Diet-Induced-Obesity Resistant Phenotypes in Humans

While many obesity studies focus on the individuals who are already overweight and obese, a complementary approach to understand such a common disease is to define the mechanisms which allow some lean individuals to resist weight gain. The predominant cause of human obesity is the inheritance of genes favoring fat storage and efficient energy utilization interacting with an obesogenic environment, characterized by readily available, energy-dense food and sedentary lifestyle. However, a persistent percentage (about 30%) of the US adult population remains thin (BMI \<23 kg/M(2)). While some of these individuals maintain their weight by vigilantly controlling their diet, exercising or taking medication(s), others may have the ability to remain thin despite an excessive energy intake and without volitional exercise. To identify these individuals and define their phenotypes will provide unique insights into energy and body weight homeostasis, and may yield novel approaches for treating obesity. In this natural history protocol, we will recruit and characterize a cohort of constitutionally lean and healthy adult volunteers (age 25-50, BMI 18.5-25 kg/M(2)) who do not have pathological or exogenous factors that are known to stimulate energy expenditure, suppress food intake, or decrease absorption. We will recruit volunteers who are weight-stable, sedentary, and non-restrictive eaters, characterize their free-living dietary and physical activity energy expenditure using food records and portable accelerometers, respectively. Using an inpatient controlled setting, we will carefully characterize the details of their 24-hr energy metabolism, body composition, core and skin temperatures, and blood chemistries while they are on a one-week metabolic diet adjusted to maintain his/her body weight (baseline) vs. another week of higher energy intake level (1000 extra kcal per day above their baseline). Overfeeding will continue for two more weeks in the outpatient setting with all meals provided by our metabolic kitchen, followed by the fourth week of overfeeding and repeated measurements back in the inpatient setting. We hypothesize that spontaneous changes in energy expenditure and/or calorie intake may differ between individuals, and such difference may explain the ability for some to resist body gain. The accruals of humans with obesity-resistant phenotypes will significantly enhance our understanding of the mechanisms of energy homeostasis and identify potential novel regulators for controlling obesity.