The genetics of obesity: the role of the melanocortin 4 receptor

Obesity, which is described clinically by a body mass index (BMI) of > 30 kg/m2 is increasing at an alarming rate, and is recognised as a chronic disease by the World Health Organization (WHO). This epidemic decreases life expectancy, and its prevalence is increasing within the global paediatric and adult populations in most African countries, South Africa included. Research has revealed the importance of the genetic component of obesity, with much emphasis to date having been placed on monogenic disease. Polymorphisms within the gene encoding for the melanocortin-4 receptor (MC4R), a hypothalamic receptor with the primary function of regulating food intake, are a significant cause of severe human obesity. Studies have shown a correlation between the degree of MC4R dysfunction and the severity and age of onset of obesity. The accepted mode of inheritance for MC4R mutations is co-dominance with modulation of penetrance and expressivity, which would explain why homozygous carriers are more obese than heterozygotes. MC4R mutation frequency is also dependent on the ethnicity of the population. The use of genetic markers for diagnostic strategies and as predictors of therapeutic outcome will be of importance in the future management of obesity.