Gene deletion lets mice eat a high-fat diet without weight gain

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Obesity is on the rise in almost all parts of the world, and while lifestyle and diet changes can protect from the associated metabolic disorders, an effective antiobesity drug remains to be seen on the market. In a recent effort to characterize new targets of obesity a collaborative effort has suggested a new mechanism that regulates obesity in the mouse’s brain. The finding may lead to a targeted approach for combating obesity.

Scientists at the Baylor College of Medicine, the National Institutes of Health and Virginia Tech Carilion Research Institute published their results in the journal Cell Reports earlier this week.

"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 in a statement.

The collaborative effort was the first to characterize a ubiquitous gene called Rap1 and its regulation in energy homeostasis in a mouse model. The researchers found that when they genetically deleted Rap1 in mice given a high-fat diet (along with a wild-type control) that the mice lacking Rap1 barely gained weight, or body fat, as compared to the control mice. 

It was only when the mice were exposed to high-fat diets, however, that the divergence in weight gain became apparent. Indeed, with mice fed normal diets there was no observable change in weight or body fat.

Fukuda said in the statement that this was because the absence of Rap1 stimulated the hypothalamus to produce POMC, a hormone that reduces appetite. Rap1 had an additional effect of lowering NPY and AgRP, two hormones which do the opposite and increase appetite. This led to mice without Rap1 resisting the high-fat diet and resulted in lower body weight, fat, blood glucose and insulin, which were elevated in wild-type mice fed the same diet.

Since leptin is an important hormone to also block appetite, the researchers wanted to see if leptin resistance, which is a hallmark of obese animals including humans, was changed in mice without Rap1. They saw no difference in leptin levels and mice were able to respond to leptin--unlike the wild-type littermates.

Taking a pharmacological approach, the researchers also targeted Rap1 with a small-molecule compound called ESI-05. The results successfully echoed the previous findings and the leptin levels could be recovered.

Targeting the new pathway involving Rap1, Fukuda said: "This new mechanism involving Rap1 in the brain may represent a potential therapeutic target for treating human obesity in the future.”