Obesity has memory and retains it in cells

Obesity leaves a deep mark on the body. So deep that, despite treatments or surgeries to lose weight, the threat of regaining fat is always there. And although the stigma surrounding the disease may lead one to think otherwise, science is beginning to shed light on the fact that this is not a matter of willpower or lack of effort. The memory of this disease is written in the cells: research published on November 18 in the journal Nature has described, in mouse models and in human cells, a molecular mechanism in fatty tissue that predisposes people to gain weight after having lost it. The authors suggest that this finding could help explain the “yo-yo effect,” or rebound, by which obese people gain weight again after bariatric surgery, for example.

Obesity, which is characterized by an excessive accumulation of fat in the body and affects one in eight people worldwide, is convoluted, complex, and chronic. Its signature and legacy persist over time, even despite patients having undergone treatments or diets to lose weight. The scientific community had long been suggesting that there was a kind of metabolic memory that facilitates weight gain, but the mechanisms behind this long shadow left by the disease were not precisely known. Until now.

The study published in Nature sheds further light on this research path and shows that adipocytes, which are cells of fatty tissue, retain a memory of obesity through epigenetic changes that persist even after weight loss. “The discovery reveals a molecular mechanism in fat cells that predisposes them to regain weight more efficiently after being exposed to increased calorie consumption. It also highlights that the difficulty in maintaining weight loss after an intervention is not simply a matter of lack of effort or willpower, but could be driven by an underlying biological phenomenon,” summarizes Ferdinand von Meyenn, author of the study and researcher at the Swiss Federal Institute of Technology in Zurich.

Inside each cell, there is a manual for life: DNA. There, in that book that contains three billion chemical letters, are the instructions for making the human being function and the genes are like pages that keep the specific recipes to make the proteins necessary to breathe, eat, or sleep. In that context, the epigenome, which is made up of chemical substances that stick to the genes without modifying their sequence, would be like a kind of spelling system that adds periods, commas, and accents to fine-tune the understanding of the instructions. Thus, if an accent is added to a word or a comma is moved, the entire meaning of a sentence can be changed.

The epigenome works like a switch, turning gene activity on and off. And what Von Meyenn’s team found is that during obesity, very specific changes occur in the epigenome of fat cells, turning genes on and off that shouldn’t be. These modifications, the scientist explains in an email response, “prepare the adipocyte to quickly regain weight once high calorie intake is resumed.” “Our research shows that some of these alterations persist after weight loss in specific genes or genomic regions. The epigenome of adipocytes previously exposed to obesity may be programmed to return to an obese state more quickly or more efficiently due to these changes,” he adds.

Due to the technical limitations for analyzing the epigenome in humans, the researchers complemented their studies in human cells with experiments in animal models, explains Daniel Castellano, co-author of the study and a postdoctoral researcher at the Clinical and Translational Cancer Research Group at the Biomedical Research Institute of Málaga (IBIMA). “The mouse gives us the opportunity to study the epigenome because we cannot do so in humans. In humans we can see which genes are working and which are not, and we saw that there was a transcriptional deregulation, genes turning on and off that should not be. And this deregulation persisted after losing weight,” he points out. Then, in mice, they also saw that this phenomenon, where some genes turned off and on, was “very similar” to what they had perceived in human cells. After studying several epigenetic modifications, they found that “this deregulation of genes was due, in a high proportion, to epigenetic alterations that had been maintained after weight loss.”

The researchers don’t know how long the obesity memory identified in adipocytes lasts. Their findings showed that epigenetic changes persisted for at least two years in humans after weight-loss surgery and up to eight weeks in mice, but there is no clear timeline, Von Meyenn admits: “The duration of this memory probably depends on the cell turnover of the tissue. For example, adipocytes have a half-life of 10 years, after which the tissue is replenished with new cells.”

Castellano also clarifies that the molecular mechanism described would not explain 100% of the rebound effect. In fact, the research does not reveal a causality between the presence of this obesogenic memory and the yo-yo effect, but there is “a concordance”: “Mechanistically, we cannot prove that this rebound effect is due to changes in adipocytes. But we have found epigenetic alterations in various areas and we see that there is an overexpression of genes related to inflammation and the metabolism of the adipocyte itself. Functionally, it makes sense with what happens to fatty tissue in obesity,” he explains. Von Meyenn adds that adipocytes alone would not be purely responsible for the yo-yo effect. “This phenomenon of epigenetic memory may also exist in these other cells. Other types of cells and organs, such as the brain (involved in the control of satiety and appetite), could also be involved.”

Correcting epigenetic memory

Von Meyenn, however, adds that the study opens the door to the development of new strategies (pharmacological, dietary, or otherwise) to correct this epigenetic memory. “Currently, there are no pharmacological strategies to erase this memory. While some drugs used in cancer therapy target the enzymes responsible for epigenetic changes, these approaches are global and do not focus on specific regions of the epigenome where long-lasting alterations could reside. There are emerging molecular strategies to induce changes in specific epigenetic regions, but they require further research and are not yet approved for use in humans. Once this phenomenon is better understood, possible strategies could include pharmacological interventions, dietary changes, or the incorporation of functional foods,” he suggests.

Andreea Ciudin, head of the Comprehensive Obesity Treatment Unit at Vall d’Hebron Hospital in Barcelona and a member of the board of directors of the Spanish Society for the Study of Obesity, describes this research, in which she did not participate, as “interesting in its results, but worrying at the same time.” “This research opens up a perspective of endless studies. Where there is DNA, there is epigenetics, because in the DNA chain there will always be factors that regulate its transcription. But it is difficult to explore epigenetics because it is very volatile and I do not know how we could influence epigenetics in a chronic way,” she says.

In statements to the Science Media Center website, José Ordovás, director of Nutrition and Genomics at Tufts University in Boston (USA), also highlights that, “although the findings are solid and supported by both human and animal data, the study has limitations, including the lack of direct epigenetic analysis in human samples, heterogeneity in human data sets, and the absence of long-term follow-up in mice [...] It does not establish causality between epigenetic changes and weight regain, so further research is required to confirm the mechanisms,” he says, although he admits that the implications of these findings in the real world are “significant”: “The study highlights the biological basis of weight regain, reduces stigma, and emphasizes the need for long-term supportive interventions. It opens avenues for targeted therapies, such as drugs or epigenetic editing, to ‘reset’ adipose tissue memory and improve weight loss maintenance. Personalized weight management strategies could be based on an individual’s genetic and epigenetic profile, while public health policies could prioritize prevention and early intervention to avoid the establishment of an obesogenic memory.”

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