High-Fat Diet Converts Beneficial Gene Variant Into A 'Villian'

A gene variant, earlier known to protect people against weight gain and insulin resistance, could have an opposite effect in people who eat a high-fat diet and are heavier, according to a study on mice.

The results indicated that the 12 percent of people who carry the so-called Ala12 version of the gene that serves as a master controller of fat differentiation would be more sensitive than most to the amount of fat in their diets.

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The fat-moderating gene is called peroxisome proliferator-activated receptor gamma isoform 2, or Pparg2.

However, the researchers said that the Ala12 gene variant is less active and less efficient in driving fat cells' formation than the more common Pro12 version.

Thus, people with Ala12 are generally less obese and more sensitive to insulin, but that can change if they shift to a less sensible, fat-laden meal plan.

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Johan Auwerx of Universite Louis Pasteur in France and the Ecole Polytechnique Federale de Lausanne in Switzerland said that genetic testing for the variant could thus be used as a diagnostic tool.

"Through dietary counseling, carriers could be informed that they really need to watch out for high fat in their diets," he said.

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Also, he added that the findings raised a potential caution about the long-term effects of drugs called thiazolidinediones (TZDs), which stimulate activity of the Pparg2 receptor and are used for the treatment of diabetes.

The findings further suggested that it might be better, at least in some settings, to have a less active receptor.

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Now, the researchers have shown that mice with two copies of the Ala12 variant, when fed a balanced diet of normal mouse chow, are leaner and have improved insulin sensitivity and better plasma lipid profiles than mice with two copies of Pro12. They also live longer.

When mice with the same genetic background were instead sustained on a diet high in fat, those benefits disappeared and in fact, the animals grew somewhat more obese than mice with the more common Pro12 variant of the gene, though not significantly so.

The findings indicate an important interaction between the Pparg2 gene and the environment.

And apparently, the basis for the effect depends on changes in the way the Pparg2 receptor interacts with its cofactors and in its sensitivity to a fat-produced hormone known as adiponectin, which influences blood sugar control and fatty acid breakdown.

"Collectively, our results establish the diet-dependent influence of Pparg2 Pro12Ala variant on metabolic control via modulated cofactor interaction and changes in gene expression patterns in mice," concluded the researchers.

They added: "These data hence consolidate Pparg2 as an important factor at the interface between genes and the environment and may provide avenues to better, possibly Pro12Ala genotype-dependent treatment strategies for insulin resistance in type 2 diabetes and the metabolic syndrome."

The study is published in the latest issue of the journal Cell Metabolism, a Cell Press publication.

Source-ANI
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