DNA catalogue behind obesity is expanding
Over the next few years, the number of DNA variants associated with obesity is expected to rise significantly. And every single new variant that crops up could potentially improve our understanding of the “highly complex genetics” responsible for excess body weight, according to Tune H. Pers and Christoffer Clemmensen, obesity researchers at the University of Copenhagen, and former Lundbeck Foundation Fellows.
Christoffer Clemmensen and Tune H. Pers both work at the Novo Nordisk Foundation Centre for Metabolic Research, University of Copenhagen
Certain explanations may seem so self-evident that they remain set in stone even after they have been disproved.
One example would be the persistent pop-science ‘calories in versus calories out’ myth; that excess body weight is caused simply by consuming more energy than the body can use, so the surplus is stored as body fat.
Yet obesity research debunked that myth some years ago. Until a decade or so ago, the main driver of overweight and obesity, and its location in the body, was more or less unknown. But from then on, the research took off with the first results released in 2015 of a scientific mapping of genetic variants associated with overweight. And these genetic variants – which in some way or another control the tendency for overweight and obesity – were all linked to different centres and regions of the brain. In subsequent mappings of genetic variants linked to obesity, this connection proved so pronounced that scientists today refer to obesity as ‘located in the brain’. This is then also a departure from previous scientific doctrine that the human DNA involved in obesity is likely to be largely associated with adipose tissue, the cells that make up body fat.
Christoffer Clemmensen and Tune H. Pers both work at the Novo Nordisk Foundation Centre for Metabolic Research, University of Copenhagen (UCPH).
Here the two scientists each head up a research team devoted to obesity studies. Clemmensen’s research seeks to understand the biological mechanisms that regulate body weight, and to develop new drugs for obesity. Pers’ research mainly involves mapping and understanding the genetic signalling underlying obesity.
They both first had the opportunity to try out the role of lead investigator when they were awarded a Lundbeck Foundation Fellowship. Pers was made a Lundbeck Foundation Fellow in 2015, and Clemensen likewise in 2017. A Lundbeck Foundation Fellowship is accompanied by DKK 10 million distributed over five years for establishing a research team. Pers also received research funding from the Novo Nordisk company.
Initially, in 2015, relatively few obesity risk genes, a mere 97, were discovered, but the number has been increasing ever since:
By 2021, obesity studies had mapped around 750 such genes, and the official count now is at around 1,000. Within 2024/2025, this is predicted to increase significantly once the results of a major study are published. Researchers worldwide are hoping that this study, which is still under wraps, will shed more light on some of the many obesity-related questions that continue to dog science, such as:
Why is obesity more prevalent among people in deprived social and financial circumstances compared to more affluent individuals?
“We desperately need new insights to help provide detailed answers to questions along these lines because overweight and obesity are running rampant worldwide. Around 1 billion people now have a Body Mass Index (BMI) of over 30, and are thus clinically obese, with all the attendant health risks such as diabetes and cardiovascular disease,” say Pers and Clemmensen. Both are obesity researchers and associate professors at the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (UCPH), where they each head up their own research team, and both are also former Lundbeck Foundation Fellows.
Because losing weight means not only losing body fat, but bone mass and muscle mass, too. When people then regain lost weight, they tend mainly to put on fat, and in that way end up lacking both muscle mass and bone mass. This in itself is unhealthy and can cause high cholesterol
POVERTY AND OBESITY
There is coffee and cake on the meeting table in Pers’ office on the 7th floor of the Maersk Tower at UCPH, with the former Panum complex next door. The assembled company eagerly sample the brunsviger, a rich, sticky cake, oozing butter and brown sugar. Perhaps indulge in just one more finger of cake as it does the rounds again? Because what’s the harm in that, since it may not show on the scales until tomorrow?
Obesity is a very complex phenomenon. Pers, who holds a PhD in integrative systems biology, and Clemmensen, who has a PhD in molecular pharmacology, have agreed to talk about some of the complexities, including the myths and misunderstandings surrounding obesity, from a scientific perspective.
The World Health Organization (WHO) defines normal weight, overweight and obesity in terms of Body Mass Index (BMI).
In adults, i.e. in people over the age of 18, a normal weight corresponds to a BMI of 18.5 to 24.9. Overweight corresponds to a BMI of 25.0 to 29.9. A BMI of 30+ indicates clinical obesity.
WHO’s statistics from 2022 show that 16 per cent of all adults worldwide today are clinically obese while 43 per cent are clinically overweight.
In Denmark, these percentages are 18 and 52, respectively.
It makes sense to open this topic in obesity research by revisiting a news story that broke media-wide a few weeks ago. The story concerned GLP-1 analogues, artificial copies of an intestinal hormone of the same name, and which form the backbone of Novo Nordisk’s best-selling obesity medication, Wegovy.
The media articles were drawn from a research article in Nature in which Clemmensen, whose work involves discovering novel drugs to treat obesity, together with a number of colleagues at Novo Nordisk Foundation Center for Metabolic Research, including Pers, describes a potential successor to Wegovy and other GLP 1-based obesity drugs.
The prospective product combines GLP-1 and another substance, which was shown to boost the effect of the obesity medication in animal studies However, there is a long way to go before this could be approved for human use, and it is not going to be a therapy to prevent obesity. Which would otherwise be amazing because obesity prevention remains an elusive holy grail in obesity research, Clemmensen explains:
“Just think if we could prevent obesity, which we have no way of doing today. When it comes to obesity prevention, there’s no two ways about it: we’re still fumbling in the dark”.
Another area in which scientists are seeking obesity-related insights concerns the influence of socioeconomic factors,” says Pers:
“One of the theories that seeks to account for why people in deprived socioeconomic circumstances are far more likely to become obese than more affluent individuals is drawn from the animal kingdom. The theory goes that this phenomenon can basically be understood as a human version of the pre-winter overeating seen in certain animals seeking to survive food scarcity in the cold months, and in some cases conserving their surplus fat by going into hibernation afterwards”.
The idea behind this analogy is that humans subject to the constant pressures of securing money for food, clothes for the kids, to pay the next rent, and who generally have trouble making ends meet, similarly – unconsciously – seek security by piling on body fat. And in doing so, statistically have a greater tendency to become overweight than people oblivious to these socioeconomic pressures.
This theory, which is not news in obesity research, was presented by researchers such as Thorkild I.A. Sørensen, professor emeritus at UCPH, and is “the best theory we currently have” to account for this socioeconomic inequality within obesity, Pers explains:
“But if this is the case, then we still need to locate the centre and the functions in the brain that regulate accumulation of body fat in response to factors like socioeconomic deprivation and worry. Just as we generally lack answers to why the brain controls weight in the way it does.”
So what about diet and exercise – do they not account for the differences in the incidence of obesity between these two groups?
The answer is no, say the two researchers, but they add that even though people who are well-educated and comfortable financially have an intuitive awareness of the importance of maintaining healthy dietary and exercise habits – and not least of instilling this in their children – that awareness in itself cannot account for the socioeconomic disparity within obesity:
“There’s no evidence to support that; there’s some other factor at work here,” says Clemmensen: “But it can be hard to accept. Fitness fanatics, for example, who insist that they are slim because they work out and eat the ‘right’ foods are difficult to sway from this notion”.
The communication that takes place between genetic variants and various centres and areas in the brain and that determines obesity largely involves the dorsal vagus system (DVS), popularly known as the brain’s ‘obesity box’. This is a one cubic centimetre-sized system located at the back of the human brain. Consisting of around 70,000 cells, the system serves as a control hub for processing gut-to-brain nerve impulses, including information about how much food the individual is in the process of digesting.
In 2021, Pers spearheaded a Danish-American project that was the first to unlock the brain’s ‘obesity box’. This gave them access to studying a large number of processes involved in obesity.
To unlock this box, the researchers first had to map all the molecular components in the 70,000 cells of the DVS. This mapping was completed with the aid of studies in mice, which was possible because mice, being mammals, also have a DVS. However, in mice, this system is far smaller than in humans, with the 70,000 cells packed in an area about the size of a poppy seed.
Through the Danish-American project published in Nature Metabolism, the researchers discovered 750 genetic variants associated with obesity, all of which are responsible for biochemical signalling in the brain. Other centres in the brain, including the hypothalamus, are assumed to be involved in this signalling which remains to be fully mapped.
For the purposes of further mapping of genetic variants related to obesity, “it would also be logical to investigate areas of the brain responsible for cognitive function, for example,” say Pers and Clemmensen.
UNHEALTHY YO-YOING
Many people who have been struggling with obesity for years know all about the ‘yo-yo’ ups and downs of body weight. But this is unhealthy, and is also one of the problems obesity researchers are very much aware of,” says Pers:
“Because losing weight means not only losing body fat, but bone mass and muscle mass, too. When people then regain lost weight, they tend mainly to put on fat, and in that way end up lacking both muscle mass and bone mass. This in itself is unhealthy and can cause high cholesterol”.
The various GLP-1-based obesity drugs on the market are so successful because they appear to affect all the systems in the brain that maintain weight loss. To put it another way: the drugs counteract the body’s natural tendency to re-establish higher body weight after weight loss. But the details of how the drugs do this are not yet fully understood, and only time will reveal if obesity medication has lasting benefit for the individual, and if it’s safe to take long term,” says Pers.
“So far, we know that GLP-1 analogues can maintain a weight loss of at least five per cent for four years in 85 per cent of all individuals with obesity if they take the medication as indicated. This is evidenced by human trials”.
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