Transcriptional and metabolic changes following repeated fasting and refeeding of adipose stem cells highlight adipose tissue resilience

Background: Obesity and related metabolic disorders have reached epidemic levels, calling for diverse therapeutic strategies. Altering nutrient intake, timing and quantity by intermittent fasting seem to elicit beneficial health effects by modulating endocrine and cell signaling net-works. This study explores the impact of cyclic nutrient availability in the form of every-other-day fasting (EODF) on human adipose stem cells (ASCs). Methods: We subjected ASCs to repeated fasting/refeeding (F/R) cycles, mimicking low glucose/high fatty acid (LGHF) conditions, and assessed phenotypic and transcriptomic changes, lipid storage capacity, insulin sensitivity and differentiation potential. Results: Four consecutive F/R cycles induced significant changes in ad-ipogenic gene expression, with upregulation of FABP4 and PLIN1 during fasting, and increased lipid storage in the ASCs. Upon differentiation, ASCs exposed to LGHF conditions retained a transient increase in lipid droplet size and altered fatty acid metabolism gene expression until day 9. However, these changes dissipated by day 15 of differentiation, suggesting a limited duration of fasting-induced transcriptional and adipogenic memory. Despite initial effects, ASCs showed re-silience, returning to a physiological trajectory during differentiation, with respect to gene ex-pression and lipid metabolism. Conclusions: These findings suggest that the long-term effects of EODF on the ASC niche may be transient; emphasizing the ability of the adipose tissue to adapt and restore homeostasis.