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.
Institut(e)Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
FörderungenETH Zurich core funding European Research Council Starting Grant Basel Research Centre for Child Health (Multi-Investigator Project 2020) Deutsche Forschungsgemeinschaft Margareta af Ugglas foundation Swedish Research Council European Research Council Synergy Grant Novo Nordisk Foundation Knut and Alice Wallenberg's Foundation (Wallenberg Clinical Scholar) Center for Innovative Medicine Swedish Society for Medical Research Swedish Diabetes Foundation Stockholm County Council Strategic Research Program in Diabetes at Karolinska Institutet European Foundation for the Study of Diabetes