Gene-Diet Interactions and Obesity

Even with a predisposition, diet trumps genes

  • by Judy George
    Contributing Writer, MedPage Today

    Medpage Today

Expert Critique

Kelsi Deaver, MD
Kelsi Deaver, MD Endocrinology Fellow, PGY5 University of Colorado Aurora, CO
Full Critique

A decade after the first robust genome-wide association studies of obesity, the role genes play still is a mystery.

Americans are getting fatter -- nearly 4 in 10 are obese, the CDC reports -- and while genes haven't changed, the environment has become much more obesogenic, Diane Gilbert-Diamond, ScD, of Dartmouth College in Hanover, N.H., observed.

"We have more highly palatable foods and cues to eat, and this environment can be most detrimental to those at genetic risk for weight gain," she said.

The Hunt for Obesity Genes

The search for human obesity genes started with two papers about twins published in the New England Journal of Medicine in 1990. One compared twins reared apart with twins reared together and found strong evidence of the influence of heredity on body-mass index (BMI). The other showed identical male twins who were overfed for 100 days had similar weight gain and fat distribution, concluding the likely explanation was their shared genetic makeup.

"By the late 1990s and early 2000s, we knew obesity had a huge genetic component," said Marc Reitman, MD, PhD, of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "But clearly there had to also be an environmental component: genes don't change over the course of tens of years; they change over millennia and multiple millennia. The fact that we have an obesity epidemic meant we also have some sort of environmental change."

From hundreds of loci identified that may contribute to obesity, two that have attracted persistent and ongoing interest are melanocortin-4 receptor (MC4R), which has been linked to morbid obesity, and a variant identified in a 2007 genome-wide association study: the fat mass and obesity-associated (FTO) gene.

How Genes Might Matter

"Most of us really thought we'd do a genome-wide association study and identify 10 or 50 genes and we'd understand the basis of human obesity," Reitman recalled. "What was very clear was that there are hundreds of contributing loci, and FTO is the biggest contributor with maybe a 1.4-fold effect size per allele."

"Now we have to figure out how the genetic signals interact, which is a very tough, complicated story."

Some studies have suggested FTO may be linked to obesity through subtle changes in food intake and preference. In 2016, MRI scans showed that children with an FTO polymorphism had differences in structural and functional brain imaging than other children.

These children had greater brain reward activity when shown food advertising and their nucleus accumbens, a region of the brain associated with reward and eating behavior, was larger, Gilbert-Diamond and colleagues reported. "This suggests that some children may be genetically predisposed to be more responsive to food advertising than others," she said.

But no research has provided concrete evidence that genes affect the amount of calories, carbohydrates, or fat consumed. In a literature analysis published earlier this year, Christina Holzapfel, PhD, of Technical University of Munich in Germany, and colleagues looked at 39 papers about single nucleotide polymorphisms (SNPs) and food intake.

FTO and MC4R were the genes they most frequently encountered in their systematic review. "There are indications of a relationship between these two genes and total energy intake," Holzapfel said. "However, the evaluation of the studies did not provide a clear picture."

Risk Versus Behavior

What has been become evident is that even with genetic susceptibility, behavior matters. In 2016, John Mathers, PhD, of Newcastle University in the United Kingdom, and colleagues showed that possessing the high-risk FTO gene didn't affect the ability to lose weight.

And this year, a paper that analyzed two long-term prospective cohorts showed that, when people with a high genetic risk for obesity stuck to a long-term healthy diet, they lost more weight than people with low genetic risk. In that analysis, for every standard deviation increase in diet quality score, BMI decreased by 0.18 (corresponding to about 0.50 kg weight loss) for people with high genetic risk for obesity, but only by 0.12 (0.35 kg weight loss) for people with low risk, Lu Qi, MD, PhD, of Tulane University in New Orleans, and colleagues reported.

Over time, the long-term effect could be substantial, not just in losing weight but in preventing weight gain, they observed.

The mechanisms remain unclear, but would be complex, Qi noted. "For example, the high-risk genotypes may be more sensitive to environmental factors such as diet," he said. In this population, unhealthy foods more likely lead to weight gain, but in contrast, these people "also more sensitive to healthy foods that results in greater weight loss," he noted. "We need more research to investigate the potential mechanisms."

Overall, the whole population -- with either high or low genetic risk -- can counteract weight gain with healthy diets like the American Heart Association's DASH eating plan, Qi added: "Specifically, increasing intake of fruits, vegetables, long-chain unsaturated fats, and whole grains and decreasing consumption of trans fat and sugary drinks would benefit everyone."

While we know much more about genetics since the early genome-wide association studies, we still haven't unraveled the story of genes and obesity. The FTO story is illustrative, said Reitman. "We're a decade out; we've got a lot of papers about FTO, but we still don't know the causal polymorphism mechanism."

"It's very sobering, if you think about the hundreds of person-years involved in trying to sort this out," he added. "A lot of progress has been made, but there's no simple answer yet."

The researchers interviewed in this article reported no competing relationships.