There’s an epidemic across the planet, one that affects both children and adults: obesity rates have tripled globally since the 1970s. According to data from the World Health Organization, more than 650 million people now suffer from it. Due to its enormous complexity, this disease — which also triggers other health problems, such as tumors or cardiovascular diseases — causes doctors and researchers to rack their brains. They’re still trying to unravel all the organic processes that are set in motion when there’s an excessive accumulation of fat in the body. Finding effective drugs to combat it is the great objective of the scientific community, although, for now, prevention continues to be the best weapon to combat this health problem. Marc Schneeberger Pané, a Spanish-born neurobiologist at Yale University, is also of this opinion. He specializes in studying how the nervous system controls metabolism and energy levels.
Schneeberger — who holds a doctorate in Biomedical Sciences — has just received the 2023 Princess of Girona award for his contributions towards the discovery of a new region of the brain, which is essential to the processes of energy intake and expenditure. The keys to understanding obesity lie in the brain, as explained by the scientist during his visit to Barcelona.
Question. Experts always warn that, when it comes to obesity, losing weight is not simply a matter of willpower. Why? What happens in the brain?
Answer. The brain is simply monitoring blood glucose levels and the physiological state of the body. Based on that, it gives signals to either start the appetite or stop it. But [the purpose is to] always maintain the body. For the brain, taking in extra nutrients isn’t an emergency situation; the emergency situation is the loss of weight. If there’s too much metabolic activity, losing weight is detected as an emergency situation — [the brain] activates the appetite signal.
Not so many years have passed since we chased animals for food. Evolutionarily, 2,000 or 3,000 years isn’t that long ago, so the brain is thinking that depositing energy at the level of adipose tissue [body fat] is good. The problem is that, with our access to high-fat, high-sugar nutrients [which are] available all the time, it creates an addiction to those kinds of products, because they’re so pleasurable.
Q. Why do we like chips or chocolate more than broccoli?
A. The brain has learned that it requires a high nutritional contribution. Since [the brain] only works with glucose and needs a constant flow of energy for neural activity, it prefers the type of food that provides it with more nutrition. Because, again, for the brain, gaining weight isn’t a bad thing. The problem is when the system deregulates — when that happens, it’s often too late. That’s why the best therapy that works against obesity is prevention: if we follow a balanced diet and exercise from a young age, we end up training our bodies in those moments of development to further promote a stable body weight. And, vice-versa, if we promote a sedentary lifestyle and the stress of our daily life — which makes us eat anything, quickly — we train our brain for that type of behavior.
Q. What are the variables that trigger the entire process that leads to obesity? Does it depend on how we eat? When we eat? What we eat?
A. We don’t have the complete answer. We believe that, until we fully understand how these circuits really work, we won’t be able to define what all the factors are. Obviously, [obesity is influenced by] exercise, diet, type of diet, components of the diet... But then there are also many things that affect our metabolic system that are secondary to it. It’s possible to determine anything that, at a moment of development, is affecting the neural circuit. We’ve seen that, for example, when children play, they stimulate certain regions of the brain. The most critical things that we’re seeing take place during the moments of development: childhood obesity may be the one that has the worst implications, because at a time when these circuits are being established, we’re preventing them from developing properly. [This is due] to toxins and foods that are not nutritious — derivatives of those nutrients activate inflammation, and neuronal inflammation (neuroinflammation) leads to neuronal death. We don’t know the implications of this yet; they can range from stress or anxiety, to cognitive deficits. We see that this age is the most important time to act.
Q. Can playing be positive for kids?
A. Social play stimulates the same neurons that stimulate metabolism. Having more social play causes more stimulation of neurons that give a signal of satiety — with that satiety, [kids] lose weight. And it’s not just about going to play soccer — it’s also the unstructured game. That social ability to interact at an early age favors the proper development of the brain.
Q. Doesn’t obesity have to do with energy expenditure, then? For kids, is doing a puzzle the same thing as playing tag?
A. Yes... With the aim of playing, independent of physical activity. The same thing happens at the nutritional level: at that moment [of consumption], the excess fat that a cookie has — and that greens don’t have — increases inflammation. That inflammation can be very disturbing for the correct development of the most fundamental brain circuits.
We’re trying to understand whether childhood obesity — this incorrect development of the brain — causes a child to later have more cognitive deficiencies, if they’re more susceptible to stress, anxiety…. or if any anxiety [that appears] during adulthood has been determined by problems stemming from development, social isolation, etc.
We’re seeing that the [consequences of the] pandemic have had a brutal impact, but more so in children than in adults, who have adapted. Adolescent depression, childhood depression and metabolic problems are increasing exponentially nowadays.
Q. Does the brain do more than the intestine to regulate our energy balance?
A. The brain dominates. It perceives what’s happening in our environment and then communicates how the body should respond. There are peripheral neurons that communicate with the central ones, but the brain clearly has a primary position. That’s why we understand obesity not as a disease of the body, but as a disease of the brain. The fundamental thing that gets deregulated and that generates the complexity of weight loss isn’t any peripheral organism — it’s our brain and how it regulates metabolism.
A very clear example is when you go to a wedding: you know that there will be an excess of nutrients. If the wedding is cancelled at the last minute, if you checked your blood insulin levels, they would be higher than normal, because the brain has already anticipated [the excess nutrients]. And [leaving a wedding before you eat] can alternatively result in hypoglycemia, because your body is prepared for it. That is to say, the brain is analyzing at all times. However, this doesn’t mean that the body is less important, because obviously the first thing that detects food is the mouth — that’s where the first signal to the brain begins.
Q. Today, studies about the gut-brain axis and the microbiome (the set of microbes, such as bacteria and viruses, that populate the body) are very much in vogue. How are they related to each other?
A. We don’t clearly understand the differences between intestinal microbiota. We have a study in which we look at the microbiome in obese and non-obese patients; we see that there are very clear patterns of specific microbes increasing or decreasing in situations of obesity, as well as what metabolites are being secreted. The microbiome acts as an informer — it can secrete some toxin that is then absorbed and reaches the brain. It’s one more communicator, but since it has hardly been explored, all the results are very shocking. For example, it’s been observed that short-chain fatty acids are produced by the intestinal microbiome and that they’re capable of communicating about whether the intestine is moving faster or slower, [if there’s] diarrhea or constipation...
All of this has been discovered from looking at the intestine, [including] the latest drugs called GLP-1 analogues. These have been seen to act in a region of the brain that causes nausea. They’ve been taken advantage of, because prolonged nausea inhibits appetite. At the moment, these are the drugs that are causing weight-loss.
Q. These drugs are very fashionable. But what implications can this process have? Because promoting a kind of permanent nausea isn’t very natural…
A. It depends. What’s being researched now is how to dissociate that nausea from the signal to stop eating. Because nausea, per se, is bad, but the signal to stop eating is associated with that nausea. We have to see if we can unravel the point where these neurons are communicating the most negative signal — this feeling of nausea — and to where they are communicating the signal to stop eating food. We can act on this circuit [if there is] some evolution of these drugs.
Q. It hasn’t been possible to alter the energy intake and expenditure process through drugs. What’s missing from these treatments?
A. As far as treatment is concerned, the best option is to prevent, rather than cure. So, let’s start by preventing childhood obesity from increasing. At the treatment level, what seems to work best — and there are laboratory studies that show this — are triple or double therapies, with drugs that bind to neuron A, which is essential for regulating intake. When this drug acts on neuron A, it releases another drug in that same molecule that subsequently acts on neuron B, which controls metabolism. As studies of animals suffering from obesity have shown, when binding at several different points takes place, weight loss is achieved at a greater rate.
Q. Do you think that it’s possible to end the obesity epidemic in the future?
A. It will be very complex at the adult level, because in these individuals, we’ll need almost individualized therapy, because each person comes from a different environment. Yes, there will be drugs that work and achieve better weight loss results [for some] to lead a more bearable life, but not so well that these obese people will return to being thin. But where we can act to eradicate obesity is during childhood: if we use these preventive strategies, there will only be the number that we traditionally had in the past — a percentage that, unfortunately, is genetic. [Some individuals have a] metabolic predisposition to gain weight.
Q. You mention people who have a tendency to gain weight. What role do genes play in this?
A. We don’t know, but we’re studying it. Because we see this happen in mice and in humans. Each one is a little different… When we put mice on a high-fat diet, there’s one that gains 50 grams, another that gains 40 and another 35. [This diet] must be affecting something at the genetic level. We want to know what’s determining that individuality. There’s the genetic component and the environmental component, but how one communicates with the other — what’s positive and negative — we still don’t know.
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