Promising news in the effort to develop drugs to treat obesity: Scientists at the University of Virginia have identified 14 genes that can cause and three that can prevent weight gain. The results pave the way for treatments to fight 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 people with obesity and other diseases. But ‘more likely to appear’ does not mean to cause disease. This uncertainty is a major obstacle to harnessing the power of the genomic population to identify targets to treat or cure obesity. To overcome this hurdle, we have developed an automated pipeline to simultaneously test hundreds of genes for a causal role in obesity. Our first series of experiments discovered more than a dozen genes that cause and three genes that prevent obesity, ”said Eyleen O’Rourke of the College of Arts and Sciences at AVU, Department of Cell Biology at the Robert M. Berne Faculty of Medicine and Cardiovascular Research Center. “We anticipate that our approach and the new genes we have discovered will accelerate the development of treatments to reduce the burden of obesity. “
OBESITY AND OUR GENES
O’Rourke’s new research is helping 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 also play an important role. But our genes also play an important role, regulating fat storage and affecting the way our bodies burn food for fuel. So if we can identify the genes that convert excess food into fat, we could seek to inactivate them with medication and decouple binge eating from obesity.
Genomics have identified hundreds of genes associated with obesity, which means that the genes are more or less prevalent in obese people than in people of a healthy weight. The challenge is to determine which genes play a causal role in promoting or directly helping prevent weight gain. To sort the wheat from the chaff, O’Rourke and his team turned to humble worms known as the C. elegans. These little worms love to live in rotting vegetation and feast on microbes. However, they share over 70% of our genes and, like humans, they become obese if fed excessive amounts of sugar.
The worms have produced great benefits for science. They have been used to decipher how common drugs work, including the antidepressant Prozac and the glucose stabilizer metformin. Even more impressive, over the past 20 years, three Nobel Prizes have been awarded for the discovery of cellular processes first seen in worms, but which were later shown to be essential in diseases such as cancer and neurodegeneration. They have also played a fundamental role in the development of therapies based on RNA technology.
In new work just published in the scientific journal PLOS Genetics, O’Rourke and colleagues used the worms to screen 293 genes associated with obesity in humans, with the aim of defining which genes caused or actually prevent obesity. To do this, they developed a model of deworming obesity, feeding some a regular diet and others a high fructose diet.
This obesity model, coupled with automation and supervised testing assisted by machine learning, allowed them to identify 14 genes that cause obesity and three that help prevent it. Attractively, they found that blocking the action of the three genes that prevent worms from becoming obese also allows them to live longer and have better neuromotor function. This is exactly the type of benefit drug developers hope to get from anti-obesity drugs.
More work needs to be done, of course. But the researchers say the indicators are encouraging. For example, blocking the effect of one of the genes in lab mice prevented weight gain, improved insulin sensitivity, and lowered blood sugar. These results (plus the fact that the genes under study were chosen because they were associated with obesity in humans) bode well that the results will be true in humans as well, the researchers said.
“Anti-obesity therapies are urgently needed to reduce the burden of obesity on patients and the healthcare system,” O’Rourke said. “Our combination of human genomics with causal testing in model animals promises to produce anti-obesity targets more likely to be successful in clinical trials due to their expected increased efficacy and reduced side effects.”
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