Endocrine Abstracts

Reducing body weight to improve metabolic health and other comorbidities is a primary goal in treating obesity. However, maintaining weight loss is a considerable challenge, especially as the body is believed to retain an obesogenic memory via biological imprinting of prior obese states that contributes to the defence of body weight. Yet, overcoming this hurdle to long-term effective treatment 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 visceral adipose tissue retain a cellular transcriptional memory after appreciable weight loss. Furthermore, we observed that the mouse adipocyte epigenome continues to bear obesity-induced alterations, negatively affecting adipocyte function. In mice adipocytes carrying this obesogenic epigenetic memory respond differently to nutritional stimuli, resulting in accelerated rebound weight gain. We find that the epigenetic memory can explain future transcriptional deregulation in response to further high-fat diet feeding. Together, our data suggests the existence of an obesogenic memory in adipocytes, and likely other cells, largely based on stable epigenetic changes. These changes appear to prime cells to respond in a pathological manner to an obesogenic environment and may contribute to the problematic "yo-yo" effect on body weight observed with dieting. Targeting these changes could potentially improve long-term weight management and health outcomes.