Anti-obesity drugs 'may still work in middle-age'

9:27am Wednesday 13th August 2014

content supplied by NHS Choices

"Drug to halt the dreaded spread of middle age," reports The Daily Telegraph, with similar headlines on the Daily Express and Daily Mail websites.

However, these claims are rather premature given the research they're based on anti-obesity drugs that aren't licensed for use in the UK. Also, the study in question involved mice, not people.

Researchers compared middle-aged, obese mice to healthy young mice. They found that existing, but unlicensed, anti-obesity medications (lorcaserin, d-fenfluramine and sibutramine) reduced food intake to a similar extent in both groups of mice.

Our brains change as we get older or more obese, leading to a "rewiring" of the parts involved in energy balance. It was thought that anti-obesity medications that work on this part of the brain might not work in older, fatter people because of the rewiring. But this study suggests that despite the rewiring, the brain machinery needed for these drugs to work still functions - at least in mice.

This research is likely to help in the development of future weight loss drugs. But for now, consuming fewer calories and burning more calories off with regular brisk walking is a better defence against middle-aged spread than holding out for a miracle weight loss pill any time soon.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and the University of Aberdeen in collaboration with researchers from the University of Michigan Medical School in the US and the Consejo Nacional de Investigaciones Científicas y Técnicas in Argentina. It was funded by Diabetes UK, the Wellcome Trust, the National Institutes of Health, and the MRC Centre for Study of Obesity and Related Disorders.

The study was published in the peer-reviewed journal Endocrinology. The article is open access, meaning it can be accessed and read free of charge.

The media reporting of the story was generally accurate, but the headline claims that there could be a pill to stop middle-aged spread aren't quite right. Two of the anti-obesity treatments (d-fenfluramine and sibutramine) tested in this study have been withdrawn from clinical use due to off-target effects. The other drug, lorcaserin (brand name Belviq), was approved by the US FDA in 2012, but it is not approved in Europe and appears unlikely to be approved.

What kind of research was this?

This was an animal study.

The researchers report that both obesity and ageing are associated with rewiring of the main brain pathway involved in energy homeostasis. This leads to reduced activity of a group of brain cells called the pro-opiomelanocortin (POMC) neurons, which are found in the hypothalamus. The POMC neurons make hormones that are important in regulating appetite and body weight.

A number of anti-obesity drugs (lorcaserin, d-fenfluramine and sibutramine) work by increasing the activity of the neurotransmitter serotonin, increasing the activity of the POMC neurons.

The researchers were concerned that the anti-obesity drugs may not work in older, obese people due to reduced activity of these neurons. They performed a number of experiments in mice to determine whether the drugs work in older, obese mice.

Animal studies are ideal for this type of basic research, but trials on humans are required before an assessment of the benefits and risks of anti-obesity medications can be made.

What did the research involve?

The researchers initially confirmed that the anti-obesity drugs work by increasing the activity of the POMC neurons. They did this by comparing the food intake of normal mice with that of mice genetically engineered to lack POMC neurons that had been given anti-obesity drugs.

The researchers then tested whether the anti-obesity drugs reduced the appetite of older, obese mice who had the POMC neurons. They tested the effect of lorcaserin, d-fenfluramine and sibutramine on normal mice, young adult mice (three to five months old) and middle-aged mice (12 to 14 months old, the equivalent of a human 40 year old according to the authors). The middle-aged mice were heavier and fatter than the young adult mice.

What were the basic results?

Food intake was significantly reduced (described as an anorectic effect) in normal mice after they were given anti-obesity drugs. However, food intake was not significantly changed in the genetically engineered mice that did not have the POMC neurones.

The researchers found that young adult mice and middle-aged mice reduced food intake to a similar extent after being given the anti-obesity drugs.

The researchers went on to do further brain studies. These found there is similar gene expression in young and middle-aged mice, and that the serotonin signalling machinery in POMC neurons still functions as well in middle-aged mice as in young mice.

How did the researchers interpret the results?

The researchers conclude that serotonin obesity medications require POMC neurons to have an effect on appetite. And while this pathway is remodelled with ageing, the anatomical machinery is preserved and appetite suppressive effects are maintained in older mice. They say that these findings are of clinical significance to the global ageing obese population.

 

Conclusion

This animal study has found that anti-obesity medications that increase serotonin signalling reduce food intake in "middle-aged, obese" mice to a similar extent as in young mice.

There had been concern as both obesity and ageing are associated with rewiring of the main brain pathway involved in energy homeostasis. The "rewiring" leads to reduced activity of POMC neurons, found in the hypothalamus and these POMC neurons make hormones that are important in regulating appetite and body weight.

A number of anti-obesity drugs (lorcaserin, d-fenfluramine and sibutramine) work by increasing the activity of the neurotransmitter serotonin, increasing the activity of the POMC neurons. As a result of the rewiring changes, it was thought these changes might mean that anti-obesity medications wouldn't work.

From the results of this study, it seems that although POMC neurons may become less active as animals become older and fatter, they can be stimulated to become active by certain drugs - at least in mice.

However, claims there could be a pill to stop middle-aged spread are not strictly true - as we've seen, this study simply found that drugs continued to work in older subjects. Further, two of the anti-obesity treatments tested in this study have been withdrawn from clinical use due to off-target effects (d-fenfluramine and sibutramine). The other drug, lorcaserin, was approved by the US FDA in 2012, but it is not approved in Europe and appears unlikely to be approved here.

For now, exercise and eating healthily is the best defence against middle-aged spread.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Summary

"Drug to halt the dreaded spread of middle age," reports The Daily Telegraph, with similar headlines on the Daily Express and Daily Mail websites. However, these claims are rather premature given the research they're based on anti-obesity drugs...

Links to Headlines

A drug could soon destroy middle-age spread: Pill could stop cells that control appetite becoming lazy with age, causing us to overeat. Mail Online, August 13 2014

Drug to halt the dreaded spread of middle age. The Daily Telegraph, August 13 2014

Scientists discover secret to losing weight in middle-age. Daily Express, August 13 2014

Links to Science

Burke LK, et al. 5-HT obesity medication efficacy via POMC activation is maintained during aging. Endocrinology. Published July 22 2014

Further Readings

Press release

University of Aberdeen. Scientists reveal new insight into combating the middle-aged spread. Published August 12 2014

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