Brain Changes that Increase Obesity Risk Could Create Treatment Target

Changes in the Rap1 gene associated with leptin resistance, which promotes obesity.

Scientists recently found a new mechanism in the mouse brain that can regulate obesity, and could potentially be used to target obesity in humans.

A high body mass index is associated with conditions such as heart disease, type 2 diabetes, and even cancer. Understanding the physical changes involved with obesity could lead to better preventative treatments.

“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,” said senior author Makoto Fukuda, PhD.

The Rap1 gene found in mouse tissue was examined by the scientists in the study. In the brain, Rap1 plays a role in memory and learning, but how it is involved with energy balance was unknown.

Scientists deleted the Rap1 gene in a selective group of neurons in the mice’s hypothalamus to determine the gene’s function in regulating whole-body metabolism, according to a study published by Cell Reports.

Both groups of mice, those with the Rap1 gene and those without the Rap1 gene, were fed a high-fat diet. It was found that the control mice, unsurprisingly, gained weight; however, the mice that lacked Rap1 had significantly reduced body weight and less body fat.

When both groups of mice were fed a normal diet, they had similar weight and body fat, according to the study.

“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,” Dr Fukuda said. “These observations were associated with the hypothalamus producing more of a hormone that reduces appetite, called POMC, and less of hormones that stimulate appetite, called NPY and AgRP.”

These mice were also observed to have lower blood glucose levels and insulin compared with control mice. Next, scientists explored whether leptin, a body weight regulator that inhibits appetite, was changed in mice that lacked the Rap1 gene.

It is known that humans with obesity do not respond to signals from leptin despite having higher blood levels of the hormone than non-obese humans. Developing resistance to leptin is an indicator of obesity in humans.

Scientists found the mice that lacked Rap1 and were fed a high-fat diet did not develop resistance, and were able to respond to the hormone, evident by lower levels of leptin in the blood.

Mice with the Rap1 gene were treated with ESI-05, an experimental Rap1 inhibitor, to determine if drug inhibition would elicit the same effects as genetically removing the 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,” Dr Fukuda said. “The mice ate less and lost weight.”

Discovering that high-fat diets can result in increased Rap1 activity that leads to decreased sensitivity to leptin and promotes obesity in mice could have important implications in humans.

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