Effort, deprivation, and those extra pounds return. Was it a failed miracle diet? Was exercise and calorie restriction not enough? Was it going back to old habits? Weight loss is not only useful for fitting into jeans but also for keeping our body healthy: our cardiovascular system, preventing type 2 diabetes, and halting the development of fatty liver disease.
Strategies focused on changes in diet and lifestyle often result in short-term weight loss, which can be regained over time, this is the dreaded yo-yo effect. A problem that, according to the research by Ferdinand von Meyenn's group at the Laboratory of Nutrition and Metabolic Epigenetics at ETH Zurich, is believed to be caused by a memory of obesity.
"One of the reasons why body weight is not maintained after initial weight loss is that fat cells remember their previous obese state and likely try to return to that state," von Meyenn points out. This means that "one would have to fight against this obesogenic memory to maintain body weight," adds the Swiss researcher. The findings have been published in a recent study in Nature.
How are these memories created in cells?
As von Meyenn explains, "the epigenome, which consists of DNA modifications or proteins that surround it, controlling the activation and deactivation of genes, is altered during obesity, and some of these changes persist even after weight loss." This is why the scientist emphasizes that reducing body weight in obese individuals is beneficial for metabolism and the cardiovascular system beyond an aesthetic goal.
"Maintaining reduced body weight may be more challenging due to that obesogenic molecular memory, which means that it is not just lack of willpower or laziness that hinders weight loss or maintenance," highlights the study's author. According to the FAD Youth Foundation, 21% of teenagers aged 15 to 19 were dieting in 2022, and a global study conducted in 30 countries found that 45% of people worldwide are currently trying to lose weight. This figure rises to two-thirds (60%) of people in Chile trying to lose weight and to over 50% in Spain, Peru, Saudi Arabia, Singapore, and the US.
"Our study is the first to investigate the role of the epigenome in this effect," explains Spanish researcher Daniel Castellano-Castillo, from the Biomedical Research Institute of Malaga (IBIMA), who participated in the study. In this regard, he explains that to identify this mechanism, they used a murine model and human cells in which "adipocytes are marked so that we can separate them from the rest of the tissue cells and analyze their epigenome during obesity and after weight loss." From this, the researchers observed that if they isolated these adipocytes previously exposed during obesity, "they behaved differently in glucose and fat incorporation," explains the Spanish researcher.
Additionally, "if we exposed those mice again to obesogenic feeding conditions, they gained weight much faster than mice that had never been obese (yo-yo effect). Interestingly, the epigenetic memory observed during the weight loss phase explained the changes in gene 'on' and 'off' during weight 'regain' (yo-yo)," argues Castellano-Castillo.
Where is the information retained in the cells? The answer to that resentful memory, since it only remembers the state of obesity and not the efforts made to lose weight, is explained by the IBIMA researcher, who responds that "it is found in the epigenome, which is a set of chemical changes that occur in DNA or in the proteins in which DNA is 'packaged'. The epigenome determines which genes define a specific cell type. During obesity, changes occur at the cellular metabolism level, which in turn causes an alteration in these epigenetic modifications. Our study demonstrates that these alterations persist over time in certain genes or genome regions."
Therefore, the study's author suggests that, although there are no pharmacological interventions targeted against the observed changes, "tools are being developed that could target the epigenome. At the moment, they are very innovative, experimental, and have not been used in humans." Von Meyenn suggests that "maintaining reduced or healthy body weight for a sufficient period may be a solution that could erase the memory." How long? The researcher acknowledges that "in our experiment, we have extended that variable and have not reached that point."
How long should the ideal weight be maintained to eliminate the memory of obesity?
This is what new studies must resolve. Castellano-Castillo details that "these studies will determine what could be the appropriate strategy or strategies to help mitigate this epigenetic memory effect, which could involve not only the use of drugs but also changes in diet or the implementation of certain functional foods."
At this point, another question that arises revolves around the new obesity drugs, the Wegoby and Mounjaro family. Can the new GLP-1 agonists reset cell memory? "We have not yet conducted experiments to see if these new drugs would erase that memory. However, it is possible that, for now, most people who stop taking these drugs regain the lost weight, suggesting that the memory could persist even with the use of these drugs," acknowledges von Meyenn. "Future studies will show if this is the case."
According to José Ordovás, Director of Nutrition and Genomics at Tufts University in Boston (USA) and member of IMDEA-Alimentación (Madrid) and CIBEROBN (Carlos III Health Institute), this research "provides a basis for innovative approaches to obesity control, integrating molecular findings with existing clinical practices to address the global obesity crisis."
Additionally, as reported by SMC, "it opens up avenues for targeted therapies, such as drugs or epigenetic editing, to 'reset' adipose tissue memory and improve weight loss maintenance." In this regard, Ordovás distinguishes between "personalized weight control strategies that 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."