Abstract: Series 106, Lecture 6

The Harvey Lectures Series 106 (2010—2011)

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Lecture #6: Thursday, April 21, 2011 — Time and Location

Molecular Mechanisms in Human Obesity and Insulin Resistance

Stephen O’Rahilly, MD

Stephen O’Rahilly, MD

Professor of Clinical Biochemistry & Medicine
Director, Metabolic Research Laboratories, Institute of Metabolic Science
Addenbrooke’s Hospital

University of Cambridge

Cambridge, United Kingdom

Dr O’Rahilly's Website

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 and have identified multiple different genetic variants that cause highly penetrant forms of these diseases, All of these disorders have provided new knowledge regarding various aspects of the physiology of human energy balance and metabolism. Genetic variants causing or predisposing to human obesity impact on appetite and satiety to a far greater extent than metabolic rate or nutrient partitioning. These observations have led to a fundamental shift in thinking about the nature of the biological underpinnings of human 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 a dramatically effective therapy.