Rap1 Gene in the Brain Could be a Therapeutic Target for Obesity in Future

Highlights

• Rap1 gene in the brain that triggers obesity in mice identified
• A high-fat diet changes the brain and triggers the accumulation of body fat
• Rap1 gene could be the new target to treat obesity

A new mechanism in the mouse brain that regulates obesity has been identified by researchers at Baylor College of Medicine, the National Institutes of Health and Virginia Tech Carilion Research Institute. The new mechanism could be a potential target to treat 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," said senior author Dr. Makoto Fukuda, assistant professor of pediatrics at Baylor and the USDA/ARS Children's Nutrition Research Center at Baylor and Texas Children's Hospital.

The researchers studied the Rap1 (Ras-proximate-1 or Ras-related protein 1) gene in the mouse. Rap1 gene is expressed in a variety of tissues including the brain where it is involved in functions such as memory and learning. But the role of Rap1 in energy balance is unknown.

The Role of Rap1 Gene in Obesity

In a mouse model, the researchers selectively deleted the Rap1 gene in a group of neurons in the hypothalamus ( the brain region that regulates body’s metabolism), to study the role of Rap1 gene.

The mice were divided into two groups. In group one, the mice were genetically engineered to lack the Rap 1 gene, while the mice in the control group had a functional Rap 1 gene. Mice in both the groups were fed a high-fat diet. Sixty percent of the calories came from fat.

The findings showed that the mice in the control group with a working Rap1 gene gained weight. But the mice in group one that lacked Rap1 had reduced body weight and less body fat. However, when mice in both the groups were fed a normal diet, both showed similar weights and body fat.

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Link Between Rap1 Gene and Appetite Stimulating Hormones

The researchers explored why the mice lacking Rap 1 gene had not gained weight despite eating a high-fat diet. They observed that mice that lack Rap1 gene were not more physically active. But they ate less and burned more body fat than mice with Rap1. The observations were linked to a hormone produced by the hypothalamus called POMC(proopiomelanocortin), which reduces appetite and also low levels of hormones that stimulate appetite called NPY and AgRP. Mice in group one had lower levels of blood glucose and insulin when compared to mice in the control group.

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Rap 1 Gene and Satiety Hormone

The researchers also studied whether the satiety hormone, leptin, changed in mice lacking Rap1 gene. Leptin is produced by fatty tissue that helps regulate body weight by suppressing appetite. However, obese people do not respond to leptin’s signals of satiety. The blood levels of leptin are higher than those in non-obese people. Leptin resistance is a hallmark of obesity.

The researchers found that mice that lacked Rap1 and ate a high-fat diet did not develop leptin’s resistance. They were able to respond to leptin, and it was reflected in the hormone’s lower blood levels.

The Effect of Inhibiting Rap1 with Drugs

Earlier the researchers studied the role of Rap 1 gene in obesity by deleting it in the neurons. The researchers wanted to study the effect of drugs in inhibiting Rap1 in mice on a high-fat diet. Fukuda and colleagues inhibited Rap1 with ESI-05.

"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," said Fukuda.

The researchers have shown that a high-fat diet cause changes in the brain that increase Rap1 activity, which leads to a decreased sensitivity to leptin, contributing to obesity. The study is published in Cell Reports.

Reference:

1. Rap1, a potential new target to treat obesity - (http://www.eurekalert.org/emb_releases/2016-09/bcom-rap090716.php)

Source-Medindia