Adipose tissue retains an epigenetic memory of obesity after weight loss [snRNAseq]

Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity. However, maintaining weight loss is a considerable challenge, especially as the body appears to retain an obesogenic memory that defends against body weight changes. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nuclei RNA-sequencing, we show that both human and mouse adipose tissue retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the mouse adipocyte epigenome, negatively affecting 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 based on stable epigenetic changes, in mouse adipocytes, and likely other cell types. These changes appear 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. Male C57BL/6J were subjected to high fat diet (HFD) feeding for 12 or 25 weeks while controls received low fat diet. Thereafter, obese mice were switched to chow diet for 8 weeks. Mice that had been on HFD for 12 weeks and lost weight during 8 weeks and their respective conrols, were subjected to 4 weeks HFD feeding. Epididymal adipose tissue at each time point from treated group and age matched controls was snap frozen and then used for snRNAseq. 5 mice were pooled per sample.