- Rap1 gene in the brain that triggers obesity in
- 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
‘The new mechanism involving Rap1 in the brain could be a potential therapeutic target for treating obesity in the future.’
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
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
Link Between Rap1 Gene and Appetite
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.
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.
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
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
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
- Rap1, a potential new target to treat
obesity - (http://www.eurekalert.org/emb_releases/2016-09/bcom-rap090716.php)