Our society seems to have accepted that weight gain is the inevitable consequence of living in a place with easy access to calories and in which physical activity plays an increasingly minor role in our private and professional lives. Aging makes weight loss even more difficult.
In the short term, the consequences of excess weight seem distant or unimportant; a problem of aesthetics, a minor limitation to mobility. But it can end up causing higher rates of diabetes or cardiovascular disease, and pose a major problem when it comes to enjoying an active lifestyle.
My job and the one of my collaborators here and in United Kingdom shows that obesity is not just a matter of fat under the skin: it is a true modification of our metabolism. It alters our way of absorbing nutrients and modifies the chemical relationships that sustain our existence. Our most recent work, published in Cell Metabolism, examined the consequences of obesity on our metabolism. My colleagues and I started this project because we recognized that there are many types of obesity, each with different consequences for the health of the person. It is what we call "heterogeneity" of the disease. If we understand the heterogeneity, we can personalize the treatments against obesity and, hopefully, have more chances of success.
My obesity, my metabolome
We are a team of researchers from different fields, including medicine, technology and complex data analysis. We studied almost 2,500 obese people with two powerful new technologies: we sequenced the entire genome of each participant in the study and analyzed more than 1,000 blood substances, or metabolites. This collection of metabolites is what we now call "metabolome" and includes such well-known compounds as glucose and uric acid, and also tongue twisters such as 1-stearoyl-2-dihomo-linolenoyl-GPC.
We include genome analysis to understand how genes predispose a person to obesity. We chose the metabolome to capture the impact of overweight in real time. Many of the study participants were followed for more than 10 years; this allowed the evaluation of the consequences of our long-term observations.
The surprising and disturbing news is that the ups and downs of weight cause changes in the levels of many hundreds of specific metabolites. Some of these changes were expected: fats or lipids -including cholesterol- increase rapidly with weight gain. However, we also observe changes in other types of metabolites and body processes: the metabolism of proteins and carbohydrates, the production of energy and the concentrations of hormones.
The general picture is that weight drastically upsets the body's metabolism. The good news is that alterations can be reversed with weight loss.
The healthy obese and the sick slim
Another fundamental observation was that the metabolic alterations had more health consequences than the mere physical aspect: some of the participants had what we call an "obese" metabolome despite its normal weight. On the other hand, some obese individuals had a very normal metabolome, similar to those of individuals with a healthy body mass index.
We are not clear why an obese person can have a normal metabolome. We do not know whether the genes or the environment are responsible for keeping this group of individuals healthier. It will be necessary to investigate more to determine it.
We are not clear why an obese person can have a normal metabolome. We do not know whether the genes or the environment are responsible for keeping this group of individuals healthier. It will be necessary to investigate more to determine it
By having medical information available at the time of the metabolic analyzes, and long-term follow-up data, we were able to see the consequences of the abnormal metabolism.
Obese individuals suffering from a major metabolic disorder developed diabetes, cardiovascular disease and hypertension. These same participants were also those who accumulated fatty tissue inside the abdomen and in the liver – the "bad" locations – instead of just adding it under the skin of the waist or the thighs. Thus, physical obesity was important, but the way in which excess weight specifically affected the internal functioning of each individual was a more accurate measure of their overall health.
The report on the metabolome could say more than the BMI
It might be tempting to think that obesity is a consequence of the genes inherited from our parents. And it's true, but the impact of our genes pales in comparison to the overwhelming impact of caloric intake and sedentary life.
There was an exception. We detected some very obese individuals with changes in a gene that controls appetite, the so-called melanocortin 4 receptor (MC4R). These patients suffered a genetic mutation that made them feel permanently hungry and led them to eat more than necessary. There are many hopes that we can treat these patients soon drugs specific. As expected, this form of obesity seriously disrupted the metabolism of the affected person.
We constantly see that science brings new knowledge about important health problems, and that such knowledge seems to disappear once the news cycle ends. But after the hype comes the incubation of new strategies that could end up making a dent in medical practice.
In the specific field of obesity, I think that calling attention to the important changes it produces in the metabolism provides a sense of urgency. This work also provides a new way to measure the harmful effects of obesity and to screen populations to determine who could benefit most from participation in clinical trials of new drugs. This includes thin individuals with an unhealthy metabolome, but who are not aware of their state of health and who would benefit from a preventive intervention.
Amalio Telenti it's pAssociate Professor in Pharmacy and Pharmaceutical Sciences at the University of California San Diego; Professor of Genomics at Scripps, Scripps Research Institute.
Disclosure clause. Amalio Telenti was previously an employee and advisor of Human Longevity Inc.