High-fat diet makes 'good' gene variant turn bad
A version of a gene that protects lean people against obesity and diabetes has the opposite effect in people with high-fat diets, according to EU-funded research published in the journal Cell Metabolism. The findings could lead to the development of diagnostic tools that would enable doctors to offer therapies and lifestyle advice tailored to an individual's genotype.
The work was partly supported by the EU through the Eugene2 ('European network on functional genomics of type 2 diabetes') project, which is financed through the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6).
The gene in question is called Pparg2, and it plays an important role in fat storage as well as the maintenance of glucose levels and insulin sensitivity. The common Pro12 version of the gene has been linked to an increased risk of type-2 diabetes. In contrast, the rarer Ala12 version, which is carried by around 12% of the population, appears to lower the risk of obesity in many people.
However, in some people Ala12 appears to have the opposite effect. In this latest study, the researchers probed this anomaly in great detail. They studied mice with different versions of the gene and fed some of them on a normal diet and some on a high-fat diet.
They found that when fed a normal, healthy diet, mice with two copies of the Ala12 version of the gene are leaner, have improved insulin sensitivity and better plasma-lipid profiles and live longer than mice with two copies of Pro12.
'Our results strengthen the view that the Pro/Pro of Pparg2 is a risk genotype that adversely affects glucose homeostasis and lifespan,' the researchers conclude.
However, when mice with two copies of Ala12 were fed on a high fat diet, the benefits disappeared and the animals grew even fatter than the mice with the Pro12 version of the gene.
According to the researchers, this highlights an important interaction between the Pparg2 gene and the environment. 'The protective role of the Ala/Ala genotype depends on the dietary context, suggesting that the metabolic impact of this mutation is highly dependent on gene-environment interactions,' the scientists write.
The researchers note that gene testing for the variant could be a useful diagnostic tool to warn people with the Ala12 version of the gene to stick to a healthy diet. 'Through dietary counselling, carriers could be informed that they really need to watch out for high fat in their diets,' noted Johan Auwerx of the Université Louis Pasteur in France and the Ecole Polytechnique Fédérale de Lausanne in Switzerland.
The researchers add that the new findings may lead to the development of new treatments for type-2 diabetes and metabolic syndrome.
Category: Project results
Data Source Provider: Cell Metabolism
Document Reference: Heikkinen, S et al. (2009) The Pro12Ala Pparg2 variant determines metabolism at the gene-environment interface. Cell Metabolism 9:88-98. DOI: 10.1016/j.cmet.2008.11.007.
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