Obesity is much more complicated than we thought, manifesting in 11 different forms

For decades, obesity was thought to take only one form and has been measured and managed using body mass index (BMI) – a simple calculation of weight in relation to height.

While this method has helped categorize individuals into weight-related risk groups, it has not fully explained the complex biological roots or forms of obesity. New research now suggests that the condition is far more intricate than previously assumed.

The study suggests there may be at least 11 biological forms, each driven by different genetic pathways.

These findings challenge how we classify, study, and treat obesity. The research pushes beyond just BMI. It focuses on the underlying biology and how that biology affects health risks.

“It’s not just about the body mass index or the body appearance; it’s more about the biology behind it and how that is related to risk factors,” says Akl Fahed at the Broad Institute.

Understanding BMI – the basics

Body Mass Index is a quick and easy tool doctors use to get a general sense of whether someone’s weight might be impacting their health.

They calculate it by dividing your weight by your height squared (in metric units), and that gives them a number.

Based on where that number lands, you get placed into a category – underweight, normal, overweight, or obese. It’s not perfect, but it helps flag potential issues at a glance, especially when they’re screening large numbers of patients.

Doctors don’t use BMI as the final word, though, because they know it doesn’t tell the whole story.

It doesn’t show how much muscle you have, where you carry fat, or what your lifestyle looks like. But it does give them a starting point.

If your BMI’s on the higher end, for example, they might want to check your blood pressure, cholesterol, or blood sugar next. It’s kind of like a heads-up – not a diagnosis.

Why BMI alone isn’t enough

BMI has long been the standard for diagnosing obesity, but it doesn’t reflect every obesity form or health risk.

For example, some people with certain obesity forms never develop breathing problems or heart issues. Others do.

That led researchers to propose a new category called “preclinical” obesity. This split groups people into those who already show symptoms and those who don’t yet but might in the future.

However, Fahed’s study shows this two-part system may be too simple.

The genetic map of obesity

The team analyzed genetic data from over 2 million people with obesity. These individuals came from diverse backgrounds.

They examined links between BMI and body measurements like waist-to-hip ratios. This helped them identify 743 regions in the genome tied to obesity. Of these, 86 were previously unknown.

Researchers then investigated how genes in these regions affected body tissues. Some influenced how the body makes insulin. Others affected hormone levels, fat storage, or immune responses.

Obesity may take 11 distinct forms

Using this method, the researchers identified 11 distinct genetic clusters, each linked to specific biological mechanisms behind obesity.

Two of these clusters fall under broad categories: metabolically unhealthy obesity, which is associated with conditions like high blood pressure and insulin resistance, and metabolically healthy obesity, where individuals have excess body fat but relatively normal metabolic health.

Six of the clusters are connected to different aspects of insulin production and regulation, highlighting how variations in blood sugar control contribute to obesity.

The remaining three clusters involve disruptions in immune system function, hormonal control of hunger and body weight, and how the body processes and stores fats.

Instead of calling these clusters “subtypes,” the researchers use the term “endotypes” because they are not mutually exclusive – an individual can have multiple endotypes that interact and influence their overall condition.

“It is clear that there many forms of obesity,” says Frank Greenway at Louisiana State University (LSU). Some people don’t respond to GLP-1 drugs like Ozempic or Wegovy. This suggests those drugs may not treat the biological cause for everyone.

Treatments may vary by obesity form

Better understanding of obesity could lead to more precise treatments.

“In acknowledging that there are many different types of obesity, it may be possible to better target treatments and preventative interventions to provide more personalized care,” says Laura Gray at the University of Sheffield.

Since six of the endotypes relate to insulin, some treatments might work across those types. However, other forms may require very different approaches.

More obesity forms may be found

The research used data from the Mass General Brigham Biobank to confirm the 11 endotypes. Yet, this may not be the final number.

“I think it’s possible that additional endotypes may be uncovered in the future, as genetic discovery continues,” says Min Seo Kim from the Broad Institute.

Gray agrees and says the limit of 11 is likely due to the data size and our current knowledge. Still, some researchers urge caution.

“I like the ideas of obesity clusters, but they have to be more refined in the future to be helpful in the clinics,” says Henriette Kirchner at the University of Lübeck. She adds that further studies will clarify how many endotypes actually exist.

This evolving picture may reshape how we design future obesity research and interventions by focusing on each obesity form. Treating obesity as a single form might soon be a thing of the past.

The study is published in medRxiv.

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