Gene discoveries present new drug targets for treating obesity
In the ongoing search for new treatments for obesity and its related conditions, scientists are turning considerable attention to the role our genes might play. The hope is that drugs could one day be developed to switch key genes on or off in at-risk subjects, and a new study has offered up some new potential targets by identifying groups of genes that appear to cause weight gain and others that prevent it.
While conventional wisdom would have it that appetite and exercise are the overarching factors driving weight gain in humans, researchers are beginning to paint a picture that is far more complex than that. Recent studies have linked obesity to structural differences in the brains of children and to bacteria in our guts, while irregular sleeping patterns may also have a part to play, through resulting metabolic dysfunction.
The interplay between genes and obesity involves many unknowns, but scientists are starting to tease out some useful insights. One 2017 study pinpointed a genetic mutation in mice that caused them to put on weight, while a 2018 study showed how altering an obesity-related gene could prevent mice on high-fat diets from becoming overweight. We've also seen interesting studies identifying the most effective forms of exercise for those with a genetic predisposition for obesity.
Another noteworthy example came in 2018, when a massive study involving more than 700,000 subjects revealed a set of 14 genetic variations linked to obesity and body mass index (BMI). While key advances like this continue to shed more light on the role genes may play in regulating fat storage and the way our bodies use food as fuel, distinguishing the genes associated with obesity from the ones that directly cause it remains a key objective for scientists in the field.
“We know of hundreds of gene variants that are more likely to show up in individuals suffering obesity and other diseases," says the University of Virginia's Eyleen O’Rourke, author of the new study. "But ‘more likely to show up’ does not mean causing the disease. This uncertainty is a major barrier to exploit the power of population genomics to identify targets to treat or cure obesity. To overcome this barrier, we developed an automated pipeline to simultaneously test hundreds of genes for a causal role in obesity."
In developing this new approach, the team turned to C. elegans. a worm that shares more than 70 percent of its genes with humans and has been the backbone for many key scientific discoveries. Some worms were placed on an unhealthy diet high in fructose to serve as a model for obesity, while a control group was given a regular diet.
The scientists then used machine learning to screen 293 genes previously associated with obesity in humans, in an effort to pick out ones directly causing or preventing the condition in the worms. This analysis led the team to report 14 genes they say promoted obesity in the mice on high-fat diets. Among those promoting it was one called KAT8, the reduced activity of which appears to boost the synthesis of fatty acids. Another example was TCF7L2, the depletion of which drives up glucose levels and correlates negatively with BMI.
The team also identified three genes that could be silenced in the worms to prevent the onset of diet-induced obesity. Knocking these genes out proved to prevent the accumulation of excess fat despite their high-fructose diets, allowing the worms to live longer and healthier lives. Blocking one of these genes in mouse models of obesity proved to prevent weight gain, improve insulin sensitivity and lower blood sugar levels.
"Our first round of experiments uncovered more than a dozen genes that cause and three genes that prevent obesity," says O'Rourke. "We anticipate that our approach and the new genes we uncovered will accelerate the development of treatments to reduce the burden of obesity.”
There is a great deal more research to carry out before we see the development of drugs that target these genes or other ones like it, as scientists work to better understand the mechanisms at play and ascertain the safety of these approaches in humans. However, the scientists believe their new approach offers a promising path forward.
“Anti-obesity therapies are urgently needed to reduce the burden of obesity in patients and the health-care system,” O’Rourke says. “Our combination of human genomics with causality tests in model animals promises yielding anti-obesity targets more likely to succeed in clinical trials because of their anticipated increased efficacy and reduced side effects.”
The research was published in the journal PLOS Genetics.
Source: University of Virginia