One in eight people in the world lives with obesity. Since 1990, the rate in adults has doubled whilst in adolescents it has quadrupled. Nevertheless, we’re gradually improving our knowledge of this pathology, in spite of its continuing high prevalence and the stigma it carries. 

Today, as part of World Obesity Day, celebrated on 4 March, we talk to the expert Miguel López, a researcher from the CaixaResearch network at the Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS) of the University of Santiago de Compostela. With him we examine the latest advances to be made in the field of obesity.

In January this year a global commission, endorsed by more than 75 medical organisations worldwide, published in The Lancet a new definition of obesity: “a condition characterised by excess adiposity, with or without abnormal distribution or function of adipose tissue, and with causes that are multifactorial and still incompletely understood”. Furthermore, the experts propose a more comprehensive approach which, in addition to the body mass index (BMI), takes into account the degree of adiposity and other determinants in the diagnosis.

 

What does this change mean, Miguel? 

“This new definition of obesity has introduced nuances. It’s more detailed and includes parameters that were not previously taken into account. Most importantly, this new approach seeks to go beyond the body mass index (BMI) when diagnosing obesity, recognising the limitations of this previous method. Another important point is that it emphasises how excess fat affects organ function and overall health, not just body mass. It also considers the multifactorial and complex nature of obesity and the need for personalised diagnoses. 

However, it should be noted that this is still a controversial issue. The European Association for the Study of Obesity (EASO) has proposed a different approach, published in Nature Medicine. This proposal recognises that the BMI alone is insufficient to diagnose obesity and emphasises the importance of how body fat is distributed; i.e. where it accumulates, as well as the presence of medical, functional or psychological impairment. Controversy arises because of the implications this has for diagnosis and treatment. 

Nevertheless, from a biological point of view the problem is still the same: a situation in which we take in more calories than we can use up. These calories are stored as fat and, in many cases, its accumulation promotes the development of associated comorbidities such as diabetes”. 

 

Obesity has a major impact on health – why do some countries still not recognise it as a disease?

“Obesity has a historical stigma attached to it. It’s often believed that people are obese because they don’t take care of themselves, they eat excessively and uncontrollably. But this is a myth we need to attack.

It’s true that some cases of obesity are lifestyle-related but many others are simply due to genetic “bad luck”. In other words, a lot of people inherit genes that predispose them to become obese. These genes were undoubtedly highly beneficial in evolutionary terms when food wasn’t readily available. 

It’s likely that this stigma still weighs heavily in many countries. Fortunately, in Spain and in the Western world, obesity is now recognised as a pathology. And I say “fortunately” because this allows us to tackle it from a public health perspective and strive to reduce its incidence and prevalence. Even so, in Spain we’re faced with a paradox: the National Health System funds the treatment of other risk factors and comorbidities such as smoking, high blood pressure, high cholesterol and diabetes but doesn’t fund the treatment of obesity. Given the high price of the latest anti-obesity drugs, this is leading to a big gap in society in terms of patients’ access to treatment”.

 

What role do genetics play in obesity?

“As I mentioned before, many people believe that obesity is due solely to a poor diet and lack of exercise. However, in many cases genetics plays a crucial role, altering the system that regulates the balance of energy. Quantitatively, it’s difficult to pin down but studies on twins have estimated the hereditary factor in obesity to be between 40-70%. 

Obesity is related to the interaction between a large number of genes, proteins and all kinds of metabolites (glucose, lipids etc.). A mutation in a gene that encodes a hormone or its receptor can lead to fat being stored. One example of this is a type of obesity caused by mutations in the gene for a hormone called leptin or its receptor, leading to morbid obesity in sufferers.

All these genetic causes end up producing the same result: an imbalance between the calories ingested and the calories expended that may be due to excess intake, deficient energy expenditure or a combination of both”.

 

So is there really a single kind obesity?

“No. What happens with obesity is similar to what happens with cancer. There’s no single disease. When we talk about cancer, we refer to a series of pathologies that share a common basis: the abnormal, uncontrolled proliferation of cells in tissue where they shouldn’t be. However, there are many kinds of mutations, or other causes, that lead to different types of cancer, each with specific treatments. And it’s the same with obesity: different alterations, genetic or otherwise, can lead to the same end result but the origin can be very different”.

 

Why do our bodies tend to store fat if this can result in pathologies?

“200,000-300,000 years ago, when Homo sapiens emerged, we didn’t eat three meals a day and finding food was a challenge. In addition, we had to be alert to predators, which required us to expend a lot of energy, both to stay alive and also to flee from anything that wanted to devour us. Under such adverse conditions, the genes that succeeded were the ones that stored energy most efficiently. It should be noted that this natural selection of such genes is not unique to humans. All previous evolutionary history, from the origin of animals, has favoured highly energy-efficient genetic profiles.

Now, if you put Homo sapiens into an environment where there’s an excess of calories and also no adequate expenditure of that energy, it’s logical for them to store those calories in the form of fat, specifically triglycerides. These lipids are ideal as energy stores; they have a perfect molecular design for it. They have a large number of bonds between carbon atoms and are hydrophobic; i.e. they don’t store water, which is acaloric“.

 

Evidence is growing that the origin of obesity is also linked to the central nervous system. 

“Yes, calorie gain and loss is controlled by the central nervous system. In particular, two key areas are involved in this process: the brainstem and the hypothalamus.

The brainstem, located at the base of the brain in the nape of the neck, acts as the communication pathway between the brain, spinal cord and peripheral nerves. In my research group, we’ve focused predominantly on studying the hypothalamus, a region that’s crucial for survival-related mechanisms such as food and water intake, energy expenditure, circadian rhythms, the sleep-wake cycle, endocrine function and reproduction. The hypothalamus receives information from both sensory stimuli and metabolic parameters, such as glucose, lipid and hormone levels, and integrates them to create an appropriate homeostatic response. In physiology, homeostasis is the tendency of systems and organs to achieve a balance, or to function well. A homeostatic response would be, for example, to induce appetite when food hasn’t been eaten for a prolonged period of time. 

Some genetic mutations that affect the control mechanisms of the hypothalamus can lead to obesity. One classic example is a dysfunction in the melanocortin receptor, a type of hormone that inhibits food intake. When they’re absent, or this receptor doesn’t work properly, people tend to overeat”.

 

If you had to pick the most promising development in obesity research in recent years, what would it be?

“I would say it was the research carried out by Jeffrey M. Friedman who, in 1994, discovered leptin, a hormone that informs the hypothalamus about fat stores and regulates the balance of energy. This discovery changed the way we look at the metabolism, endocrinology and everything to do with the study of obesity. There have been a large number of advances since then but I don’t think any of them has contributed as much as Jeffrey M. Friedman.

If I had to choose a more recent development, from the last fifteen years, I would pick the creation of drugs based on GLP-1, a hormone that’s fundamental in the regulation of blood glucose. These drugs act as GLP-1 agonists; i.e. they bind to the same receptor and activate the same pathways as GLP-1. Their development has represented a paradigm shift in the treatment of various diseases.

Also very important are all the studies carried out that have improved our understanding of the relationship between the hypothalamus and obesity. For example, the identification of the AMPK protein as a key energy sensor at the hypothalamic level. Our research group has been actively involved in this study because it has great therapeutic potential. Recent advances in “-omics” also indicate that the hypothalamus, which is one of the most anatomically and functionally complex areas of the brain, is even more complicated than we thought. These studies have raised new questions and herald an exciting future. In particular, we’re realising that it’s crucial to understand the key role played by the hypothalamus in other pathologies related to body mass, for example, cachexia, the inflammation-associated decrease in body mass, and the anorexia that accompanies cancer, an area on which my research group is actively working”.

 

You talk about GLP-1 analogues, which drugs such as Ozempic and Mounjaro are based on and which enhance our “fat burning” mechanisms. Do they work?

“These drugs based on GLP-1 analogues have triggered a revolution in the treatment of obesity, demonstrating very potent effects at a clinical level. The key is that they have a very powerful, in fact I would say an incredible dual effect: they inhibit intake and also reduce body mass. Another interesting point about these new drugs is that they’re not only effective in treating obesity but also help to resolve numerous pathologies associated with this condition, such as diabetes. Clinical trials are even demonstrating their efficacy in cardiovascular prevention, renal protection and sleep apnoea.

In addition to all the positive effects, they don’t seem to have any serious side effects so far, apart from some intolerance when doses are increased and a feeling of intestinal or stomach discomfort”.

 

Are other treatments in the pipeline? 

“A large number of pharmaceutical companies are now focusing on developing more specific treatments, targeted at specific types of obesity, since not all patients respond in the same way to these drugs. For example, there’s a lot of interest in triple agonists (of GLP-1,+GIP+ and glucagon molecules) that have demonstrated really spectacular effects (more than 25% loss in body mass) in preclinical models and also in clinical trials. 

One crucial consideration when developing such treatments is to ensure that the loss of body mass is focused on reducing fat and not muscle mass, which could lead to other health problems. 

In my view, what would be important, and what the pharmaceutical industry seems to be ignoring, is the development of drugs that not only reduce intake related to homeostasis (the need to ingest calories) and hedonism (the pleasure from eating) but also increase energy expenditure, or ideally regulate both intake and expenditure. Another very important aspect would be the ability to understand and treat the gender differences associated with the development of obesity“.

 

Can we expect an increase in or stabilisation of cases in the coming decades?

“These drugs are a very significant step forward. I hope the overall situation will stabilise and the number of cases will start to decrease. In fact, society is becoming increasingly aware of the importance of a healthy lifestyle. There’s also very important scientific and medical work going on, which is attempting to change people’s habits. Such things cannot be achieved from one day to the next but I’m optimistic and believe that, between the development of new therapies and the improvement of lifestyles, the situation can be brought under control. Little by little, although we’re talking about several decades”.

 

What public policies could make a difference in preventing obesity?

“It’s essential to find out more about the mechanisms that lead to obesity and support for research is key to this. Like the exceptional work being carried out by “la Caixa” Foundation. Progress isn’t feasible without investment in research. We should never forget that all the great advances made in the history of mankind have come about like that.

In this respect, it’s essential to share information in order to boost the social and especially political awareness of these issues. In terms of the population, it’s also vital to encourage people to adopt healthier lifestyles, and for us to commit to treating them whenever it’s necessary. 

It’s important to emphasise that doctors have the final say in the treatment of patients. We should forget about miracle diets and fat-burning drugs (which are so rampant on the internet) and talk to the professionals, such as endocrinologists and metabolic specialists, who really know how to treat and advise patients”.

 

What are you currently investigating?

“We’re doing research to find a treatment for obesity at the level of the hypothalamus, without the need for invasive interventions. Our strategy consists of using exosomes, small vesicles that cells produce to communicate, and loading them with tools that enable us to alter “the instructions” given by the hypothalamus, specifically the activity of the AMPK protein. Our project, which has been fully funded by CaixaResearch, represents a turning point in this area of research. 

We’ve had several articles published in prestigious journals, such as Nature Metabolism in 2021 and Metabolism in 2023. We’ve also developed a patent, which has already been licensed and from which a spin-off called Gazella Biotech has now emerged. Using exosomes, we’ve also developed another patent for the treatment of ischaemic stroke, a disorder associated with obesity. In fact, an article on this topic has just been published recently, in the journal Metabolism.

The advantages of exosome therapy are its specificity, the fact that we know the mechanism of action perfectly (which is not the case with many of the drugs in use and/or under development), and the total absence of side effects in preclinical models. With exosomes, we treat an extremely limited number of neurons in the hypothalamus and achieve very marked changes in the animals that have been studied, which lose a lot of body mass regardless of what they ingest. In other words, we’ve managed to make mice that eat a diet with 60% fat lose a lot of weight, but without stopping eating. Moreover, they kept their body mass down for a long time, without any associated side effects. 

As I said before, we’re now trying to develop combinations of exosomes that enable us to simultaneously treat energy intake and expenditure, as well as modulate other molecules in addition to AMPK, and to improve their forms of administration (currently intravenous)”.

 

Could it be applied to humans?

“I sincerely hope so. Right now we’re carrying out trials to develop a product that, if it passes all the regulatory requirements, could be used in humans at some point. But for that we need to get the necessary funding, because we’re talking about a long process, costing many millions of euros. 

Unless it’s a global emergency like Covid-19, when all protocols are greatly accelerated, developing drugs always takes time. From the initial discovery and publication to use in humans can easily take more than 15 years. The process is slow and laborious, and it has to be because the number of parameters to be controlled is large and, above all, side effects must be avoided”.