Obesity amplifies across generations; can folate-rich diets stop it?

Many measures to curb the obesity epidemic are aimed at young children. It's a sensible strategy - we know that overweight children have a good chance of becoming overweight adults. Family homes and schools have accordingly become critical arenas where the battle against the nation's growing waistlines is fought. But there is another equally important environment that can severely affect a person's chances of becoming overweight, but is more often overlooked - the womb.

Overweight parents tend to raise overweight children but over the last few years, studies have confirmed that this tendency to transcend generations isn't just the product of a shared home environment. Obesity-related genes are involved too, but even they aren't the whole story. Research has shown that a mother's bodyweight in the period during and just before pregnancy has a large influence on the future weight of her children.

For example, children born to mothers who have gone through drastic weight-loss surgery (where most of the stomach and intestine are bypassed) are half as likely to be obese themselves. On the other hand, mothers who put on weight between two pregnancies are more likely to have an obese second child. In this way, the obesity epidemic has the potential to trickle down through the generations, like a snowball rolling its way into an avalanche.

Now, Robert Waterland from the Baylor College of Medicine has demonstrated how the snowball gains momentum by studying three generations of mice that have a genetic tendency to overeat. And using a special diet that was high in folate and other nutrients, he found that he could stop the snowball's descent and spare future generations of mice from a heightened risk of obesity.

Fat-rats

Mice carry a gene called agouti that causes their hair to produce a yellow pigment rather than a black one. Waterland's mice carry a mutant version of agouti called A^vy, which is switched on throughout their entire bodies, rather than just their hair follicles. That gives the mice a mottled yellow colour, but as an unexpected side effect, the ever-present gene also blocks signals in the animals' brains that tell them that they're full.

And that makes the mice prone to overeating. If they are given free access to an all-you-can-eat buffet, they invariably get fat. There are obvious parallels to modern humans, who have constant access to cheap, calorific food at massive portions after evolving to cope with conditions where food is often lacking.  

Waterland followed three generations of these gluttonous mice, where females with one copy of A^vy were mated with males without any. The result was a family, where grandmothers, mothers and daughters alike all carried the same version of agouti , which predisposed them to overeating. Despite these genetic similarities, and despite the fact that they were all raised on the same diet, successive generations became fatter.

In the first generation, 45% of A^vy carriers weighed more than 50g (that's heavy for a mouse). By the second generation, 54% passed this mark and by the third, a whopping 72% had gone beyond it. In each generation, the mother's weight predicted the weight of her offspring, so that heavier mums begat heavier pups. By eye, you can tell that the mice are fatter rather than just larger or more muscular, and an X-ray measure of body fat confirmed it.

These results are unique. Other studies have used artificially manipulated diets to examine the link between obesity in mothers and children, but Waterland's work is the first to show that natural variations in obesity can cascade down the generations. If the same process applies to humans, and there is evidence that it does, it is likely that the increase in obesity rates among women of a childbearing age could help to explain the enormous rises in average bodyweight over the past few decades.

How it works

Now remember that the researchers took steps to ensure that the A^vy gene was the same in all three generations of mice. This means that the process is not a genetic one. Instead, the changes are epigenetic, a term which means that a gene itself stays the same, but the way it behaves is altered. Genes can be switched on or off, turned up or down, by adding chemical groups to their DNA sequence. For example, simple methyl groups  consisting of one carbon atom and three hydrogens serve to silence genes. These add-ons are like Post-It notes on a book that affect how it is read, even though the underlying text is the same.

Many of these epigenetic changes remain when cells divide and they can persist across generations (copy the book and the Post-its are copied with it). This process provide a route for environmental factors - in this case, a mother's body fat - to be passed down from the family line.

Waterland confirmed that epigenetics was involved by showing that a cocktail of nutrients, including folate, vitamin B12, betaine and choline, could curtail the generational fattening in his mice. These nutrients provide a rich source of methyl groups, which serve to silence various genes throughout the rodents' genomes. A^vy was certainly one of these. But Waterland thinks that other genes are shut down too, including some that are involved in the development of the hypothalamus, a part of the brain that controls appetite.

The exact details of this process, and which genes are affected, are still unknown. But the end-results are clear. With this special diet, the first and second generation mice had similar proportion of obese individuals (45% and 52% respectively) as their peers but in the third generation, a mere 44% were obese, compared to 72% in the other mice. Among the supplemented families, the weight of mothers did not influence the weight of their offspring and successive generations didn't get fatter and fatter.

The field of epigenetics is one of the hottest in modern biology. We now know that problems with epigenetic marking play a big role in the development of cancer, and it's likely to change the way we see other diseases too. According to Waterland, we know "virtually nothing" about the ways the epigenetic control of genes that are involved in eating or hunger. Given the increasing rates of obesity across the globe, filling in this void of ignorance is "of crucial importance".

Reference: Waterland, R.A., Travisano, M., Tahiliani, K.G., Rached, M.T., Mirza, S. (2008). Methyl donor supplementation prevents transgenerational amplification of obesity. International Journal of Obesity DOI: 10.1038/ijo.2008.100