Scientists develop drug that curbs weight gain without reducing food intake

Fexaramine mimics the effect of a meal and tricks the body into burning fat but has so far only been tested in mice.

Ronald Evans, director of Salk’s Gene Expression Laboratory, has developed a compound called fexaramine that acts like an imaginary meal.

Scientists have developed a drug that curbs weight gain and corrects the metabolic defects associated with obesity without reducing food intake, according to results published in Nature Medicine (online, 5 January 2015)[1]
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Developed at the Salk Institute in California, the drug, called fexaramine, mimics the effect of a meal and tricks the body into burning fat. So far, it has only been trialled in mice. Nonetheless, obesity expert Anthony Barnett, professor of medicine in endocrinology, diabetes and metabolism at the University of Birmingham, believes the drug shows promise.

“Fexaramine offers a new and exciting potential treatment for this difficult-to-treat condition,” he says.

Oral fexaramine prevented weight gain in mice with diet-induced obesity, despite the mice consuming the same amount of food as mice given placebo. Glucose control also improved and white fat tissue was converted into brown fat tissue, resulting in a rise in the core body temperature of the mice of around 1.5 degrees Celsius. Body fat percentage of treated mice was also significantly lower than that of untreated mice.

Fexaramine is an agonist of the farnesoid X receptor (FXR), which responds to the production of bile acids secreted into the intestine after a person eats a meal. It offers a different mode of action from many weight loss medications that are currently available or in development — these mainly target appetite control and the central nervous system.

Previous experiments in mice have used fexaramine administered systemically, activating the FXR receptors throughout the body. This worsened weight gain and glucose control in obese rodents. The scientists at the Salk Institute realised that if the drug is administered orally, it stimulates the intestinal FXR receptors but is poorly absorbed and so does not activate FXR receptors in other organs.

Ronald Evans, senior author of the paper, believes that the oral preparation of fexaramine is effective because it triggers a response to a meal that is closer to the natural order in which the body’s molecular pathways react 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.”

The poor absorption of oral fexaramine also makes it less likely to result in extra-intestinal adverse events. “This is important,” says Barnett. “The psychological and cardiovascular side effects of weight loss medications resulted in many being withdrawn from the market.”

However, Barnett cautions that the benefits seen in the rodent study may not translate to humans. “Obesity in humans is a complex disease with complex psychological, behavioural, metabolic, environmental and genetic interactions and results from rodent studies may not be easily transferable into humans,” he says.

The Salk Institute researchers, however, are optimistic about the potential of the drug, saying that the results of the trial make it an “excellent candidate for a rapid transition into human clinical trials”.

References

[1] Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nature Medicine 2015. doi:10.1038/nm.3760.

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Citation
The Pharmaceutical Journal, PJ, 17 January 2015, Vol 294, No 7845;294(7845):DOI:10.1211/PJ.2015.20067531