Epigenetics: "Losing weight is still very good"

Ferdinand von Meyenn is Assistant Professor of Nutrition and Metabolic Epigenetics at ETH Zurich. Together with colleagues, he published a study this week in the journal Nature (DOI 10.1038/s41586-024-08165-7) on the question of whether being overweight creates a kind of "memory" in our cells that makes it difficult to stay at a normal weight in the long term. In an interview with heise online, he talks about the results – and the question of what can be done to combat the infamous yo-yo effect.

Anyone who is struggling with obesity and has ever lost large amounts of body weight through dieting knows the problem: the weight is often back on much faster than it came off. Why did you decide to investigate this area?

Exactly for the reason you mentioned. It is of course a very widespread phenomenon. So far, it is not really clearly understood why this is the case. What is the reason why people put on weight so quickly? What is the molecular mechanism behind it? One option is, of course, long-term changes that affect cells and cell functions. These are often epigenetic in nature. So we thought about which organ or tissue we should look at. We then came directly to the fatty tissue – and the question of how this changes during weight gain and, above all, to what extent these changes remain even after weight loss. What is involved in these processes?

How can something like this be investigated in concrete terms?

In our case, we initially started with human studies. This means that we worked with clinical collaborators who often have overweight people in their studies. These people usually underwent gastric sleeve surgery and then lost a lot of weight within a short period of time.

In these operations, it is also possible to extract a small amount of fat tissue to obtain a "before" picture. After the weight loss, another fat sample was taken and we then compared these two samples. We found that there were still differences at the transcriptional level, i.e. where the genes are expressed that are later translated into protein, despite the weight loss compared to people of normal weight.

After we had investigated this in a human system, we took an animal model and tried to replicate the experiment and this process there. So we took overweight mice and fed them a very high-calorie diet, which is also called the "Western Diet" because it is roughly equivalent to what we would probably consider a classically unhealthy diet. They were then fed a normal diet again and lost weight. Here, too, a before-and-after comparison could then be made. It turned out that we were also able to detect changes of an epigenetic nature. This means that many of the changes that take place during weight gain are not erased when weight is lost. They are not reversed back to the state in normal-weight animals.

What does epigenetics mean in this context?

These are phenotypic changes that are long-term, but do not involve a change in the DNA sequence. So if you think of genetics as a blueprint of the body, then epigenetics is a marker that is present on the different sides. The blueprint, the DNA, represents the house, the epigenetics that you should build a kitchen in room 1 and a bathroom in room 2.

What markers have you found that affect changes in adipose tissue in overweight people?

That in itself is a relatively large set. It's not as if you could say that this is a gene that is deregulated, but we see it in a large framework. Many of the genes that we see deregulated affect the way fat cells store fat.

On the one hand, more genes are expressed that have an inflammatory effect, i.e. classic immune-related functions. On the other hand, many of the genes that are normally important for fat metabolism are downregulated. So our theory is that the adipose tissue takes on and maintains the signature of a more unhealthy or overweight state.

That doesn't sound very good for people who want to lose weight. How can they buck this trend and stay at a normal weight once they have reached their desired weight?

The first thing to say, of course, is that losing weight is still very good. We have also observed this. Both humans and mice are physiologically much healthier after losing weight. This applies to blood values, fat, blood sugar, all of which normalize, overall fitness is better. Accordingly, the very first message from our study should be: Losing weight is good, is healthy and can be recommended to anyone who is overweight.

However, we now see that losing weight is not enough in itself, but that people who have lost weight have a preference to put it on again. That means you have to keep at it. You can't just lose weight and say, well, now I've done it, now it's over, but it's a long-term, active process because the body resists it to a certain extent.

Does this only affect fatty tissue?

These changes, these epigenetic memories of being overweight, are possibly also present in other types of tissue, perhaps also in the brain, where food control takes place. But I think the key point is that once you've gained too much weight and you want to lose it again, it's a long-term process. So people need to stay active, change their diet and ideally combine it with exercise.

High body weight – or the fact that you put on weight quickly – also has a large hereditary component. You get the feeling that some people only have to look at a plate of food to put on weight. Would the effect you discovered also occur in people who tend to be normal or even underweight?

We did not specifically investigate genetic risk factors in our study. Of course, known hereditary causes are an important factor. So there are definitely people who have a genetic preference to become overweight.

But at least our data so far indicate that the effect of epigenetic memories of obesity is also likely to occur in people without a genetic predisposition. However, the group of people who tend to be overweight are likely to gain weight much more easily, even with the yo-yo effect.

Does this mean that people should generally avoid becoming overweight if at all possible?

Yes, someone who has never been overweight is obviously less at risk. But of course there are many factors involved – Education, prevention, stress, sport and much more. In view of our findings, however, we would advise that people should generally avoid becoming overweight. It should tend to be healthier food, the portions should not be too large and sport is of course also part of it.

Someone who is not overweight will also have less of a need to eat a lot later on – and therefore less of a risk of becoming overweight.

What therapeutic approaches could there be in view of the correlations you have discovered?

We don't yet know how long the effect of the epigenetic memory of obesity lasts; so far we have only looked at a certain period of time, about 2 years in humans. Of course, it could be that someone can reverse the process after a longer-term switch to a healthy diet while maintaining a normal weight. These are issues that we will be looking into in the future.

The hope is, even if this is still a long way off, that one day we will be able to reverse the effect. Epigenetics is a very dynamic part of our body. It is not permanent. Therapeutics that specifically intervene here could be developed in the future. There are initial approaches that show that lipid parameters in the blood could be changed in some cases. Epigenetically modulating drugs are already being used in the field of oncology.

However, these are all still approaches that do not have a targeted effect, but which affect certain changes in epigenetics on a large scale. At the moment, we still lack a real toolkit for this. But at least there are now approaches that we need to look for.

Can people who are overweight also be healthy?

It is possible. We know that some people are relatively metabolically healthy despite being overweight –, which means that this person does not suffer from metabolic syndrome (which is associated with high blood pressure and insulin resistance, among other things) and their metabolic organs are still fully functional. However, being overweight still has negative effects, for example on our musculoskeletal system, as it puts unnecessary strain on it.

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