Although there is still a stigma in society about overweight and obesity, scientists working on the causes of this very complex disease are increasingly finding that it is not a matter of lack of willpower. In most cases, it is a combination of complex factors, often genetic.
While the effects of exercise on health and weight loss are well documented, the fact is that long-term commitment to exercise is not just a matter of choice. Certain genes can actually influence the extent to which we enjoy physical activity. Our social background and the geographical area where we live also determine our access to sports. However, the genes that strongly influence the development of obesity seem to work at the level of appetite regulation. A recent review of the literature, published in Nature Genetics, looked at the discovery of the genes and the understanding of the metabolic pathways involved.
39% of the world’s population is currently overweight and 12% are obese. This prevalence has tripled since 1975. While it is stabilizing in developed countries, it is increasing dangerously in developing countries. The increase in childhood obesity is also alarming: from 1% in 1975 to 7% in 2016. Furthermore, previous studies of twins showed, that obesity appears to be more or less heritable: from 40% to 70%. In fact, we do not choose to become obese. Our genetics and our environment largely determine the disease in a large number of cases.
Obesity is the general term for the situation where an individual’s body mass index (BMI) exceeds kg/m². Although BMI is a quick clinical tool, it can give many false positives and says nothing about the causes of the disease. On the other hand, the genetic approach makes it possible to distinguish between different forms of obesity and their pathophysiology. First, a distinction must be made between monogenic obesity, where a single mutation in a single gene is sufficient to cause the disease, and polygenic obesity, which corresponds to an accumulation of variants in the genome that predispose to obesity.
The polygenic forms of obesity are currently the most widespread and we have a much better understanding of the biochemical mechanisms these mutations alter. The vast majority of monogenic and polygenic obesity is linked to changes in the central nervous system.
Indeed, most of the genes associated with obesity are expressed in the nervous system. One metabolic pathway is particularly well studied given its importance in the development of obesity: the leptin-melanocortin pathway. This metabolic pathway regulates hunger through several biochemical mechanisms. Patients with a genetic mutation that alters this pathway have no sense of satiety. Consequently, it is particularly difficult for them to regulate their food intake.
Ongoing clinical trials
If there are as many types of obesity as there are genetic mutations associated with this disease, we cannot hope to have a proper treatment without knowing which type of obesity the patient suffers from. In a French study, the genome that can distinguish the different types of obesity is gradually being identified: “This is a project currently under development for patients suffering from monogenic obesity, in coordination with the Pitié-Salpêtrière hospital. They are trying to sequence the genome of these patients because the treatment of these patients is currently inadequate. Also because we have effective pharmacological treatments (Setmelanotide )for this type of obesity, it is crucial to get the correct diagnosis. Reportedly, after one year of regular injections of Setmelanotide in phase 3 clinical trials, patients with certain forms of obesity lost an average of 25.6% of their original weight, and 80% achieve a 10% weight loss. Side effects seem to be minor: hyperpigmentation, nausea, and Spontaneous penile erections. Nothing like the disasters that bariatric surgery can cause in these patients.
If our genome predisposes us to obesity, the environment should not be ignored. The food we eat and the exercise we do can have a positive feedback effect on the expression of our genes. This is the case for the FTO (Fat Mass and Obesity Associated Protein) gene, where studies show that lifestyle can reduce the effect on obesity by 30-40%. Other possibilities should be explored, such as food ratings to encourage people to make better choices in the supermarket, even if each push has only a small effect at the individual level. Finally, the stigma towards obese people probably needs to be stopped once and for all. Unless we adhere to a dualistic philosophy of mind (which holds that the mind is of a different nature than the body and therefore immaterial), our will is not disconnected and independent of our social environment, our neurobiology, and ultimately our genome.