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Ferdinand von Meyenn is assistant professor of nutrition and metabolic epigenetics at ETH Zurich. He and his colleagues are having one this week Study in the journal Nature (DOI 10.1038/s41586-024-08165-7), which revolves around the question of whether being overweight creates a kind of “memory” in our cells that makes it difficult to remain 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 against the infamous yo-yo effect.
Prof. Dr. Ferdinand von Meyenn is an assistant professor in the Department of Health Sciences and Technology at ETH Zurich.
(Image: ETH)
Every person who struggles with being overweight and has ever lost large amounts of body weight through diets knows the problem: the weight often comes back on much faster than it came off. How did you come to want 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. What is the reason why you gain weight back so quickly? What is the molecular mechanism behind it? And one option, of course, is long-term changes that affect cells and cell functions. These are often epigenetic in nature. So we thought about which organ and tissue we should look at. We then came directly to the fatty tissue – and the question of how does it change during weight gain and, above all, to what extent do these changes remain even after weight loss. What is involved in these processes?
How can something like this be investigated specifically?
In our case, we initially started with human studies. That means we worked with clinical collaborators who often have obese people in their studies. These people usually underwent gastric sleeve surgery and then lost a lot of weight within a short period of time.
During these operations it is also possible to extract a small portion of fatty tissue to obtain a “before” image. After the weight loss, another fat sample was taken and we then compared these two samples. We were able to determine that at the transcriptional level, i.e. at which the genes are expressed that are then later translated into protein, there were still differences compared to people of normal weight despite the weight loss.
After studying this in a human system, we took an animal model and tried to recreate 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’s roughly equivalent to what we would probably consider classic unhealthy food. They then returned to normal nutrition and lost weight. Here too, a before and after comparison could be made. It turned out that we could also detect changes of an epigenetic nature. Many of the changes that occur during weight gain are not erased during weight loss. They are not turned back to the state of 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 the 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 relate to changes in adipose tissue in overweight people?
This is a relatively large set in itself. It’s not that you could say this is a gene that is deregulated, but rather we see this on a larger scale. Many of the genes we see deregulated relate to 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 fatty tissue takes on and maintains the signature of an unhealthier or overweight state.
That doesn’t sound particularly good for people who want to lose weight. How can you continue to stay at a normal weight against this trend after you have reached your desired weight?
The first thing you have to say is that losing weight is still very good. We observed that too. The people and also the mice are physiologically much healthier after weight loss. This applies to the blood values, the fat, the blood sugar, everything normalizes, the “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.
But we now see that losing weight in itself is not enough, but that people who have lost weight have a preference to gain weight again. That means you have to stick with 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 defends itself against it in a certain way.
Does this only affect fatty tissue?
These changes, these epigenetic memories of excess weight, may also be present in other types of tissue, perhaps including the brain, where eating control occurs. But I think the key point is that if you’ve had too much weight and want to lose it again, it’s a long-term process. So people have to stay active, change their diet and ideally combine it with exercise.
High body weight – or the fact that you gain weight quickly – also has a large hereditary component. It feels like some people just have to look at a plate of food to gain weight. Would the effect you discovered also occur in people who tend to be normal or even underweight?
We did not specifically examine 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 suggests that the effect of epigenetic memories of being overweight is also likely to occur in people without a genetic predisposition to it. The group of people who tend to be overweight probably gain weight much more easily, even with the yo-yo effect.
Does that mean you should generally avoid becoming overweight at all, if at all possible?
Yes. Someone who has never become overweight appears to have a lower risk. Of course, this has many factors – education, prevention, stress, sport and much more. However, in view of our findings, we would advise that you should generally avoid becoming overweight. The food should tend to be healthier, the portions should not be too large and, of course, exercise should also be part of it.
Someone who is not overweight will have less of a strong need to eat a lot later on – and accordingly have less of a risk of becoming overweight.
What therapeutic starting points could there be given the connections you discovered?
We currently don’t know how long the effect of epigenetic memory of obesity lasts; so far we have only looked at a certain period of time, around 2 years in humans. Of course, it could be that after a long-term change to a healthy diet while maintaining a normal weight, someone can reverse the process. These are topics that we will devote ourselves to in the future.
However, these are all still approaches that do not have a targeted effect, but rather affect certain changes in epigenetics on a large scale. So at the moment we still lack a real toolkit for this. But at least there are now approaches where we have to look.
Can people who are overweight also be healthy?
It is possible. We know that some people are relatively metabolically healthy despite being overweight – this 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 can still function fully. However, excess weight still has negative effects, for example on our muscular and skeletal system, as it puts unnecessary strain on it.
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How can understanding the psychological aspects of eating habits contribute to developing more effective strategies for long-term weight management?
Questions to encourage thoughtful and diverse perspectives from students. Here are some possible questions related to the article:
1. What are some ways we can prevent or combat the “yo-yo effect” of weight gain after significant weight loss?
2. How do epigenetic changes in fat tissue contribute to the long-term maintenance of weight loss?
3. Can a person with a genetic predisposition towards obesity still achieve and maintain a healthy weight through diet and exercise?
4. What are some other factors that influence a person’s risk of becoming overweight or obese besides genetics?
5. How can we define “metabolic health” in terms of weight and overall well-being?
6. Are there any new experimental treatments or therapies being developed to target epigenetic changes in fat tissue for weight loss?
7. What role does diet and nutrition play in maintaining a healthy metabolism and preventing weight gain?
8. How can individuals assess their own metabolic health and take steps to improve it?
9. Can lifestyle choices such as regular exercise and healthy eating habits reverse the effects of epigenetic memory on fat tissue and promote sustained weight loss?
10. As a class, discuss the ethical implications of potentially manipulating epigenetic changes for therapeutic purposes related to weight loss.
