“Weight loss drug fools body into reacting as if it has just eaten,” The Guardian reports. The drug, fexaramine (or Fex), stimulates a protein involved in metabolism that is usually activated when the body begins eating, though it has only been tested in mice.
Researchers found that obese mice given Fex stayed the same weight despite continuing to eat the same amount of a high-fat diet. However, unlike some media claims, they did not actually lose any weight. It had no effect on mice of normal weight.
The protein that is stimulated, FXR (farnesoid X receptor), is present in many organs of the body and plays a complex role in metabolism that is not fully understood.
Previous drugs developed to activate this protein have shown conflicting results, possibly because they entered the bloodstream and so acted on all of the organs. Fex has been developed so that it appears to be barely absorbed into the blood stream, and so only acts on the FXR in the intestines. This provided better results for obese mice and also reduces the risk of side effects.
Further animal and primate studies will need to be conducted before the drug would be allowed to progress to human trials, but these are promising results. However, even if these trials passed with flying colours, we would estimate that it would take at least 5-10 years before any drug based on this research came to market.
Where did the story come from?
The study was carried out by researchers from the Salk Institute for Biological Studies in California and several other institutes in the US, Australia and Switzerland. It was funded by the US National Institutes of Health, the Glen Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, the California Institute for Regenerative Medicine, the Ellison Medical Foundation, the National Health and Medical Research Council of Australia, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
A financial conflict of interest was reported. Many of the contributing authors “are co-inventors of FXR molecules and methods of use, and may be entitled to royalties from their use”.
The study was published in the peer-reviewed journal Nature Medicine.
In general, the media have reported the story accurately, pointing out that it is in the early stages of development and that it has only been tested on mice. However, as mentioned, headlines such as the Daily Mirror’s “'Imaginary meal' diet pill tricks body into losing weight”, or The Daily Telegraph’s assertion that the “pill makes you feel full” are inaccurate. None of the mice lost weight and none of their appetites were suppressed.
What kind of research was this?
This was an animal study to test whether a new drug could improve the metabolism of mice. The researchers conducted a variety of experiments of the drug, comparing their response with mice receiving a placebo.
The drug was created to mimic an effect of eating food. Food causes bile acids to be secreted and this activates a protein called FXR (farnesoid X receptor).
FXR plays a complex role in metabolism that is not fully understood. It is present in many organs of the body, including the kidney, stomach, intestines, gall bladder, liver and both white and brown fat cells.
Previously, drugs have been developed to activate FXR, but they have encountered problems because of activating FXR in all of the organs. This gave conflicting outcomes. For example, mice of normal weight given these drugs had improved glucose tolerance, whereas obese mice put on more weight and had even poorer glucose tolerance. It was not clear why this happened, so the researchers wanted to investigate whether just activating FXR in the intestines improved metabolism.
They developed Fex to activate the intestinal FXR drug instead of food, without it being absorbed into the general circulation, to see if this made a difference. They also say that limiting absorption means there would be less potential for side effects.
What did the research involve?
The researchers developed a drug called Fex and performed a number of tests using mice.
They first tested the absorption of Fex into the general circulation. They gave mice either a Fex pill by mouth or an injection of Fex into the fluid that surrounds the abdominal organs. The researchers then measured the level of FXR activation in each organ.
The researchers then gave normal weight mice either a Fex pill or a placebo for 35 days. They then compared their weight, metabolic rate and sensitivity to insulin.
Lastly, mice were fed a high-fat diet (60% fat) for 14 weeks to make them obese. The researchers then gave them different doses of the Fex pill or a placebo for five weeks. They compared their weight, metabolic rate, extent of unhealthy white fat and healthy brown fat, and markers of tissue inflammation.
What were the basic results?
The oral Fex pill activated FXR in the intestine and did not activate it in the liver or kidneys. The researchers say this shows that it was only minimally absorbed into the general circulation. This was in comparison to the injection of Fex into the abdominal cavity, which stimulated FXR in the intestine as well as the liver and kidneys.
There was no difference between normal weight mice given oral Fex for five weeks in terms of weight gain (small amount) and other metabolic measurements, compared to normal weight mice given placebo.
In obese mice, the Fex pill caused an improvement in metabolism compared to placebo, including:
- reduced weight gain
- increased sensitivity to insulin
- more unhealthy white fat turning into healthy brown fat
- reduced inflammation
These obese mice were 34 grams at the start of the experiment (normal weight mice would be around 28 grams). They continued on the high-fat diet (60% fat) for five weeks. Those given placebo increased in weight to 44 grams, but those given the highest dose of Fex did not gain any more weight. None of these mice lost weight. The researchers report that there was no change in appetite or food consumption between the mice given Fex and those given placebo.
How did the researchers interpret the results?
The researchers concluded that Fex might be a “promising” approach to stimulating FXR, in order to improve metabolism. The say that the “absence of a change in food intake is notable, as failure of appetite control is a major reason for weight gain”. They say that, as this drug appears to improve metabolism without any change in food intake, it “may offer a viable alternative for obesity treatments”. They also point out that as Fex is only minimally absorbed and only stimulates the intestinal FXR, it offers “improved safety profiles” by not circulating around the whole of the body.
This animal study has shown that a new drug called Fex prevents obese mice from further weight gain, despite remaining on a high-fat diet. There were also other metabolic improvements, including improved sensitivity to insulin and a reduction of unhealthy white fat cells. There were no differences in measures of metabolism between mice of normal weight given Fex or placebo, although both groups gained a small amount of weight.
This preliminary study appears to show that, unlike previous drugs that have stimulated FXR from the general circulation and shown conflicting results, by targeting intestinal FXR, obese mice benefit. As it has only been tested in mice for five weeks, there is limited information on what these side effects might be in humans.
Further animal and primate studies will need to be conducted before the drug would progress to human trials, but these are promising results.
As the drug appears to improve metabolic function rather than promote weight loss, it could be a candidate to treat diseases of the metabolism, such as type 2 diabetes or metabolic syndrome (where a person has a combination of diabetes, high blood pressure and obesity).
Due to the length of time it takes to bring a drug to market, as well as the chance of a drug proving to be ineffective or unsafe in humans, we can’t envisage Fex (or a variant) appearing in your local pharmacy anytime soon.
In the meantime, tips to help you lose weight can be found here.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
The Guardian, 5 January 2015
Mail Online, 5 January 2015
The Independent, 5 January 2015
Daily Mirror, 5 January 2015
Links to the science
Nature Medicine. Published online January 5 2015