The age-old saying “a moment on the lips, forever on the hips” just got a modern update thanks to an epigenome-based study of obesity! New research now describes the existence of epigenetic memory in the adipose tissue of obese individuals that persists after significant weight loss.
A team led by Ferdinand von Meyenn (ETH Zurich) sought to understand a significant challenge to maintaining weight loss – the retention of an “obesogenic” memory – via single-cell transcriptomic/epigenetic analyses in human/mouse adipose tissues before and during obesity and after weight loss. Their findings – that adipose tissue retains obesity-associated transcriptional and epigenetic alterations after weight loss – may help end the never-ending weight-loss journeys of some and significantly improve metabolic health and related comorbidities.
Let’s hear from Hinte and colleagues on the discovery of epigenetic obesogenic memory in adipocytes:
- snRNA-seq in human adipose tissue reveals persistent obesity-induced gene expression deregulation after weight loss
- snRNA-seq in adipocytes describes the persistent downregulation of adipocyte metabolism/functional pathways and upregulated fibrotic/apoptotic pathways in obese individuals after weight loss
- Analysis of a mouse model of obesity/weight loss suggests that obese-related pathophysiology resolves after weight loss, although the transcriptional memory of obesity persists (mirroring human adipocytes)
- Analysis of H3K27me3 and H3K4me3 via CUT&Tag at gene promoters in mouse adipose tissue (indicating genes’ transcriptional status) reveals the presence of obesity-induced promoter dysregulation at the epigenetic level that persists after weight loss
- Promoters persistently epigenetically repressed map to adipocyte function-related genes, while promoters persistently active map to genes involved in extracellular matrix remodeling and inflammatory signaling
- Analysis of enhancers via H3K27ac/H3K4me1 levels and chromatin accessibility (via ATAC-seq) in mouse adipose tissue demonstrate the gain of “new” H3K4me1-modified active enhancers during obesity that persist after weight loss and modulate the expression of genes, which results in a persistent shift toward an inflammatory, less-adipogenic identity
- Subsequent studies using cultured mouse adipocytes reveal altered glucose/lipid uptake and adipogenesis, demonstrating that the epigenetic memory primes mature adipocytes to respond differently to nutritional stimuli
- Analyses in mice found that after weight loss, mice gain weight more rapidly (accelerated “rebound” or “yo-yo” weight gain) and display transcriptional deregulation in response to a high-fat diet
Overall, adipose tissue retains an obesogenic epigenetic memory that primes cells for pathological responses when the dieting stops (prompting the oft-observed ‘yo-yo’ effect). Knowledge of this novel epigenetic mechanism may provide a means to improve long-term weight management and health outcomes through complementary therapies.
For more on how an epigenetic mechanism helps adipocytes remember their obese past and influences future weight loss, see Nature, November 2024.