More effective diet pill: 'Imaginary meal' tricks the body into losing weight

January 5, 2015, Salk Institute
Ronald Evans, director of Salk's Gene Expression Laboratory, has developed a compound called fexaramine that acts like an imaginary meal. Fexaramine, which tricks the body into reacting as if it has consumed calories, could lead to an effective obesity and diabetes treatment in humans. Credit: Salk Institute

Salk researchers have developed an entirely new type of pill that tricks the body into thinking it has consumed calories, causing it to burn fat. The compound effectively stopped weight gain, lowered cholesterol, controlled blood sugar and minimized inflammation in mice, making it an excellent candidate for a rapid transition into human clinical trials.

Unlike most diet pills on the market, this new pill, called fexaramine, doesn't dissolve into the blood like appetite suppressants or caffeine-based diet drugs, but remains in the , causing fewer .

"This pill is like an imaginary meal," says Ronald Evans, director of Salk's Gene Expression Laboratory and senior author of the new paper, published January 5, 2014 in Nature Medicine. "It sends out the same signals that normally happen when you eat a lot of food, so the starts clearing out space to store it. But there are no calories and no change in appetite."

In the United States, more than a third of adults are obese and 29.1 million people have diabetes, according to the Centers for Disease Control and Prevention. Both obesity and diabetes lead to an increase in health spending, a greater risk of health complications and a shorter lifespan.

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 for digestion, but also changes 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.

Researchers at the Salk Institute have developed a fat-burning compound called fexaramine that leads to weight loss without typical side effects in animal models. Fexaramine tricks the body into reacting as if it has consumed calories and could lead to an effective treatment for type 2 diabetes and obesity in humans. Credit: Salk Institute

"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 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 .

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.

So, why does fexaramine in the intestines work even better than drugs that simultaneously activate FXR throughout the body? Evans thinks it has to do with the natural order in which the body's molecular pathways normally responds to a meal.

"The body's response to a meal is like a relay race, and if you tell all the runners to go at the same time, you'll never pass the baton," says Evans. "We've learned how to trigger the first runner so that the rest of the events happen in a natural order."

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.

Explore further: Receptor may be key to treating nonalcoholic fatty liver disease

More information: Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance, Nature Medicine, DOI: 10.1038/nm.3760

Related Stories

Receptor may be key to treating nonalcoholic fatty liver disease

December 15, 2014
Inhibiting a nuclear receptor in the gut could lead to a treatment for a liver disorder that affects almost 30 percent of the Western world's adult population, according to an international team of researchers.

Adjusting bacteria in intestines may lead to obesity treatments

September 24, 2013
A drug that appears to target specific intestinal bacteria in the guts of mice may create a chain reaction that could eventually lead to new treatments for obesity and diabetes in humans, according to a team of researchers.

New discoveries linking gut bacteria with cholesterol metabolism give hope for the future

February 18, 2013
(Medical Xpress)—Researchers at the Sahlgrenska Academy, University of Gothenburg, Sweden, show that cholesterol metabolism is regulated by bacteria in the small intestine. These findings may be important for the development ...

Researchers identify a mechanism linking bariatric surgery to health benefits

April 22, 2014
Bariatric surgery has positive effects not only on weight loss but also on diabetes and heart disease. Researchers at the Sahlgrenska Academy and University of Cincinnati have shown that the health benefits are not caused ...

One injection stops type 2 diabetes in its tracks in mice without side effects

July 16, 2014
In mice with diet-induced diabetes—the equivalent of type 2 diabetes in humans—a single injection of the protein FGF1 is enough to restore blood sugar levels to a healthy range for more than two days. The discovery by ...

Gut metabolism changes—not stomach size—linked to success of vertical sleeve gastrectomy

March 26, 2014
It's not the size of the stomach that causes weight loss after a specific type of bariatric surgery, but rather a change in the gut metabolism, say researchers from the University of Cincinnati (UC), the University of Gothenburg ...

Recommended for you

Obesity rates keep rising for U.S. adults

March 23, 2018
Obesity rates have continued to climb significantly among American adults, but the same hasn't held true for children, a new government report finds.

Obesity trigger identified within the human gut

March 22, 2018
The key chemical for happiness and sadness, serotonin, is also a force in our body's weight gain and calorie control, and scientists say more research could reduce obesity rates.

How obesity dulls the sense of taste

March 20, 2018
Previous studies have indicated that weight gain can reduce one's sensitivity to the taste of food, and that this effect can be reversed when the weight is lost again, but it's been unclear as to how this phenomenon arises. ...

High-energy breakfast promotes weight loss

March 18, 2018
In patients with obesity and type 2 diabetes, a meal schedule that includes a high-energy breakfast promotes weight loss, improves diabetes and decreases the need for insulin, new research from Israel reports. The study results ...

Early puberty linked with increased risk of obesity for women

March 15, 2018
Girls who start puberty earlier are more likely to be overweight as adults, finds new research from Imperial College London.

New link between gut bacteria and obesity

February 26, 2018
Researchers at Lund University in Sweden have discovered a new link between gut bacteria and obesity. They found that certain amino acids in the blood are connected to obesity and the composition of the gut microbiome.


Adjust slider to filter visible comments by rank

Display comments: newest first

1.8 / 5 (5) Jan 05, 2015
tell that to those who starve
5 / 5 (2) Jan 06, 2015
I would be very interested to know exactly how fexaramine affects gut bacteria and absorption of essential nutrients.
not rated yet Jan 09, 2015
This is so incredibly backwards and should be a wakeup call to anyone who thought for a second that this might be "that thing that finally helps me lose weight".

The problem isn't too much food or even too many calories. We've "progressed" so much as a society so that we can create cheap food to feed the world's starving, but in the process we've forgotten what real food is.

The problem is too much food that your body gets nothing BUT calories from. Eat whole foods, produce, real meat, nutrient dense, bio-accessible. Your body will realize it's not starving and you'll stop overeating. FYI, nutrients in most grains are the least bioaccessible.

Used to be that was all we had... and low and behold, we didn't have obesity, heart disease, alzheimer's, crohn's, autism... the list goes on. Now they're all skyrocketing.

This will never fix our real issues with food if you're still eating crap for the rest of your meals. Stop kidding yourselves.
not rated yet Jan 13, 2015
10 mg = €195

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.