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Fat cells may retain 'memory' of obesity even after weight loss
Last reviewed: 02.07.2025
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Epigenetic changes caused by obesity can have long-lasting effects, altering gene activity and fat cell function even after weight loss.
In a recent study published in the journal 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 to weight regain.
Using advanced ribonucleic acid (RNA) sequencing techniques, the researchers studied these persistent cellular and genetic changes to better understand the long-term impact of obesity on metabolic health.
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, is critical to obesity management. However, one of the major challenges in obesity treatment remains the “yo-yo” phenomenon, in which people regain weight after initially losing it.
Research suggests that this weight regain may be the result of a form of persistent metabolic memory that persists even after weight loss and is expressed in a variety of tissues, such as adipose tissue, liver, and immune cells. Epigenetic mechanisms, which influence gene expression without altering DNA sequence, may play a key role in maintaining these effects.
Despite recent advances, the precise cellular mechanisms underlying this obesity memory and its impact on long-term weight management remain unclear. Therefore, in this study, the researchers analyzed the persistence of obesity-related changes in adipose tissue in both humans and mice.
They collected biopsies of subcutaneous fat and omental fat (a special type of fat in the abdominal cavity) from obese people before and two years after weight loss due to bariatric surgery. To ensure reliable comparisons, they also included biopsies of the same tissues from normal-weight people. These samples were processed using single-nucleus RNA sequencing (snRNA-seq) to capture gene expression patterns in thousands of cells and analyze changes associated with obesity.
For the mouse experiments, the researchers used mouse models with markers specific to adipose tissue, allowing for precise profiling of transcriptional and epigenomic changes. Mice were divided into groups based on exposure to a high-fat diet and subsequent weight loss. Adipose tissue samples were collected, and after nuclei were isolated from the cells, snRNA-seq was performed to identify genetic changes retained in the nuclei.
The researchers also used ATAC-seq (analysis of transposase-accessible chromatin with sequencing) to assess chromatin accessibility in adipocytes and identify epigenetic marks. In addition, histone modification analysis was performed to determine changes in the regulation of gene expression in different types of adipose tissue cells.
The results showed that adipose tissue in both humans and mice retains significant transcriptional and epigenetic changes after significant weight loss. Human adipose tissue samples collected before and two years after bariatric surgery showed persistent changes in gene expression profiles, particularly in adipocytes. These changes included the activity of genes associated with metabolic processes, inflammation, and cell signaling.
Epigenetic profiling of the mice showed that adipocytes also retained markers indicating previous exposure to obesity. These markers persisted even after weight loss, suggesting the development of epigenetic “memory” that influences cellular responses.
The researchers noticed that histone modifications, which are key epigenetic regulators of gene activity, were retained in previously obese mice. This epigenetic memory made the cells more susceptible to weight regain when re-exposed to a high-fat diet, leading to faster weight regain compared to mice without prior obesity.
Furthermore, the study found that these changes occurred primarily in adipocytes, but were also observed in other types of fat cells, indicating a broad tissue effect. These findings highlight the role of persistent epigenetic marks in obesity and demonstrate how they can contribute to weight regain even after successful intervention.
In conclusion, the results showed that cellular and epigenetic changes caused by obesity may predispose individuals to weight regain due to stored memory in fat cells. Understanding these persistent changes may help to develop future treatments aimed at eliminating the cellular memory of obesity. Disrupting this memory may improve the long-term success of weight loss interventions and improve the metabolic health of people with obesity.