Scientists develop a weight-loss pill that fools the stomach

Obese patients ready to lose weight have three FDA-approved prescription weight-loss pills — known commercially as Belviq, Qsymia and Contrave — and a newly approved injectable medication, Saxenda, to help. But the quest for better weight-loss drugs is far from over.

Enter fexaramine, billed as a new approach in the treatment of obesity and metabolic syndrome — the cluster of cardiovascular risk factors that often precedes the development of full-blown Type 2 diabetes in the obese.

Fexaramine — known affectionately as Fex by drug developers at the Salk Institute — isn’t a drug candidate yet. Human trials are expected to get underway soon.

A new study, however, finds that in mice, fexaramine protected against weight gain induced by a diet of high-fat, high-calorie chow. Fex appeared to turn up the thermostats on mice that got it, so they burned more calories and made better use of fats for fuel. Signs of damaging inflammation decreased, their blood sugar levels declined, and their organs’ and muscles’ sensitivity to insulin improved.

And as a bonus not even envisioned by the Salk researchers, mice that got fexaramine experienced a notable change in their fat cells, such that some stores of white fat — the trouble-making kind that is best at begetting more of itself — transformed into a healthier, fuel-burning form of fat called “beige” or “brown” fat.

Not bad for a pill that relies on physiological trickery to induce weight loss.

The fexaramine compound mimics the farnesoid X receptor, or FXR, a protein that responds to an influx of food by triggering the release of bile acids for digestion, changing blood sugar levels and prompting the body to burn some fats in preparation for an incoming meal. Normally, FXR is activated right at the beginning of a meal.

The FXR protein is active in the liver, kidneys and adrenal glands, as well as the intestines. In a bid to treat diabetes, liver disease and obesity, other drug developers have worked on molecules that activate FXR throughout its far-flung range. These drug candidates inevitably turned on processes far beyond those intended: Because they weren’t narrowly targeted, they had side effects.

The Salk team wondered whether an FXR activator that acted only in the intestines might work as well, with fewer unwanted side effects. By building a once-a-day pill that acts only in the intestines and never reaches the blood stream, they found, Fex set off a cascade of events, each occurring in its natural order, to create a more adaptive response to incoming calories.

“This pill is like an imaginary meal,” says Ronald Evans, director of Salk’s Gene Expression Laboratory and senior author of the new study, published this week in the journal Nature Medicine. “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.”

In mice, at least, Fex didn’t curtail appetite: It made their bodies better able to clear the extra calories they were fed. In humans, the researchers said, improved diet and increased exercise would ideally be part of the equation, with Fex helping to burn up fuel at a higher rate.

Administration of Fex even changed the mix of microbiota in the guts of mice, although the researchers acknowledged that they were uncertain whether or how such changes might have promoted weight loss.

The Salk researchers believe that because Fex does not act directly on systems beyond the intestines, it will probably have fewer of the safety issues that have dogged the development of weight-loss drugs that act more systemically.

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