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Trailblazing Salk research on "imaginary meal" pill draws worldwide attention

The lab of Ronald Evans developed a compound called fexaramine that acts like an imaginary meal, prompting the body to react as if it has consumed calories.

Ronald Evans, director of the Gene Expression Laboratory, and his team pioneered a new type of pill that tricks the body into thinking it has consumed calories, causing it to burn fat. Details of the new compound made headlines across the globe and drew widespread interest from the scientific community and the public for effectively stopping weight gain, lowering cholesterol, controlling blood sugar and minimizing inflammation in animals.

The work was published January 5, 2015 in Nature Medicine and was quickly picked up by USA Today, TIME, CBS News, NPR, The Washington Post, the Los Angeles Times, The Guardian and Public International Radio’s Science Friday, among many others. The story also prompted thousands of social media shares and even a skit on The Late Show with David Letterman. Unlike most diet pills on the market, the new compound, called fexaramine, doesn’t dissolve into the blood like appetite suppressants or caffeine-based diet drugs, but remains in the intestines, causing fewer side effects.

“This pill is like an imaginary meal,” says Evans. “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.

”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.

Evans and his colleagues developed the fexaramine compound by departing from the drug scaffold that most pharmaceutical companies typically pursue when targeting FXR. “It turns out that when we administer this orally, it only acts in the gut,” explains Michael Downes, a senior staff scientist at Salk and co-corresponding author of the new work. Giving one such drug in a daily pill form that only reaches the intestines—without transporting into the bloodstream that would carry the drug throughout the body—not only curtails side effects but also made the compound better at stopping weight gain.

When the group gave obese mice a daily pill of fexaramine for five weeks, the mice stopped gaining weight, lost fat and had lower blood sugar and cholesterol levels than untreated mice. In addition, the mice had a rise in body temperature—which signals metabolism ramping up—and some deposits of white fat in their bodies converted into a healthier, energy-burning beige form of the tissue. Even the collection of bacteria in the guts of mice shifted when they received the drug, although what those changes mean isn’t clear yet.

Since fexaramine doesn’t reach the bloodstream, it is also likely safer in humans than other FXR-targeting drugs, the researchers hypothesize. They’re already working to set up human clinical trials to test the effectiveness of fexaramine to treat obesity and metabolic disease. Ideally the drug, administered under a doctor’s guidance, would work in conjunction with diet and lifestyle changes, similar to weight-loss surgeries or other obesity or diabetes drugs.