"This pill is like an imaginary meal," noted senior author Ronald Evans, director of Salk's Gene Expression Laboratory, in a release. "It sends out the same signals that normally happen when you eat a lot of food, so the body starts clearing out space to store it. But there are no calories and no change in appetite."


The new study, which now appears in Nature Medicine, showed that the compound can stop weight gain, lower cholesterol, control blood sugar, and minimize inflammation in mice.


More from the Salk Institute:

Evans' laboratory has spent nearly two decades studying the farensoid X receptor (FXR), a protein that plays a role in how the body releases bile acids from the liver, digests food and stores fats and sugars. The human body turns on FXR at the beginning of a meal, Evans and others have shown, to prepare for an influx of food. FXR not only triggers the release of bile acids for digestion, but also changes blood sugar levels and causes the body to burn some fats in preparation for the incoming meal.

Pharmaceutical companies aiming to treat obesity, diabetes, liver disease and other metabolic conditions have developed systemic drugs that activate FXR, turning on many pathways that FXR controls. But these drugs affect several organs and come with side effects. Evans wondered whether switching on FXR only in the intestines–rather than the intestines, liver, kidneys and adrenal glands all at once–might have a different outcome.

"When you eat, you have to quickly activate a series of responses all throughout the body," says Evans. "And the reality is that the very first responder for all this is the intestine."


The researchers believe that fexaramine works better in the intestines on account of the natural order in which the body's molecular pathway typically responds to incoming calories. A good analogy is a relay race in which every runner starts at the time time. By targeting the intestines, the metabolic response can commence in a natural order.

Certainly interesting! And clearly a promising alternative to other drugs and gastric bypass surgery. But we clearly need to temper our expectations before human studies are carried out. As noted in The Guardian:

Many drugs that work well in mice turn out to be far less effective in humans and fail to make it to market.

"We now know that our sense of 'fullness' after meals is largely dependent on hormones produced in specialised cells scattered along the gut. These cells sense the nutritional content of our food and send out those signals in response to digested and partially digested food. If we could fool those cells into thinking we have had a meal that could be a way of reducing people's food intake to produce safe weight loss," said Professor Sir Stephen O'Rahilly, director of the MRC metabolic diseases unit at Cambridge University.

"The authors of this paper show that a particular drug they have tested can do that in mice. While these are interesting observations, only a modest percentage of drugs that seem effective in mice ever make it into the clinic for patients," he added.

Nick Finer, a specialist in obesity medicine at UCL, said the work was "potentially of great importance to our basic understanding of how energy intake is balanced by energy expenditure, and potentially as to why this system is mismatched in those who gain – or lose – excessive weight.


You can find more details here and here.

Image and video: Salk Institute for Biological Studies.