Memories of obesity can linger in fat cells long after weight loss

Epigenetic changes from obesity can have long-term effects, altering gene activity and fat cell function even after weight loss.

In a recent study published in Nature, a team of scientists examined how adipose tissue, specifically fat cells, retains transcriptional changes even after significant weight loss, potentially leading to a predisposition for weight regain.

Using advanced ribonucleic acid (RNA) sequencing techniques, the researchers investigated these lasting cellular and genetic alterations better to understand the persistent effects of obesity on metabolic health.

Background

Obesity poses serious health risks and almost inevitably leads to metabolic diseases related to insulin regulation and cardiovascular disease. Effective weight loss, whether through diet, lifestyle changes, medications, surgery, or a combination of these approaches, is critical in managing obesity. However, a recurring challenge in obesity treatment is the ‘yo-yo’ phenomenon, where individuals regain weight after initial loss.

Studies suggest that this weight regain may result from a form of persistent metabolic memory even after weight reduction and may manifest in various tissues, such as adipose tissue, liver, and immune cells. Furthermore, epigenetic mechanisms, which influence how genes are expressed without changing the deoxyribonucleic acid (DNA) sequence, may play a crucial role in sustaining these effects.

About the study

Despite recent advancements, the exact cellular mechanisms underlying this obesogenic memory and its impact on long-term weight management remain unclear. Therefore, in the present study, researchers analyzed the persistence of obesity-related cellular changes in both human and mouse adipose tissue.

They collected biopsies of subcutaneous adipose tissue and omental adipose tissue, which is a specialized type of fat tissue found in the peritoneal cavity, from individuals with obesity both before and two years after bariatric surgery-induced weight loss. To ensure reliable comparisons, they also included biopsies of the same tissues from healthy-weight individuals. These samples were processed using single-nucleus RNA sequencing (snRNA-seq) to capture gene expression patterns across thousands of cells. These were analyzed to identify cellular transcriptional changes associated with prior obesity.

For the mouse model experiments, the researchers used crosses of murine models that have adipose tissue-specific expression markers, which allowed them to profile the transcriptional and epigenomic changes precisely. The mice were divided into groups based on exposure to a high-fat diet and subsequent weight loss. Adipose tissue samples were obtained from the mice. After the nuclei from the cells were isolated, snRNA-seq was performed to identify the genetic alterations that were retained in the nuclei.

Additionally, the researchers used an assay for transposase-accessible chromatin with sequencing (ATAC-seq) to assess chromatin accessibility in adipocytes, providing insights into retained epigenetic marks. Furthermore, a histone modification analysis was conducted to identify changes in gene expression regulation across different cell types within adipose tissue.

Results

The results reported that adipose tissues from both humans and mice retain significant transcriptional and epigenetic changes after major weight loss. Human adipose tissue samples collected before and two years after bariatric surgery displayed lasting alterations in gene expression profiles, particularly in adipocytes. These modifications included changes in gene activity related to metabolic processes, inflammation, and cell signaling.

Furthermore, the murine model epigenetic profiling revealed that adipocytes also retained markers that indicated prior exposure to an obesogenic environment. Moreover, these markers persisted even after weight reduction, suggesting the development of an epigenetic ‘memory’ that influences cellular responses.

The researchers observed that histone modifications, which are key epigenetic regulators of gene activity, were sustained in formerly obese mice. This epigenetic memory predisposed the cells to an enhanced response upon re-exposure to a high-fat diet, leading to accelerated weight regain compared to mice without prior obesity.

Furthermore, the study also demonstrated that these changes occurred primarily in adipocytes but were also observed in other cell types within the adipose tissue, suggesting a broad tissue-level impact. These findings underscored the role of lasting epigenetic marks in obesity and highlighted how they might predispose individuals to regain weight even after successful weight loss interventions.

Conclusions

To summarize, the findings suggested that cellular and epigenetic changes from obesity may predispose individuals to regain weight due to retained memory within fat cells. Recognizing these persistent alterations could inform future treatments targeting the cellular memory of obesity. By disrupting this memory, it may be possible to enhance the long-term success of weight-loss interventions and improve metabolic health outcomes for individuals with obesity.

Journal reference:

• Hinte, L. C., CastellanoCastillo, D., Ghosh, A., Melrose, K., Gasser, E., Noé, F., Massier, L., Dong, H., Sun, W., Hoffmann, A., Wolfrum, C., Rydén, M., Mejhert, N., Blüher, M., & von Meyenn, F. (2024). Adipose tissue retains an epigenetic memory of obesity after weight loss. Nature. doi:10.1038/s41586024081657, https://www.nature.com/articles/s41586-024-08165-7