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ABSTRACT
Obesity represents one of the biggest public health challenges facing us today. Urbanisation, sedentary lifestyles and the availability of inexpensive, highly palatable foods have promoted the increasing prevalence of obesity over the past 30 years. However, some people gain weight more easily than others, and there is strong evidence that, within a given environment, this variance in body weight is influenced by genetic factors. This article discusses how genetic studies have contributed to our understanding of the mechanisms involved in the regulation of body weight. We now understand that weight is regulated by neural mechanisms that regulate appetite and energy expenditure and that disruption of these pathways can result in severe obesity in some patients. These studies provide a framework for investigating patients and ultimately may guide the development of more rational, targeted therapies for genetically susceptible individuals with severe obesity.
KEYWORDS: Appetite, genetics, hypothalamus, leptin, obesity
Introduction
Since their inception in 1639, the Goulstonian Lectures have frequently addressed the clinical challenges of the time. Unsurprisingly, yellow fever and febrile contagion (1806) and the 'nature and affinities of tubercle' (1867) occupied physicians for much of the nineteenth century. Given the impact of obesity and associated disorders such as type 2 diabetes, it is perhaps appropriate therefore, that obesity was the focus of my lecture in 2013.
Obesity as a disorder of energy homeostasis
In its simplest terms, obesity arises when there is an imbalance between energy intake and energy expenditure. Evidence clearly shows that both increases in energy intake and reductions in energy expenditure during physical activity have driven increases in the mean body mass index (BMI) seen in many countries over the past 30 years.1 However, the interaction between an individual's genetic predisposition and their environment influences where they lie within the population's BMI distribution. Family, twin and adoption studies suggest that the heritability of body weight ranges between 40% and 70%. Genetic influences seem to be more potent at the extremes of the BMI distribution and in people from some ethnic groups who seem to be particularly susceptible to developing obesity (eg Polynesians). Given the estimated heritability of BMI, genetic approaches can be a useful tool to investigate the mechanisms involved in weight regulation and how those mechanisms are disrupted...