Scientists discover 14 genes that cause obesity
Promising news in efforts to develop drugs to treat obesity: University of Virginia scientists have identified 14 genes that can cause and three that can prevent weight gain. The findings pave the way for treatments to combat a health problem that affects more than 40% of American adults.
“We know of hundreds of genetic variants that are more likely to appear in individuals with obesity and other diseases. But ‘likely to appear’ does not mean causing disease. This ambiguity is a major barrier to exploiting the power of population genomics in identifying targets for treating obesity. To overcome this barrier, we developed an automated pipeline to simultaneously test hundreds of genes for a causal role in obesity. Our first round of experiments revealed more than a dozen genes that cause and three that prevent obesity,” said Eileen O’Rourke of the College of Arts and Sciences at UVA University, Department of Cell Biology in the College of Medicine, Robert M. Berne Cardiovascular Research. We expect that our approach and the new genes we have uncovered will accelerate the development of treatments to reduce the burden of obesity.”
Obesity and our genes
O’Rourke’s new research helps shed light on the complex intersections of obesity, diet, and our DNA. Obesity has become an epidemic, driven in large part by high-calorie diets loaded with sugar and high-fructose corn syrup. Increasingly sedentary lifestyles play a large role as well. But our genes also play an important role, regulating fat storage and affecting how well our bodies burn food for fuel. So if we can identify the genes that turn excessive food into fat, we can seek to disable them with drugs and disentangle overeating from obesity.
Genomic scientists have identified hundreds of genes associated with obesity — meaning that the genes are more or less common in obese people than in people of a healthy weight. The challenge is to identify genes that play causal roles by directly promoting or helping to prevent weight gain. To sort wheat from the chaff, O’Rourke and her team turned to the humble worms known as C. elegans. These little worms love to live in rotting plants and enjoy feasting on microbes. However, they share more than 70% of our genes and, like people, become obese if they are fed excessive amounts of sugar.
Worms have produced great benefits for science. They’ve been used to decipher how common medications work, including the antidepressant Prozac and the glucose stabilizer metformin. Even more impressive, in the past 20 years three Nobel Prizes have been awarded for discovering cellular processes that were first observed in worms but then turned out to be crucial to diseases such as cancer and neurodegeneration. It has also been instrumental in developing therapeutics based on RNA technology.
In new work just published in the scientific journal PLOS Genetics, O’Rourke and her collaborators used worms to examine 293 obesity-related genes in people, with the goal of determining which genes were actually causing or inhibiting obesity. They did this by developing a worm model of obesity, feeding some regular diets and some high-fructose diets.
This obesity model, combined with automated supervision and automated learning-assisted testing, allowed them to identify 14 genes that cause obesity and three that help prevent it. Intriguingly, they found that blocking the action of the three genes that prevented the worms from becoming obese also led to them living longer and having better motor neuron function. These are exactly the kind of benefits drug developers hope to get from anti-obesity drugs.
Of course, more work must be done. But the researchers say the signs are encouraging. For example, the effect of a gene in lab mice prevented weight gain, improved insulin sensitivity and lowered blood sugar levels. These findings (plus the fact that the genes under study were selected because they were linked to obesity in humans) hold promise that the findings will hold true in people, too, the researchers say.
“Anti-obesity therapies are urgently needed to reduce the burden of obesity in patients and the healthcare system,” O’Rourke said. “Our combination of human genomes with causal tests in model animals promises that anti-obesity targets are more likely to succeed in clinical trials due to their expected increased efficacy and reduced side effects.”
Materials provided by University of Virginia Health System. Note: Content may be edited for style and length.
Wonfan Qi, Jordan N. Reed, Chenyu Yang, Noel Higason, Layla Ryan, Carolina Wallaby, Ann Carpenter, Mette Selleck, Ellen J. O’Rourke. The genes in human obesity loci are the causal obesity genes in C. elegans. PLOS Genetics, 2021; 17(9): e1009736 DOI: 10.1371/journal.pgen.1009736