Why skinny people are dying of ‘fat’ diseases

New research suggests that the body’s inner workings are more important than weight when it comes to disease risk. And a revolutionary blood test could hold the answers for YOU...

CHUBBY, but fit, might sound like the kind of excuse overweight people use to keep at the crisps. In fact, there is evidence that — contrary to mainstream thinking — some overweight people lead long and healthy lives, while some slim, apparently healthy people die prematurely of ‘fat diseases’ such as diabetes and heart disease. Now doctors appear to have discovered what’s going on, heralding a breakthrough in our understanding of weight and disease: in future, it may not be your weight that matters so much as what’s going on inside your body.

And finding out could involve nothing more than a blood test. What it will mean is that instead of doctors saying being over a certain size

means you’re automatically ‘at risk’, they would use the results of this blood test to work out your personal risk. This could even help identify foods that are problems for you, because of how they affect you in particular.

As one leading expert told us, this ‘is the next big thing in medicine’. Konstantinos Manolopoulos, a clinician scientist in endocrinology and metabolism, explains: ‘It’s a major step towards personalised medicine — where the aim is to provide customised treatment options for patients.’

For nearly 200 years, BMI (body mass index) has been used as a measure of obesity and health risk. It’s calculated by dividing your weight by your height, and dividing the answer by your height again. A score of 25 or more means you’re categorised as ‘overweight’ and your risk of developing conditions such as diabetes and heart disease is raised significantly.

But, increasingly, there have been questions raised about the reliability of BMI as a predictor of health because it doesn’t show the full picture. For example, someone can be at risk of disease, and yet be slim and have a normal BMI — or have no health problems, despite being classed as overweight according to their BMI.

Now US researchers say they have developed a replacement, an advanced blood test that may provide a more accurate method of identifying our risk of diseases. It hones in on and measures all of the compounds in our blood — collectively known as the metabolome. In an analysis of these compounds, scientists were able to identify people at a higher risk of diabetes and heart disease early.

FUTURE BENEFITS

THEY say this principle could one day be applied to other diseases, such as high blood pressure, autoimmune diseases such as rheumatoid arthritis, and even cancer — where doctors would look for molecular ‘signatures’ in the blood that would indicate someone’s risk before they develop them — and decide on the best action.

‘By looking at metabolome changes, we could identify individuals with a several-fold increase in their risk of developing diabetes and cardiovascular disease over the ensuing years,’ said Amalio Telenti, a professor of genomics at Scripps Research Institute in California, who led the new study, published in the journal Cell Metabolism. It could even be used to check how well a person would respond to certain medication.

‘The hope is that the metabolome result is better than others — including BMI — and it has potential to be the best test we have to assess disease risk,’ Elizabeth Cirulli, a research scientist in the study, told Good Health.

BMI CAN MISLEAD

WHILE it can be useful to give a general indication of health, BMI has been criticised for a number of weaknesses, says Dr Manolopoulos. ‘For example, it doesn’t measure fat distribution, or take into account age, sex, or muscle mass that all contribute to our health and risk of diseases.’ For instance, super-fit rugby players might have an ‘obese’ BMI because their bodies are packed with muscle. A 2016 study in the International Journal of Obesity found that half of participants categorised as ‘overweight’ according to their BMI were in good heart health and had normal cholesterol, blood pressure and blood sugar readings.

Meanwhile a third whose BMI was ‘normal’ had unhealthy results in these tests, which assess heart and metabolic health.

‘BMI has been overplayed and it does not measure the actual amount of body fat or what it is doing in the body,’ says Fredrik Karpe, a professor of metabolic medicine. ‘There is a need for better tools that would allow us to stratify patients more accurately.’

A HEALTHY FAT?

THE new approach is based on a study of the health records of around 2,000 people that had been monitored for an average of 13 years. The US scientists looked at their BMIs and genes, and the levels of around 1,000 compounds in the blood — such as fatty acids, sugars, hormones and vitamins — and how these change.

These compounds (which make up the metabolome), are known to change due to age and lifestyle — and weight gain. What they found, though, was that there was a pattern which could predict each person’s risk of developing obesity-related diseases later on. People who had a specific pattern in their metabolome — which the scientists called the obesity ‘signature’ — at the start of the study were significantly more likely to be obese or end up with diabetes or heart disease by the end of the follow-up period.

They were also more likely to have accumulated fatty tissue in the liver or around internal organs — known as visceral fat — which releases toxic chemicals.

Surprisingly — and this is significant — these problems occurred later in life regardless of the person’s body weight. Some people who were slim but had the abnormal metabolome pattern at the start of the study also developed diabetes or heart disease. Meanwhile, some obese people in the study had a normal metabolome and didn’t develop these conditions.

The abnormal metabolome could explain why some slim people develop certain conditions such as high blood pressure, diabetes and cardiovascular disease, and why some obese people live long, healthy lives without illness, the researchers concluded.

The study supports the existence of the so-called ‘healthy obese’, where some people who are obese can live free from diseases you might expect them to develop. This is a matter of great debate in the scientific community.

‘The cause of weight gain is complex, but is predominantly due to excessive calorie intake and insufficient activity levels — this is the only way we can explain the three-fold rise in obesity levels over the past few generations,’ says obesity specialist Dr Ian Campbell.

‘But some people are clearly at greater risk of cardiovascular complications at a much lower weight; conversely some super heavy people seem to avoid complications, too. The science described here is in its infancy.

‘But this study shows that there are complex biological reasons why some people develop ill health.’

SLIM AT RISK

SO why would a slim person have this ‘fat’ metabolome? And why, if they have it, aren’t they visibly fat? The simple answer is that the scientists don’t know yet, Professor Telenti told Good Health, but there are some theories.

One is that their genes change how they deposit fat around their body. ‘Different genes determine how much fat you lay down and where,’ explains Kevin Murphy, a professor of endocrinology and metabolism. ‘You could be slim, have a low BMI and not much fat but have genes that put it in the wrong place — around your liver and heart, for example — and that puts you at risk.’

As Professor Telenti puts it: ‘It shows us that dangerous obesity and our risk of complications is a metabolomic issue, not necessarily a visual one.’

REVOLUTIONARY APPROACH

IN fact, those who study the metabolome say it could be the next major player in developing personalised medicine, just as important as the influence of our genes and the role of the microbiome — the community of bacteria that live in and on us.

‘Arguably the metabolome is more important because it is influenced by genes and lifestyle — it is also easier to measure and interpret than the microbiome,’

says Dr Cirulli. Warwick Dunn, a professor of analytical and clinical metabolomics, agrees. ‘We have around 10,000 compounds in our metabolome — such as glucose (sugar), cholesterol, and all sorts of chemicals involved in the breakdown of fats and proteins — and levels are dynamic,’ he says.

‘The fact that it is so dynamic and influenced by so many processes in our body means the levels can give us a much more accurate idea of our risk than BMI ever could. More studies are showing us that the metabolome in our blood are a good indicator before diseases ever develop — and this will help doctors intervene to choose the best possible medication or lifestyle changes that could reduce the risk of that particular condition.’ In the new study, the researchers pinpointed a ‘signature’ made up of 49 compounds that had a strong association to the risk of obesity- related diseases.

For example, the unhealthy signature had higher levels of uric acid, a waste chemical produced when the body breaks down purines, substances found in foods including red meat. The obesity ‘signature’ was also higher in bad fats — as expected.

Interestingly, says Dr Cirulli, ‘levels of a compound called cinnamoylglycine were lower — this is known to be released by good bacteria in the gut and is key to a healthy microbiome’.

She says this compound is part of the mechanism behind socalled ‘healthy obesity’.

‘If we had just used BMI to assess people’s risk of diseases, many would have been told they were fine and sent home,’ says Dr Manolopoulos. ‘Based on the metabolome and if they had this obese “signature”, we would now tell more people — even those who are slim — that they’re at risk and need monitoring or to change their lifestyle.’

The beauty of the test is that if it’s thought red meat, for example, is a problem, ‘we can tell them to eat less, and very quickly get a readout of whether that intervention helps using the test again’, says Professor Telenti.

PILLS DON’T WORK?

THE new test could also be used to see if patients will respond to certain medicines too. ‘For example if we want to prescribe metformin for diabetes we could give a patient one tablet to try and then take a blood sample to analyse the metabolome,’ says Professor Telenti.

‘As a result we can get an immediate result of what the drug is doing in the body and decide if it’s suitable for them to take it long-term or they are better suited to another treatment — this is at the heart of personalised medicine.’

EARLY ALERTS

AS Professor Murphy explains: ‘BMIisacrudemeasurement. With this new test, we may soon be able to screen people using their metabolome data and see if they are healthier — or indeed less healthy — than their BMI would suggest.’

Professor Karpe adds: ‘We already measure some of the compounds used in the test — glucose, uric acid and fats in obesity and diabetes. This new blood test pulls this all together to provide one ultimate blood test where we would theoretically take a sample and identify a “signature” that would highlight our risk of various diseases.

‘It will be expensive though — around €500 per person.’

SIGNATURE SYSTEM

THE study didn’t go far enough to explain what causes the different metabolic signatures, but it seems differences in lifestyle such as diet, stress and exercise seem to play a critical role — more so than genes thought to predispose people to obesity or the associated diseases.

‘The take-home message is that in order to stay healthy, you should be focused on these habits,’ says Dr Cerulli.