Memory and Learning Gene Linked to Obesity

Scientists have appreciated for some time the contribution of the central nervous system to metabolic disorders and obesity, yet the underlying molecular mechanisms have remained elusive. However now, a team of investigators from Baylor College of Medicine, the National Institutes of Health, and Virginia Tech Carilion Research Institute have discovered a new mechanism within the mouse brain that seems to regulate obesity. Moreover, the findings from this new study, which were published recently in Cell Reports in an article entitled “Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions,” describe the new mechanism as having the potential to be targeted for treating obesity.

“It’s well known that the brain is involved in the development of obesity, but how a high-fat diet changes the brain, so it triggers the accumulation of body fat is still unclear,” explained senior study investigator Makoto Fukuda, Ph.D., assistant professor of pediatrics at Baylor and the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital.

The researchers homed in on the mouse Rap1 gene, which is expressed in the brain—as well as variety of other tissues—and is involved in functions such as memory and learning. Since little was known of the role brain Rap1 plays in energy balance within the mouse model, the scientists selectively deleted the Rap1 gene in a group of neurons within the hypothalamus, a region of the brain that is involved in regulating whole-body metabolism.

Utilizing two groups of mice, a control group that had a functional Rap 1 gene and a genetically engineered group that lacked the Rap1 gene, the scientists fed the mice in both groups a diet in which 60% of the calories came from fat. As expected, the control mice with a working Rap1 gene gained weight; however, in comparison, the mice lacking Rap 1 had markedly reduced body weight and less body fat.

Remarkably, when both groups of mice were fed a regular diet, both showed similar weights and body fat. This finding greatly intrigued the researchers, forcing them to look closer at why the mice lacking the Rap1 gene had not gained weight despite eating a high-fat diet.

“We observed that the mice lacking Rap1 were not more physically active. However, they ate less and burned more body fat than mice with Rap1,” noted Dr. Fukuda. “These observations were associated with the hypothalamus producing more of a hormone that reduces appetite, called POMC [pro-opiomelanocortin], and less of hormones that stimulate appetite, called NPY [neuropeptide Y] and AgRP [agouti-related protein].” These mice also had lower levels of blood glucose and insulin than controls.

This piece of data led the scientists to hypothesize what would happen if the satiety hormone leptin—which is produced by fatty tissue and helps regulate body weight by inhibiting appetite—was altered in the Rap1 knockout mice. Leptin resistance is often considered a hallmark of human obesity, as obese individuals do not typically respond to leptin’s signals of satiety, and blood levels of leptin are higher than those in nonobese people.

Interestingly, mice that lacked Rap1 and ate a high-fat diet, on the other hand, did not develop leptin resistance—they were able to respond to leptin, and this was reflected in the hormone’s lower blood levels.

Using an inhibitor of Rap1, called ESI-05, on control mice that were on a high-fat diet showed similar results to genetic ablation of the Rap1 gene.

“When we administered ESI-05 to obese mice, we restored their sensitivity to leptin to a level similar to that in mice eating a normal diet. The mice ate less and lost weight,” Dr. Fukuda remarked.

The researchers were excited by their findings and were able to describe a new mechanism by which the brain can affect the development of obesity triggered by consuming a high-fat diet. Consuming a high-fat diet results in changes in the brain that increase Rap1 activity, which in turn leads to a decreased sensitivity to leptin, and this sets the body on a path to obesity.

“This new mechanism involving Rap1 in the brain may represent a potential therapeutic target for treating human obesity in the future,” Dr. Fukuda concluded.