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Some forms of obesity seriously disrupt the metabolic pathways that keep us healthy. Credit: Farik Gallery, MarShot / Shutterstock.com / Evans Love
Our society seems to have recognized that weight gain is an inevitable consequence of growing up in a place where access to calories is easy and where physical activity plays a diminishing role in our professional and private lives. Aging makes weight loss even more difficult.
In the short term, the consequences of being overweight seem distant or unimportant; an aesthetic problem, a minor limitation of mobility. But this can eventually lead to higher rates of diabetes and heart disease and pose a significant challenge to having an active lifestyle.
My own work and that of my collaborators here and in the UK shows that obesity is more than just a little more fat under the skin – it's a real change in our metabolism. It changes the way we treat nutrients and modifies the chemical reactions that support our existence. Our most recent work, published in Cell metabolism, examined the consequences of obesity on our metabolism. My colleagues and I undertook this project because we recognized that there are many types of obesity – each with different consequences on the health of each person. This is what we call the disease "heterogeneity". If we understand heterogeneity, we can customize obesity treatments, hopefully with more success.
My obesity, my metabolome
We are a team of researchers from a variety of backgrounds, including in medicine, technology and complex data analysis. We studied nearly 2,500 obese people with two powerful new technologies: We sequenced the entire genome of each study participant and analyzed more than 1,000 blood chemicals, or metabolites. This collection of metabolites is what we now call the "metabolome" and includes well-known compounds such as glucose and uric acid, as well as language virelangers such as 1-stearoyl-2-dihomo linolenoyl GPC.
We have included genome analysis to understand how an individual's genes predispose him to obesity. We chose the metabolome to capture the real-time impact of being overweight. Many of the participants in the study were followed for more than 10 years; this allowed us to evaluate the long-term consequences of our observations.
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This graphical summary shows that the metabolome captures clinically relevant types of obesity and is a better predictor of health than genetic risk. Credit: Cirulli et al. / Cell metabolism, CC BY-SA
The surprising and disturbing news is that weight changes affect hundreds of unique metabolites. Some of these changes were expected: Fats or lipids – including cholesterol – increase rapidly with weight gain. However, we also observed changes for other types of metabolites and body processes: protein and carbohydrate metabolism, energy production, and hormone levels.
The overall picture was that weight greatly disrupts the body's metabolism. The good news is that changes can be reversed with weight loss.
Healthy obese and meager unhealthy
A second basic observation was that metabolic alterations had more health consequences than just the physical aspect: some participants had what we call an "obese" metabolome despite normal weight. In addition, some obese individuals had a fairly normal metabolome, similar to that of individuals with a healthy body mass index.
We do not know how an obese person could have a normal metabolome. We do not know if it is their genes or their environment that are responsible for the health of this group of individuals. It will take more research to understand.
As we had medical information at the time of metabolic analyzes and long-term follow-up data, we were able to see the consequences of abnormal metabolism.
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Vector illustration of body mass index from underweight to extremely obese. The BMI may not accurately reflect whether an individual is in good or bad health. Credit: MarShot / Shutterstock.com
Obese people who have suffered the greatest deregulation of metabolism developed diabetes, heart disease and hypertension. These same participants are also those who have accumulated adipose tissue in the abdomen and in the liver – the "bad" sites – instead of just adding them under the skin of the waist or buttocks. Physical obesity was therefore important – but the way in which excess weight uniquely affected the internal functioning of each individual was a more accurate measure of overall health.
The metabolome ratio may say more than your BMI
It may be tempting to think that obesity is the consequence of genes inherited from our parents. That's true, but the impact of our genes is minimal compared to the impressive impact of high caloric intake and sedentary living.
There was an exception. We identified some very obese individuals who presented changes in an appetite-controlling gene called the melanocortin-4 (MC4R) receptor. These patients had a genetic mutation that made them hungry permanently and pushed them to eat more than necessary. There are high hopes that this type of particular obesity will soon be treated with specific drugs. As expected, this form of obesity has severely disrupted the metabolism of the affected person.
We see all the time that science is providing new insights into important health issues that seem to fade at the end of the news cycle. But after the hype, new strategies emerge that could eventually find their place in medical practice.
As for research on obesity, I think that drawing attention to the important changes in metabolism provides a sense of urgency on the ground. This work also provides a new way to measure the adverse effects of obesity and to screen populations to identify those that could benefit from participation in clinical trials of new drugs. This includes lean people and having an unhealthy metabolome, but unaware of their health status and benefiting from early intervention.
Explore further:
The metabolome: a way to measure obesity and health beyond BMI
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