Many people have tried dietary changes, lifestyle interventions, medications, and bariatric surgery, and other methods for managing their obesity. While they may help in the short term, the “obesogenic” metabolic memory causes many of them to put the weight back on.
A recent study in Nature suggests that the epigenome plays a critical role in driving the long-lasting obesogenic metabolic memory, making it hard to keep weight off after obesity treatment. Researchers primarily based in ETH Zurich demonstrated that the epigenome of cells in adipose tissue of mice and humans with obesity goes unchanged upon weight loss, which correlates with transcriptional and physiological changes. Furthermore, this impression on the epigenome primes mice that had previously experienced obesity for accelerated weight gain and future transcriptional dysregulation when exposed to high-fat diets.
These results have far-reaching consequences, including the possibility of new therapeutic directions and an explanation for why some people experience weight gain after taking GLP-1 receptor agonists like semaglutide or tirzepatide.
Obesity creates lasting epigenome changes
Despite prior efforts to investigate epigenetics’ role in obesity—and the identification of chromatin and DNA methylation alterations linked to obesity—human studies have yet to resolve cell type variations in adipose tissue during weight loss and regain. Considering the lack of information and the significance of epigenetic pathways for adipocyte differentiation and identity, a group of researchers headed by co-authors Daniel Castellano-Castillo and Laura C. Hinte set out to discover how epigenetics keeps the metabolic memory in adipocytes during weight loss and gain.
Hinte and Castellano-Castillo analyzed fat tissue samples obtained from individuals who with obesity before and following bariatric surgery, in addition to samples from individuals who were of a healthy weight. Using single-nucleus RNA sequencing, they discovered transcriptional changes in adipocytes, endothelial cells, and adipocyte progenitor cells (APCs) that persisted after subjects with obesity underwent bariatric surgery and lost weight. More specifically, obesity-induced genes remained deregulated, with downregulated metabolic genes and upregulated fibrosis and apoptosis-related genes, implying that obesity causes molecular changes in adipose tissue that weight loss cannot fully reverse.
The researchers then used a mouse model to investigate the molecular mechanisms of metabolic memory in obesity. Mice fed a high-fat diet for 12 or 15 weeks were then given a standard chow diet, allowing them to lose weight. Using this model, the researchers examined the molecular alterations in epididymal adipose tissue that persist after weight loss using snRNA-seq, translational profiling, and other sequencing-based epigenetic readouts. Like the human data, Hinte and Castellano-Castillo discovered that upon weight loss, adipocytes from mice maintained an upregulation of inflammatory- and extracellular matrix remodeling-related pathways. In contrast, adipocyte-specific metabolic pathways remained downregulated, mirroring the findings from human adipocytes.
Furthermore, the researchers found that adipocyte promoters and enhancers retained an epigenetic memory upon weight loss, which could explain the persistent translational obesity-associated changes after weight loss. Notably, 57–62% of downregulated and 68–75% of upregulated persistent translational differentially expressed genes after weight loss could be accounted for by one or more of the analyzed epigenetic modalities. Overall, these results strongly suggest the presence of stable cellular, epigenetic, and transcriptional memory in mouse adipocytes that persists after weight loss.
Therapeutic implications for obesity
While GLP-1 receptor agonists such as semaglutide or tirzepatide have emerged as a promising non-invasive strategy for significant weight loss, the extent to which these agonists cause long-term weight loss and physiological changes in humans beyond withdrawal is poorly understood. Studies on semaglutide and tirzepatide have shown that substantial weight regain occurs after their withdrawal, indicating that at least these treatments do not induce stable, persistent changes. Whether this is also the case for other GLP-1 receptor agonists remains to be investigated.
A putative obesogenic epigenetic memory in adipocytes and potentially other cells suggests new therapeutic avenues to improve weight loss maintenance in humans. Further studies are needed to elucidate whether these treatments could erase or diminish an obesogenic memory better than other non-surgery-based weight loss strategies.
