Obesity-related gene that controls cravings and exercise motivation in mice could inspire new therapies

Could a single gene reduce our craving for sugary foods while at the same time increasing our desire to exercise? Researchers from the National Institutes of Health (NIH) believe they’ve found such a gene in mice—and that the discovery could point to new treatments for obesity.

The gene is called Prkar2a, and it’s particularly active in a small region of the brain that controls several responses, including those to pain, anxiety and reward. When the researchers knocked out the gene in mice, the animals cut down on their consumption of high-fat foods, even after fasting, they reported (PDF) in the journal JCI Insight.

The NIH study builds on a previous discovery in mice that lacked working copies of Prkar2a. When those animals were fed high-fat foods, they were less likely to become obese than their normal counterparts were.

In this study, mice lacking Prkar2a showed “decreased consumption of palatable, 'rewarding' foods and increased motivation for voluntary exercise,” the researchers wrote in the study. In fact, Prkar2a-negative mice ran two to three times longer on a treadmill than normal rodents did.

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The NIH researchers suggested that the key to Prkar2a’s influence in obesity-related behaviors is an enzyme called protein kinase A (PKA). The gene makes critical components of PKA, which “speeds reactions inside cells in many species,” according to a statement. The study concluded that the reduction in PKA signaling in the Prkar2a-knockout mice improved their motivation to exercise and decreased their craving for unhealthy foods.

Several research teams have linked particular genes with obesity. In May, a team led by the University of British Columbia showed that variations of ALK—a gene that, when mutated, has been linked to some cancers—can make some people naturally resistant to weight gain.

An Australian team removed the gene RCAN1 in mice and found that those animals did not gain weight, even after eating a high-fat diet. The key there was that blocking the gene helped turn white fat into calorie-burning brown fat—the goal of many ongoing obesity studies. Harvard University researchers, for example, reported over the summer that they used CRISPR-Cas9 gene editing to activate the gene UCP1 in white-fat precursor cells, creating cells that were more like brown fat.

The NIH researchers hope their new study on Prkar2a will inspire future research aimed at preventing obesity.

“Achieving weight loss and maintaining energy balance by moderating food intake and increasing physical activity underlies the battle against dietary obesity and weight gain,” the researchers wrote. Thus, “further study of PKA regulation in the various distinct cell subtypes is warranted.”