not occur. Fructose also increases triglyceride levels in both humans and animals and induces hypertension in rodents. Comprehensive long-term studies of the effects of fructose consumption have not been conducted in humans or in nonhuman primates. We hypothesize that, over time, a diet high in fructose would promote weight gain, obesity and hyperlipidemia, resulting in an increased risk for type-2 diabetes. However, it is first critical to establish the effects of high-fructose versus high-glucose meals on circulating insulin and leptin levels in humans, and to determine if differences in insulin and leptin subsequently affect appetite and food intake. To test this hypothesis in human subjects, we propose to measure and compare 24-hour circulating leptin levels and appetite parameters in normal weight men and women during a 24-hour period during which the subjects consume 3 meals with 30% of calories as either free fructose or free glucose in a randomized crossover design. We expect that leptin concentrations will be lower over 24 hours when the subjects consume the high fructose meals. To examine the impact of the changes in leptin, we will then assess the effects of prior dietary carbohydrate type on appetite and caloric intake over a subsequent 24-hour period. We expect that the subjects will report greater sensation of hunger and eat more after consuming the fructose meals than after consuming the glucose meals. Together, these results will provide critical background data and additional rationale for controlled long-term studies on the effects of dietary fructose on body adiposity, energy expenditure, insulin sensitivity, lipids, and blood pressure in humans.
