Human white adipose tissue undergoes major remodelling during sustained weight gain that may compromise tissue function and drive cardiometabolic comorbidities. Although weight loss reverses many of these complications, the cellular and molecular adaptations of adipose tissue to different weight loss interventions are poorly understood. Here we profiled abdominal subcutaneous adipose tissue (SAT) from men and women living with severe obesity using single-nucleus RNA sequencing (snRNA-seq). Biopsies from the same individuals were collected at baseline, after modest lifestyle-induced (8–10%) weight loss, and again after bariatric surgery-induced (20–45%) weight loss. Lifestyle-induced weight loss activated proadipogenic gene programmes in progenitor cells, indicating early beneficial effects on SAT. Subsequent surgery-induced weight loss drove profound compositional and transcriptional remodelling of SAT, including increased vascularization and marked reduction of myeloid cell populations. Collectively, our study indicates that following major and sustained weight loss, SAT from individuals with severe obesity has the capacity to return to a state comparable to that observed in lean individuals.
