Researchers have picked the lock of the brain’s “obesity box”

Following scientific efforts that required full mapping of the molecular components of 70,000 cells, a team of obesity researchers from Denmark and the USA have now managed to reveal the secrets of a hitherto unpickable “box” in the hindbrain of humans and other mammals.

‘The work has given us completely new knowledge about the neurons involved in development of obesity – and, in the long term, this could lead to new types of drug for treating obesity,’ says Tune H Pers, associate professor and Lundbeck Foundation Fellow at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (UCPH).

Together with PhD student Mette Q Ludwig, he headed the project that was recently published in the highly ranked scientific journal Nature Metabolism.

The “box” the research team has painstakingly unlocked can also be described as a control centre.

It actually consists of three centres that make up the dorsal vagal complex (DVC), and one of its jobs is to register nerve impulses sent from the gut to the brain. This includes information about the amount of food that is currently being digested.

Tune H Pers explains that science has long been aware that the DVC plays a role in obesity:

‘But we weren't aware of the full scale of the different types of cell in this control centre. So, we didn't know how these cell types worked, and how they could affect our risk of developing obesity. We’ve now begun to tackle this mapping process – and, ultimately, the aim is to obtain the knowledge we need to develop efficient drugs to treat obesity, which is a growing health problem all over the world.’

Obesity genes in the brain

For a long time, it was a common scientific assumption that the part of the human DNA involved in development of obesity was particularly linked to fatty tissue.

This connection seemed logical. However, in recent years, numerous scientific studies have demonstrated that this is not how obesity genetics work.

Six months ago, on a different project, Tune H Pers and two of his colleagues from UCPH were able to demonstrate, among other things, that the approximately 750 genetic variants research had previously been able to link to obesity in humans are regulated in the brain:

‘We could see that all 750 variants were active in the brain – but didn't seem to be anywhere else in the body,’ says Tune H Pers.

 

This finding, which was published in the scientific journal eLife in September 2020, acted as a stepping-stone to the current article in Nature Metabolism.

 

Because when it became clear that the 750 genetic variants behind obesity conduct their biochemical signalling activity in the brain – and not in fatty tissue – Tune H Pers and his Danish and American colleagues did not hesitate to pounce on the dorsal vagal complex. As he says:

‘It now really made sense to target the DVC, which together with another region of the brain – the hypothalamus – can register hormones and other chemical substances in the bloodstream and pass the signals on to the brain. But it was difficult to get into the DVC, almost like trying to pick the lock of a safety deposit box with an extremely clever, complex code. We basically had to map and record all molecular components of the complex’s 70,000 cells. Once we’d done that – and had analysed huge volumes of data – the door of the box cracked open.’

The huge volume of cells the research team analysed in order to map the DVC were taken from laboratory animals – from mice. And although mice and humans are quite different in many respects, as mammals we have so many basic biological traits in common that it is possible to perform this mapping based on mouse studies.

‘We conducted a range of studies, giving a group of laboratory mice a drug that mimics one of the body’s own hormones that we know plays a role in the development of obesity. We then put the mice down, removed their DVC and analysed the communication from the various cell types in the complex. Finally, we compared our findings with similar analyses of the DVCs of a control group which had not been given the drug,’ says Tune H Pers.

Like a poppy seed

How large is the DVC of a mouse?

The answer is: slightly bigger than a poppy seed. And this tiny mass contains the 70,000 cells analysed by Tune H Pers and his colleagues – cell by cell, animal by animal.

They used powerful computers and a special technique that enables mapping of genetic activity at single-cell level.

But how can knowledge about the cell types of the DVC be used to eventually develop new types of obesity drug.

It is primarily all about hormones; about how we can use special substances – so-called agonists, which are synthetic copies of hormones – to affect the DVC.

When we do this, we can regulate production of certain natural hormones linked to hunger and feeling full, thus relieving the craving to eat.

One of these synthetic hormones – a so-called GLP-1 receptor agonist – has now been approved for market release to treat obesity, and other types of agonist are also under development.

‘When we were finally able to unlock the door to the dorsal vagal complex, we could see the cell types that register and pass on signals from the body’s weight-regulating hormones,’ Tune H Pers explains.

‘And it’s this precise knowledge that makes it realistic to believe that we could develop new obesity therapies in the form of drugs that take into account a long list of hormonal effects.’

 

Obesity is on the rise

Numbers published by the WHO show that the percentage of the world’s population who are either overweight or decidedly obese has steadily increased since 1975.

Today, 13% of all adults in the world are clinically obese, and from a clinical point of view 40% can be classed as overweight. In Denmark, these percentages are 17 ad 51, respectively.

The WHO’s definitions for normal weight, overweight and obesity are given in relation to Body Mass Index (BMI).

Normal weight corresponds to a BMI of 18.5 to 24.9.

Overweight corresponds to a BMI of 25.0 to 29.9.

Obesity corresponds to a BMI of 30 or above.

Read more about the research in the relation between the brain and obesity: