New research suggests that a person’s adipocytes – fat-storing cells in fat tissue – retain epigenetic memory when they have had overweight. A researcher says that this discovery may explain why sustaining weight loss is especially challenging for such people.
People who have lost weight often struggle to sustain the loss and eventually regain the weight. People using modern weight-loss medications experience a similar pattern, with most regaining weight when they stop taking the medication.
Conversely, many people who have never had overweight can eat almost anything without gaining much weight.
Researchers have now identified a possible explanation for these differences in experiments with mice. The adipocytes retain long-term memory of having had overweight. Mice that previously had overweight regained weight more easily than those that had never had overweight.
“The findings indicate that combatting obesity globally may require focusing on prevention – ensuring that individuals never have obesity in the first place. Another possibility is modulating the memory of adipocytes, enabling them to lose the memory. Ultimately, the goal is to determine effective strategies for achieving weight loss and sustaining it over time,” explains a researcher behind the study, Ferdinand von Meyenn, Professor, Department of Health Sciences and Technology, ETH Zurich, Switzerland.
The research has been published in Nature.
Studying unique fat tissue before and after weight loss
Ferdinand von Meyenn and colleagues aimed to improve understanding of the molecular and mechanical changes that occur when people gain weight and then lose it.
They examined fat tissue collected from individuals who had undergone bariatric surgery to reduce the size of the stomach.
Some of the fat tissue samples analysed were from the tissue surrounding internal organs. These samples were obtained from people who had undergone bariatric surgery twice, spaced two years apart.
This provided an opportunity to study fat tissue from the same individuals before initial bariatric surgery and again after significant weight loss.
“This unique access to fat tissue before and following substantial weight loss enabled us to investigate the specific changes fat tissue undergoes during weight loss. This is normally not feasible, since it requires collecting organ-associated fat tissue from the same individuals at different times,” says Ferdinand von Meyenn.
Adipocytes retain memory of obesity
The researchers examined gene expression in adipocytes and found that weight loss induces numerous changes throughout the body.
At the organism level, weight loss resulted in improved glucose tolerance, lower body-mass index, lower triglyceride levels and other benefits. However, in fat tissue, obesity strongly dysregulated many genes, and this persisted after weight loss.
Despite the weight loss, the adipocytes continued to exhibit genetic behaviour typical of obesity.
The dysregulated genes included those linked to the extracellular matrix and lipid metabolism, which failed to return to their previous state.
“This experiment demonstrated that adipocytes retain memory. They adapt to prolonged exposure to high energy intake, and this is not reversed after weight loss,” explains Ferdinand von Meyenn.
Mouse adipocytes remember whether they had overweight
The team then shifted focus from studying how human adipocytes retain memory to investigating this in mice. The researchers fed the mice a diet high in fat, sugar and calories. Within three to six months, the mice were obese.
The researchers then shifted the mice to a normal diet, and they lost weight. The mice improved in markers of obesity, including reduced blood glucose, triglycerides and inflammation. These mice did not noticeably differ from those fed a normal diet throughout the study.
However, obesity had dysregulated certain genetic programmes related to obesity. Importantly, losing weight did not normalise these gene activity changes.
Epigenetics may represent adipocytes’ memory
The researchers then explored whether the previous overweight had caused epigenetic changes in the mice: modifications that influence whether genes are activated or deactivated without altering the underlying genetic code. These changes strongly determine which genes are expressed and which remain inactive.
Although the mice had lost weight, many of the epigenetic changes associated with having overweight persisted.
Notably, the researchers identified changes in promoter and enhancer regions, which regulate gene activity.
“These epigenetic changes could represent the memory of adipocytes, although future studies need to confirm or reject this hypothesis,” notes Ferdinand von Meyenn.
Finally, the researchers discovered that mice that previously had obesity gained weight much more rapidly than mice that had never had obesity when both groups were placed on a diet high in fat, sugar and calories.
Further experiments revealed that adipocytes from mice that previously had obesity were far more effective at absorbing fat and glucose.
“These findings suggest that the cellular memory in adipocytes is not merely a scientific curiosity but contributes to the challenge of maintaining weight loss,” says Ferdinand von Meyenn.
Achieving long-term weight loss
Ferdinand von Meyenn emphasises that the research focused solely on adipocytes, even though several other types of tissue influence weight regulation, such as the liver, muscles and brain, which constantly interact and communicate.
Many more studies are therefore necessary to fully comprehend how the body manages weight and to identify potential ways to intervene effectively.
Ferdinand von Meyenn and colleagues are eager to explore how modern weight-loss medications affect the epigenetics of adipocytes. This could shed light on the relative ease or difficulty of sustaining the weight loss achieved through these medications.
“This could mark the beginning of efforts to develop weight-loss strategies that are easier to sustain, and we anticipate that this topic will attract considerable attention in the future,” he concludes.
