The goal of this proposal is to understand the biological basis for susceptibility to obesity in order to improve treatment and prevention of obesity. Human subjects can be characterized by their behavioral and metabolic susceptibility to obesity. The intent of this proposal is to understand why some human subjects are more metabolically susceptible to obesity than others. In many individuals, obesity may develop not from sustained massive Overeating or a markedly low level of physical activity, but from the cumulative effects of numerous instances of positive energy balance resulting from relatively acute periods (days or weeks) of overconsumption, relative inactivity, or both. The underlying hypothesis of this application is that a high reliance on carbohydrate (CHO) as an oxidative fuel following perturbations to energy-balance (e.g. overfeeding, fasting, physical activity) leads to sparing of dietary fat and existing body fat from oxidation, a situation which contributes to positive fat balance and obesity. Using an approach developed during our last grant period, where daily nutrient balance is assessed with the aid of a whole-room indirect calorimeter and used to estimate changes in body composition, we will study changes in body fat content during and following acute perturbations to energy balance. We will recruit 3 groups of subjects: 1) non-obese subjects with no family history of obesity; 2) non-obese subjects with a family history of obesity; and 3) weight stable reduced-obese subjects. This should ensure inclusion of subjects showing extreme differences in metabolic susceptibility to obesity. Those who show the greatest positive fat balance following each perturbation (obesity susceptible) will be compared, using discriminant analysis, with those who show the least positive fat balance (obesity resistant).
In Specific Aim #1, we will measure fat balance acutely following overfeeding (protocol 1), sustained fasting (protocol 2) and different types of physical activity (protocol 3). We will devise a classification system, based on the distribution of resulting fat balance to define individuals most and least metabolically susceptible to obesity. The perturbations chosen amplify the 3 main perturbations encountered daily by human subjects - overfeeding (following meals), fasting (between meals and overnight) and physical activity.
In Specific Aim #2, we will use physiological markers to construct a univariate or multivariate model to predict who is most and least metabolically susceptible to obesity. We believe the most likely discriminating variables will be: 1) ratio of CHO/fat in the fuel mixture oxidized; 2) insulin sensitivity; 3) oxidative vs glycolytic capacity of skeletal muscle; 4) LPL mRNA levels in muscle/adipose tissue.
In Specific Aim #3, we will validate the predictive model developed in aim 2.
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