Endocrine Abstracts

The genetic component of quantitative metabolic traits is complex with a mixture of common alleles of small effect and rarer alleles of larger effect. We have principally focused on finding the latter through the study of extreme human phenotypes of obesity and insulin resistance, including lipodystrophy. By applying both candidate and hypothesis-free genetic approaches we have identified multiple different genetic variants that cause highly penetrant forms of these diseases. Some of these disorders, e.g. melanocortin 4 receptor deficiency are among the commonest human Mendelian disorders. All of these disorders have provided new knowledge regarding various aspects of the physiology of human energy balance and metabolism and functional studies as at a molecular and cellular level have provided valuable insights into structure–function relationships in key regulatory molecules. Genetic variants causing or predisposing to human obesity impact on appetite and satiety to a far greater extent than on metabolic rate or nutrient partitioning. These observations have led to a fundamental shift in thinking about the nature of the biological underpinnings of obesity of obesity. Rather than being a ‘metabolic’ disorder, obesity is essentially a heritable neurobehavioral trait, albeit one with adverse metabolic consequences. These discoveries have altered the way the severely obese child is evaluated clinically and, in the rare case of congenital leptin deficiency, have led to the institution of a dramatically effective, life saving therapy.