'Master switch gene for obesity'

Tuesday May 17 2011

“The ‘master switch’ gene which causes obesity has been identified,” reported the Daily Mail . It said that the breakthrough could help treat “obesity-related diseases such as heart disease and diabetes”.

This genetic study looked at how genetic variations associated with changes in the activity of one gene (called KLF14) had knock-on secondary effects on the activity of a network of genes involved in metabolism. The activity of these secondary genes in fat cells was associated with body mass index, blood sugar and cholesterol levels, and how well the insulin system controlled blood sugar.

This study does not immediately lead to new treatment options but does show that the genetics underpinning metabolic conditions such as obesity and diabetes are complex. The findings highlight the importance of looking at a network of interacting genes rather than one gene in isolation.

The study itself did not look at the activity of these genes in obese people and it is too early to say if KLF14 is ‘the gene that makes you fat’.

Further studies are needed to understand how this network of genes influences obesity and obesity related diseases.

Where did the story come from?

The study was carried out by researchers from King’s College London and the University of Oxford. Funded was provided by the Wellcome Trust. The study was published in the peer-reviewed scientific journal Nature .

The Daily Mail and Daily Mirror covered this story. Neither newspaper go into detail about this complex study and both have over-simplified the findings. The impression might be had from reading these articles that the gene KLF14 is the main cause of obesity, when it is actually likely to be an interplay of multiple genetic and environmental factors.

What kind of research was this?

This was a genetic study that looked at how certain genetic variations that have been found to be associated with type 2 diabetes and levels of cholesterol in the blood might have an effect on other genes related to metabolism.

The messages to switch genes either on or off can come from regions of DNA close to the gene itself. This is called cis regulation. Genes can also be switched on by regions of DNA that are far from the gene, and this is called trans regulation.

The researchers say that genome-wide association studies have shown that genetic variations near to a gene called KLF14 are associated with type 2 diabetes and cholesterol regulation. The gene KLF14 codes for a type of protein called a transcription factor, which regulates how active certain target genes are.

In this study, the researchers looked at the possibility that these genetic variations that are near to KLF14 may also be having an effect on the switching on of other genes located far from KLF14.

What did the research involve?

The researchers collected blood and tissue samples from 856 female twins who were of European descent and were participating in the Multiple Tissue Human Expression Resource (MuTHER) study. Of these, the full genome-wide genotype and adipose tissue expression profiles (a measure of which genes were active in their fat cells and how active they were) were known for 776 women. The participants were on average 62 years of age. The eldest women in the study were 87 and the youngest 40.

The researchers carried out a variety of experiments to investigate whether the genetic variations that are near to KLF14 (called SNPs) might effect the switching on of genes that are far away from it, by having an effect on KLF14.

They looked at whether there was an association between one SNP upstream of KLF14 called rs4731702 and the activity of 16,663 genes in the fat biopsy. They then focused their attention on 10 genes highlighted by this analysis to be trans regulated by KLF14. They then tried to test these findings by repeating their experiment in a second set of fat tissue samples.

The researchers carried out various assessments of these 10 genes, including examining whether their activity was associated with body mass index (BMI), cholesterol levels, fat, blood sugar levels, insulin levels and the ability of insulin to regulate blood sugar levels.

What were the basic results?

The researchers found that the genetic variation (SNP) rs4731702, which lies near the KLF14 gene and is known to influence KLF14 activity, is also associated with how active a range of genes are in fat tissue. These genes lie far away from the KLF14 gene are potentially being trans regulated by KLF14.

They focused on 10 genes in which the levels of activity were related to rs4731702. On repeating their experiment on a second set of fat tissue samples, they found that seven of these genes still showed an association with rs4731702. The researchers suggest that rs4371702 is associated with between 3% and 7.8% of the variation of activity of these trans regulated genes.

When the researchers looked at the activity of these 10 trans regulated genes and obesity related measures in the cohort of women, they found that:

  • six of the genes were associated with BMI and cholesterol levels
  • five were associated with fat and insulin levels in the blood
  • four were associated with how well insulin could regulate blood sugar levels
  • two were associated with blood glucose levels

How did the researchers interpret the results?

The researchers said that the KLF14 gene acts as a master trans regulator of adipose (fat) gene expression (activity) and that the activity of genes regulated by KLF14 in this way are associated with changes in metabolism that are associated with disease risk.


This genetic study showed how a single letter change in the DNA sequence near to one gene can be associated with effects on genes far away. The research found that such a change in the DNA upstream of a gene called KLF14 not only affected the activity of that gene, but also influenced other genes in fat tissue that are associated with metabolism.

When understanding the complex genetics underpinning why some people may be more likely to develop metabolic conditions, this study highlights the importance of looking at networks of interacting genes rather than a particular gene in isolation.

At this point, it is too early to say whether this research will lead to any treatment options for obesity related diseases. The research itself did not look directly at the activity of these genes in obese people, and this will need to be examined for a better idea of how they may contribute to obesity. Further studies are needed to gain a deeper understanding of how the network of genes affects risk of obesity and obesity related diseases.

Analysis by Bazian
Edited by NHS Choices