Unravelling the Obesity Code

How can some people eat and eat, and never gain a kilogram, while others starve themselves and remain overweight? And does being ‘ fat’ always mean you are ‘unhealthy’? Scientists studying obesity are attempting to resolve these questions, and more.

Elizabeth Fritz was in her mid-twenties when she first started struggling with her weight. It happened after the writer and blogger stopped using oral contraceptives because she wanted a break from medication. “This was the first time I had prolonged weight gain, especially around the middle,” states Fritz, now 47. Thus began 20 years of weight fluctuations as Fritz tried numerous diets, exercise programmes and alternative remedies.

Fritz’s situation is very common. The New Zealand Ministry of Health Survey of 2016/17 found that 34 per cent of Kiwi adults were overweight, while a further 32 per cent of adults were obese. Currently, ‘overweight’ and ‘obese’ are defined by body mass index (BMI) – a calculation that uses a person’s height and weight.

Being overweight or obese is linked with several health problems, including cardiovascular disease and type 2 diabetes. However, the reason for the connection isn’t always clearcut. Not everyone who is obese ends up with these associated diseases – and others who aren’t overweight or obese can still have the problems of someone who is. To help clarify who is most at risk of developing weightrelated complications, researchers are looking beyond people’s BMI to other ways of measuring metabolic health. One of these is the ‘metabolome’, a measure that looks at the chemicals found in a biological sample.

The metabolome is “the molecules and compounds that are floating around in your blood,” explains Dr Elizabeth Cirulli, from Duke University’s School of Medicine in North Carolina. It is measured by taking a blood sample and running it through a device to measure the substances within it. It involves the collection of small chemicals – like amino acids, sugars, vitamins, fatty

acids and antibiotics – that are produced by cells during metabolism. These chemical products are known as metabolites, and they help provide information about the activity of the body’s cells at the time the sample was taken – including the effects of lifestyle and environment, as well as factors related to genes and disease.

Cirulli is part of a team that recently completed a study into the metabolome, the genome (a person’s complete set of DNA), and their unique relationship to BMI. They took body and metabolic measures from nearly 2000 adult twins, finding that about one-third of the metabolites were associated with changes in BMI.

The researchers say this could profoundly change how we measure who is metabolically healthy, with a range of metabolites being linked to various diseases.

A healthy BMI is considered to be 18.5 to 24.9 in most adults aged 18- 65 – with a BMI of between 25.0 and 30 considered overweight, and over 30 seen as obese. But Cirulli believes that it is also advisable to measure a person’s metabolites to determine their risk for developing health issues related to weight. “You will miss at-risk people if BMI is all you use,” she says.

It’s not clear yet whether obesity causes changes in the metabolome, or vice-versa. However, Cirulli says their data suggests that obesity changes the metabolome.

“We didn’t find any evidence that having certain metabolites predisposed you to gaining weight,” she says. “It does make sense that as you eat or exercise differently, that your metabolite levels would change concordant with your weight gain or loss. It makes sense that if your body has a different composition, such as more or less fat from gaining or losing weight, that your metabolome would change as well to reflect that.”

But while some suggest that these findings could radically change how we assess obesity, not everyone agrees. Professor Joseph Proietto AM, from the University of Melbourne, says that it just confirms what we already know – that obesity affects every organ in the body. The implication that new metabolome testing is a clever way of separating the sick from the non-sick is “a little bit naïve”, he says.

“To do all these assays is a lot of work and money,” states Proietto, an endocrinologist and world-renowned obesity investigator. “It’s too complex, whereas a simple measure of BMI and waist circumference already tells you the vast majority of what you need to know. If you’re going to measure anything [else], you do it in a targeted way.” This might include blood tests like insulin levels and triglycerides.

For Fritz, having her BMI measured didn’t prove particularly helpful. But when she missed periods, developed extra hair growth and got pimples around her jaw line, chest and upper back, her GP sent her for a pelvic ultrasound. This revealed that she had polycystic ovary syndrome – a hormonal condition that affects up to one in five girls and women in their reproductive years.

“You can’t assume that you are in good health just because you have a low BMI.” DR ELIZABETH CIRULLI

“This was the beginning of an all-consuming mission to try to fix it,” Fritz says. After losing some weight, her cysts receded – but she started to experience migraines, gut pain, severe bloating, fluid retention and other hormone-related imbalances.

In her younger years, Fritz was a vegetarian, and she’d thought she was relatively healthy. “But I actually consumed a high- carbohydrate diet, lots of biscuits and cakes, bread and pasta, and lots of alcohol,” she states. She now believes that her diet caused significant damage. “This is why I am now very sensitive to carbohydrates and struggle with my weight.”

Cirulli notes that people who are normal weight are sometimes metabolically obese, and people who are obese can be metabolically healthy.

“Long-term health consequences appear to be more in line with the metabolite profile than the obesity status,” she states. “So … you can’t assume that you are in good health just because you have a low BMI.”

Professor Proietto agrees that it is possible to be overweight and metabolically healthy. He explains that some people have an almost unlimited capacity to make new fat cells. If they overeat, fat gets stored in them, not causing any harm. However, other people can only increase their fat cell number a small amount. When they continue eating, fat gets deposited in places where it shouldn’t – like the liver and muscles. “That then is a sick obese individual,” he states.

There are diseases that can impact your weight and metabolic health. One of Proietto’s patients, for example, is “as skinny as a rake”, yet has type 2 diabetes and a severe lipid abnormality. She has generalised lipodystrophy – a condition in which the body destroys fat cells, forcing the fat to be distributed where it doesn’t belong. Proietto says people with this condition often “are fairly skinny but have the worst insulin resistance and metabolic derangement”.

Genetics are sometimes blamed as the cause for weight problems, but the relationship between the two is highly complicated. There is no such thing as an ‘obesity gene’, explains Dr Beben Benyamin, a senior lecturer in biostatistics at the University of South Australia – “but hundreds of genes have been associated with obesity”.

Benyamin explains that while genetics plays a role in the development of obesity, it is not the sole cause. “Both genetic and environmental factors contribute to obesity,” he states. “It has been estimated that 40 to 75 per cent of difference between individual susceptibility to obesity is due to genetic factors. The latest genomic studies using DNA from more than a half-million individuals identified hundreds of sites in the human genome that contribute to [BMI].”

He also notes that these genetic factors can affect people’s body weight in either direction – so some people will have the tendency to stay slim.

He adds that genetics also plays a role in the diseases associated with obesity. “For example, scientists have estimated that 30 to 60 per cent of the difference in individual susceptibility to hypertension and 25 to 80 per cent [of the difference in susceptibility to] type 2 diabetes is due to genetic factors,” Benyamin says. “Using the latest DNA sequencing technology in hundreds of thousands of individuals, hundreds of genes have been identified to affect these conditions.”

Dr Elizabeth Cirulli’s research found that the genetics of obesity had a big impact on BMI, but not as clear an impact on metabolic health. She says they were surprised to find that people whose BMIs were higher than expected given their metabolome (meaning their metabalome was unexpectedly healthy) had a higher than average genetic predisposition to being obese. On the other hand, people whose BMIs were lower than expected given their metabolome (that is, their metabalome was unexpectedly unhealthy) had a lower than average genetic predisposition to being obese.

“In other words, some people with genetic predispositions to being obese seemed to have healthy lifestyles that let them be metabolically healthy despite being overweight or obese,” she states, “and people with genetic predispositions to being lighter seemed to have unhealthy lifestyles that made them metabolically unhealthy despite being of normal weight.”

However, while obese people may have a normal metabolism, “even the so-called healthy obese are not healthy, because obesity causes sleep apnoea [and] increases the risk of cancer – so it’s more than just metabolism,” Proietto points out.

Of course, the question then becomes, how do overweight people get to a place of health? For Fritz, at least, the solution lay in making longterm, sustainable changes. She no longer eats sugary or processed foods or starchy carbohydrates, controls her portion sizes, doesn’t snack, drinks less alcohol, and eats mostly organic and free-range foods.

“Diets don’t work,” she says simply. “I learned the hard way through … experimenting with countless diets that essentially it’s all about choosing healthy food, respecting your body and focusing on nutrition – eat foods that serve your body well. Staying active is very important too, but everything has to be in moderation otherwise it simply becomes unsustainable and morphs into a new cause of stress. Now, more than ever, I feel I am healthy.”