Single-nucleus RNA sequencing Resolves Microenvironmental Dynamics in Brown/Beige Adipose Tissue after Bariatric Surgery
Obesity, a chronic disease marked by pathological adipose expansion, drives systemic comorbidities such as type 2 diabetes, cardiovascular disease, and cancer, severely impairing quality of life. Bariatric surgery remains the most effective intervention for sustained weight loss and metabolic improvement, yet the mechanisms underlying adipose tissue remodeling post-surgery remain poorly understood. Using single-cell RNA sequencing, we generated high-resolution transcriptional maps of murine brown adipose tissue (BAT) and beige adipose tissue pre- and post-bariatric surgery, uncovering dynamic microenvironmental shifts. Following surgery, both BAT and beige adipose tissues displayed a notable expansion of myofibroblast (myoFB) populations and a parallel reduction in adipocytes (AP). Cell communication analysis via CellChat revealed enhanced AP-myoFB crosstalk mediated by IGF1 signaling activation, alongside suppression of VEGF pathway interactions between AP and endothelial cells (EC). Pseudotemporal trajectory analysis identified an AP subpopulation (AP6) enriched in fibrosis-associated genes (Zbtb16, Fkbp5) that progressively upregulated 11 genes during differentiation toward myoFB. Spatial correlation analysis further demonstrated co-localization of these genes with Igf1r in myoFBs. Collectively, this work delineates surgery-induced microenvironmental reprogramming in thermogenic adipose depots and proposes a novel mechanism whereby 11 potential transition regulators synergize with IGF1 signaling to drive AP6-myofibroblast transdifferentiation. Overall design: A total of four samples were included in this study, with two derived from brown adipose tissue (BAT) and the other two from beige adipose tissue (BeAT). Within each adipose tissue group (BAT or BeAT), the two samples were further categorized into either a high-fat diet surgical intervention group (HFD-operated) or a high-fat diet sham surgery control group (HFD-sham).