Not surprisingly, there has been intense interest in the genetics of obesity in recent years.  Obesity is a major health problem, resulting in tens of thousands of premature deaths and billions of dollars in healthcare costs each year in the United States, and it is known from twin and family studies that weight is a highly heritable trait.

The genetic mutations and variations identified so far explain only a small percentage of the variability in body mass seen in the population.  Some exciting clues have been found, however, as to why some people are more prone to obesity than others and how this might be counteracted.  But new research, published online this week in the American Journal of Human Genetics, shows that caution must be taken in moving from genetic discoveries to drug development.

Variations in the FTO gene have consistently been associated with obesity. On average, people who carry two copies of the “risky” version of this gene weigh six to eight pounds more than those who carry none. Mice completely lacking the FTO gene were shown to be leaner than their normal littermates, despite being less active.  These results have led some to suggest that inhibiting the FTO protein with a drug could be a good for obesity treatment or prevention.

(23andMe customers can see their FTO data in the Obesity Research Report.)

But an international team of researchers led by Sarah Boissel of the Université Paris Descartes in France has found that a mutation that interferes with the function of the FTO protein is associated with a lethal genetic condition.  Members of a large, inbred Palestinian family born with two copies of this mutation had multiple developmental abnormalities and died before the age of three.  Based on their results, Boissel and her colleagues warn that any research exploring the use of FTO inhibitors as obesity treatments must include a “careful assessment” of the potential to cause birth defects and other toxic side effects.

More about FTO:

SNPwatch: Gene Variant Linked to Obesity Affects Food Choices in Children

It’s Not Genes or Environment, It’s Genes AND Environment

ShareThis

It seems simple enough: if you eat only as many calories as you burn, you won’t pack on the pounds. Yet for many, balancing this equation is anything but easy. Obesity has become one of the most significant public health threats facing the United States and other developed countries. One-third of adults in the United States today can be considered clinically obese.

While lifestyle choices are certainly important, research has shown that genetics plays a significant role in determining a person’s propensity for being overweight or obese. One especially potent variant in the FTO gene has been consistently linked with weight in Europeans.

In a study of Scottish children published online yesterday by the New England Journal of Medicine, researchers suggest that this FTO variant may contribute to obesity by leading kids to chose foods that, pound for pound, pack a more powerful calorie punch.

[23andMe customers can see their data for an FTO SNP equivalent to the one used in this study by referring to the Health and Traits research report on obesity or using the Browse Raw Data feature. The T version of rs3751812 (equivalent to the A version of rs9939609 reported in this study) is associated with obesity]

Seventy-six kids between the ages of four and 10, selected from a larger study of 2,726 children who were having their height, weight, and FTO genotypes evaluated, also had their energy expenditure and food intake measured.

There was no difference in the number of calories burned while at rest between children who carried the higher weight-associated version of FTO and those who did not. Energy burned due to physical activity was actually higher for carriers than non-carriers. This suggests that the FTO variant isn’t affecting the basal metabolism rate or conferring a proclivity for a sedentary lifestyle.

There was also no difference in the total weight of the food ingested by the kids with the version of FTO linked to obesity. But these children did consume more calories than their non-carrier friends. The foods they chose during the test meals had “higher energy density” — they contained more calories per unit weight.

The authors note that most obesity disorders caused by defects in single genes (such as MCR4) affect eating behavior. These new results, and those of other studies (a few examples here, here, here and here), show that the common FTO variant is no different. It is unclear, however, whether FTO affects appetite regulation or the ability to sense how much food has been ingested.

In an accompanying editorial in NEJM, Dr. Rudolph Leibel says that although the proportion of obesity in the general population that can be attributed to variation in the FTO gene region is high, it’s probably still not enough to start using this SNP as a clinical screening tool.

But he goes on to say that in the not-so distant future more variants such as this one will be found and physicians will be able to assess a “score” based on maybe 15 to 20 genes to predict an individual’s risk for obesity.

“The important role that environment plays in enabling or resisting such susceptibility is clear evidence that such risk can be modified,” Leibel concludes.

ShareThis