Adipose tissue retains an epigenetic memory of obesity after weight loss
Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.
Obesity and its related comorbidities represent substantial health risks1. A primary clinical objective in managing obesity is to achieve appreciable weight loss (WL), typically through rigorous dietary and lifestyle interventions, pharmaceutical treatments or bariatric surgery (BaS)2. Strategies relying on behavioural and dietary changes frequently only result in short-term WL and are susceptible to the ‘yo-yo’ effect, in which individuals regain weight over time3,5,6. This recurrent pattern may be partially attributable to an (obesogenic) metabolic memory that persists even after notable WL4,7,8,9,10 or metabolic improvements11,12,13. Indeed, lasting phenotypic changes from previous metabolic states, that is, metabolic memory, have been reported in mouse adipose tissue (AT) or the stromal vascular fraction (SVF)14,15,16, whereas in liver these were reversible15,16,17. Persistent alterations after WL in the immune compartment18, and transcriptional and functional memory of obesity in endothelial cells of many organs19,20,21,22, have also been reported.
