Understanding the etiology of obesity : a multi-faceted approach

Obesity, caused by an excessive accumulation of body fat due to a chronic energy surplus, is a serious public health concern with numerous comorbidities. It is a complex disease with many factors contributing to its manifestation; it is thought that obesity results from the action of multiple genes in combination with lifestyle and environmental factors. At the current time, only a fraction of the genes involved in obesity have been identified. The aims of this thesis were first, to characterize the obesity phenotype in the Newfoundland population and second, shed light on its genetic etiology. This goal was achieved using data from two different studies - the large scale, population-based CODING (Complex Diseases in the Newfoundland Population: Environment and Genetics) Study and an intervention-based, 7-day overfeeding study. -- We have shown that body mass index (BMI) misclassifies adiposity status in nearly one-third of individuals compared to the more accurate reference method, dual energy X-ray absorptiometry (DXA). Furthermore, we found that approximately half of obese subjects were metabolically healthy when using DXA criteria, which was significantly higher than previous reports using BMI. Among BMI-defined normal weight individuals, higher body fat percentage (%BF) determined using DXA was associated with a 3-fold increased risk of cardiometabolic disease. To further understand the genetic etiology, a candidate gene, genetic association approach was utilized. We identified two SNPs (rs10882280 and rs11187545) within RBP4, a newly discovered adipokine, that were associated with increased serum HDL cholesterol but no other obesity-related parameter. No significant associations were observed between genetic variation in another novel adipokine, NAMPT, and parameters of glucose and lipid metabolism, obesity, or systemic inflammation. We also sought to explore the response of lean and obese subjects to a 7-day hypercaloric diet. We found that RBP4 was not regulated by the overfeeding challenge but could serve as a predictor of insulin resistance in lean subjects. In addition, 45 novel obesity candidate genes have been identified that were regulated by the nutritional challenge; of these, six were differentially expressed between lean and obese and as such, represent the most promising targets for downstream work related to obesity