Fat mice provide genetic clues to obesity puzzle

11 April 2012

A new study published in Nature Medicine provides clues as to how a gene mutation may lead to obesity. 

Mutations in the brain-derived neurotrophic factor gene (BDNF) have previously been shown to cause obesity in mice and have been identified in severely obese children. Genome-wide association studies have also confirmed BDNF as a susceptibility gene for common obesity in humans.  

The study investigated the mechanism by which BDNF mutations lead to obesity.  Obesity is caused by an excess of energy, which can result from high energy intake, low energy expenditure, or both. Obesity was caused solely by overeating in mice with BDNF mutations, which consumed up to 80% more food than those without the mutation (‘wild type’ mice). When the mice with the mutation were restricted to the amount of food that that the wild type mice chose to eat, they did not become obese. 

Further investigation revealed that mice with the BDNF mutation were resistant to leptin. Leptin is a hormone produced by fat tissue which acts on the brain to reduce food intake. Whilst the wild type mice reduced their food intake by a more than a quarter when injected with leptin, no such reduction occurred in those with the mutation. 

Comment: Genetic differences are responsible for a large proportion of the variation in body fatness between individuals. At least 50 areas of the human genome have been associated with obesity-related traits in humans, but these only explain a fraction of the total genetic variation and much is still unknown about the responsible genes and biological pathways. 

Studies such as this contribute to our understanding of the biological basis of obesity and help to elucidate the mechanisms by which susceptibility genes confer increased risk. However, this particular study was entirely in mice, and mutations that completely disrupt the BDNF gene are rare in humans, so the direct impact on understanding of human obesity biology is limited.

Moreover, understanding the role our genes play in determining body weight is complicated by interactions between multiple genes, and between genes and our lifestyle and environment. Our environment promotes high energy intakes and sedentariness. How we behave in the face of this environment is influenced by many factors including, as this study shows, our genes, which in this case affected the appetite of the mice with BDNF mutations. Interventions against the growing public health burden of obesity may need to take account of the environmental, behavioural and genetic determinants in order to have the greatest effect. 

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