Scientists have successfully used drugs to suppress ‘fat genes’ in mice – sparking hopes of one day developing a slimming pill.
The gene, Rap1, has been associated with metabolism, weight gain, and overeating in previous studies.
But until now, scientists could not determine a direct link.
Now, a team at Baylor and Texas Children’s Hospital has successfully suppressed the gene in lab mice and stopped them from overeating – simply by using a drug.
The finding has been hailed as a breakthrough in weight-loss research as America grapples with a burgeoning obesity epidemic.
A team at Baylor and Texas Children’s Hospital has successfully suppressed the gene in lab mice and stopped them from overeating – simply by using a drug
To explore the role Rap1 plays in a mouse model, the scientists selectively deleted the Rap1 gene in a group of neurons in the hypothalamus, a region of the brain that is involved in regulating whole-body metabolism.
The scientists had two groups of mice.
In one group, the mice were genetically engineered to lack the Rap1 gene, while the control group had a functional Rap 1 gene.
Then, the scientists fed the mice in both groups a high-fat diet in which 60 per cent of the calories came from fat.
As expected, the control mice with a working Rap1 gene gained weight.
But, in comparison, the mice that lacked Rap 1 had markedly reduced body weight and less body fat.
When both groups of mice were fed a normal diet, both showed similar weights and body fat.
The scientists then looked 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,’ said Fukuda.
‘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 also had lower levels of blood glucose and insulin than controls.
The scientists also were interested in studying whether leptin changed in mice lacking Rap1.
Leptin, the ‘satiety hormone’ produced by fatty tissue, helps regulate body weight by inhibiting appetite.
Obese people, however, do not respond to leptin’s signals of satiety, and the blood levels of leptin are higher than those in non-obese people.
The finding has been hailed as a breakthrough in weight-loss research as America grapples with a burgeoning obesity epidemic
Leptin resistance is a hallmark of human obesity.
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.
Fukuda and colleagues also tested the effect of inhibiting Rap1 with drugs instead of deleting the gene on mice on a high-fat diet.
The scientists inhibited RAP1 action with inhibitor 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 scientists have shown 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,’ said Fukuda.