Beyond calories: Genetic determinants of eating, satiety and metabolism underlying obesity

Abstract

Genetic and environmental factors interact to regulate body weight. Overall, the heritability of obesity is estimated to be 40% to 70%. Rare variants in the coding sequences of major candidate genes account for an obese phenotype in only 5% to 10% of individuals, indicating that the genetic routes to obesity are complex and likely to involve several interacting pathways. Genes potentially affecting obesity can be considered in three broad categories: regulation of food intake, regulation of adipocyte differentiation and fat storage, and regulation of oxidative phosphorylation and energy metabolism. Healthy individuals show marked heterogeneity in their ability to lose weight in response to precise caloric restriction. Resistance to weight loss may have had evolutionary advantages, in accordance with the ‘thrifty gene' hypothesis. Our recent studies are focused on defining the molecular regulation of energy metabolism relevant to weight loss success.