Obesity is not equally harmful for everyone. Some people develop obesity-related diseases and others do not – and it all comes down to your genes. The built-in risk is written into your DNA. And now, a new study shows that this risk can already be spotted in childhood.
Jens is 47 years-old and weighs 140 kg. His body-mass index (BMI) classifies him as having severe obesity – and he has had this ever since he reached adulthood, when the fat started to build up around his belly. These days, he feels it every time he gets up from the couch.
The stairs to his third-floor apartment have become a daily struggle.
Several people in his social circle have developed complications from their weight. A childhood friend has type 2 diabetes, and a former football teammate died from a blood clot at 52 years old. Although Jens regularly gets his blood pressure and cholesterol checked by a doctor, he still worries a lot about whether he will end up in the same situation.
But now, a new international study based at the University of Copenhagen suggests that his future might not be as grim as he fears. The study shows that his genetic make-up may make him more resistant to diseases that often accompany obesity – from type 2 diabetes to heart disease. So maybe his future is brighter than he thinks.
And Jens is not alone: the same science that may change his outlook could soon change how doctors understand obesity for millions of people around the world.
A new way to view obesity: not one condition but many
The research, carried out at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, confirms that the health risk arising from obesity is highly individual and largely shaped by genes. And once that profile is known, you also have a clearer idea of what kind of health risk that person is likely to face: more harmful or less harmful. That opens a new way to categorise obesity – and, in turn, new approaches for prevention and treatment.
This is exactly the progress the research team made – and recently published in Nature Medicine. Leading the study is renowned Belgian researcher Ruth Loos, Professor of Genetic Epidemiology at the University of Copenhagen in Denmark. She devotes her time to understanding the genetic and biological reasons why some people develop obesity and related diseases.
“Our study focused on breaking obesity down into different types – because not everyone with obesity has the same kind,” Ruth Loos explains. “Some have related health problems, and others do not.”
“When we talk about obesity, we do not just focus on treatment but also on prevention. The earlier you know what you are genetically predisposed to, the earlier you can act,” she adds.
She points out that many chronic illnesses – like type 2 diabetes and high blood pressure – usually show up later in life. “But if you have 40 years of living healthily, you can often prevent them . Obesity, in contrast, tends to emerge earlier – which makes early insight crucial,” she says.
Analysing half a million lives to decode fat and health
To understand how some people with obesity stay metabolically healthy – meaning that their blood glucose, cholesterol and other key markers remain normal – whereas others do not, the researchers turned to a vast collection of genetic and health data from nearly half a million adults in the UK Biobank.
They began by developing a set of new biological profiles. They compared how much body fat a person had – for instance, measured by BMI – with concentrations of substances in the blood such as triglycerides and glucose. They then looked at how far each person was from the average on both measures. If someone had a high BMI but low triglycerides, they scored high – meaning that they carried a lot of fat and yet their body handled it well.
Each of these pairings created a new scale, and the researchers built many of them – one for every combination of body-fat and health measures. This enabled them to focus on people who looked perfectly healthy at first glance despite carrying extra fat – and on others who showed warning signs of illness even with less fat.
The researchers then used these scores in their genetic analysis. Instead of sorting people into fixed groups, they treated the scores as a sliding scale – and searched across the genome for tiny differences in DNA –genetic variants – that lined up consistently with either a low-risk or high-risk profile.
Why some fat protects – and some fat harms
By working this way, the team discovered hundreds of genetic variants associated with how fat interacts with the human body’s metabolic systems – and whether it triggers illness or not.
Some of the patterns fit what scientists already knew about how the body processes fat – the biological pathways that control storage and energy use. Others were entirely new and indicated mechanisms that may change how researchers think about obesity in the future.
The basic difference is that some people have lots of roomy fat cells under the skin and a body that is good at filling them up efficiently, says Loos. Others have fewer, smaller fat cells and a biology that does not fill them up very well.
This forces the body to push fat cells out to other parts of the body. There, they often gather in and around vital organs such as the liver and heart, where they suffocate the tissue – dragging the person into a downward spiral of disease.
“When we connect biological mechanisms to genetic patterns, we begin to understand what the human body does differently among those who stay healthy,” says Ruth Loos.
Genetic fingerprints of obesity appear in childhood
The tool turned out to be even more powerful than the researchers had expected. When Ruth Loos and her team tested it on health data from overweight children in the HOLBÆK cohort in Denmark, they were surprised to find that the two scores also worked there – and were spot-on in describing the health future the children might be facing.
The scores accurately predicted whether the children were likely to develop a more or less harmful type of obesity as they grew – effectively translating adult genetic patterns into early-life risk signals.
The analysis showed that children with a more benign profile had high weight but normal blood pressure, blood glucose and cholesterol. In contrast, the children with the high-risk profile already showed signs of health problems.
“What we saw in adults we also saw in children. That tells us that how the human body handles fat is shaped by something you are born with – and that these biological mechanisms are already active in childhood,” says Ruth Loos. She believes that these findings could help to identify and prevent complications earlier than ever before.
“Since your genetic make-up is set from birth, you could – in principle – know someone’s obesity profile early in life,” she explains.
“Our findings show that the genetic risk for obesity and related diseases appears already in childhood. You can think of it as the starting-point of the conditions that may show up later in life,” she adds.
A long way to go before it is in the doctor’s toolkit
Ruth Loos imagines a future in which tools such as the genetic scores her team has developed become part of the healthcare system – as an extra tool alongside such markers as blood pressure, blood glucose and cholesterol measurements. People with a genetic profile suggesting that they are especially vulnerable to obesity might require closer follow-up. If the score shows low risk, that might provide some peace of mind.
But even if someone is likely to develop the low-risk type of obesity, it does not mean their health is completely in the clear. Just carrying extra weight puts more strain on joints, can cause varicose veins and can lead to skin problems, she stresses.
“Genes are only part of the picture. Lifestyle and environment still matter a lot,” says Ruth Loos. “Even with a favourable profile, keeping a healthy weight remains important.”
She believes that these new genetic scores can help doctors and researchers focus on those who need closer attention – and give others peace of mind. But to enable this, healthcare professionals must learn how to use and interpret the scores properly, she adds.
“The genetic score is a valuable tool and not a verdict. It only tells part of the story, and how that story unfolds still depends on your choices and environment.”
A slow revolution in understanding obesity
And development will not stop here. Many more genetic scores are on the way – ones that will enable both doctors and laypeople to track how their health risk changes over time.
“In the future, you might have a genetic profile that shows your risk for conditions such as obesity, type 2 diabetes, heart disease, Alzheimer’s disease or schizophrenia. The big advantage is that these scores can – in theory – be calculated at birth, because your genes do not change,” she says.
Although these scenarios are still a bit down the road, she is confident they are within reach.
“Several of the scores we developed could already be used today. Some are quite precise – such as the one for general obesity – whereas the new score for healthy obesity still needs to be refined. But we are heading in the right direction,” she concludes.
