Single-nucleus RNA sequencing resolves microenvironmental dynamics in brown/beige adipose tissue after bariatric...

Obesity is a chronic condition characterized by excessive adipose tissue accumulation, which significantly contributes to a range of systemic comorbidities, including type 2 diabetes, cardiovascular diseases, and various forms of cancer. These associated health issues severely compromise individuals' quality of life and pose substantial challenges for public health. Despite the known benefits of bariatric surgery as the most effective intervention for achieving sustained weight loss and improving metabolic profiles, the underlying biological mechanisms that facilitate adipose tissue remodeling following surgical intervention remain inadequately understood.

In this study, we employed single-nucleus RNA sequencing to construct high-resolution transcriptional maps of murine brown adipose tissue (BAT) and beige adipose tissue both before and after bariatric surgery. This comprehensive analysis allowed us to explore dynamic changes in the adipose tissue microenvironment post-surgery.

Our findings revealed a significant post-surgical expansion of fibroblastoid (FBO) populations in both BAT and beige adipose tissues. This expansion was accompanied by a marked reduction in adipocytes (AP). To further understand the cellular interactions underlying these changes, cell communication analysis was conducted through the CellChat platform. This analysis indicated enhanced crosstalk between adipocytes and fibroblastoid cells, predominantly mediated by IGF1 signaling activation. In contrast, interactions involving the VEGF pathway between adipocytes and endothelial cells (EC) were suppressed. Moreover, pseudotemporal trajectory analysis identified a distinct subpopulation of adipocytes, termed AP6, that was enriched for fibrosis-associated genes and showed progressive upregulation of 11 genes along differentiation toward fibroblastoid states.

We delineate post-bariatric microenvironmental reprogramming in thermogenic adipose depots and highlight a candidate pathway in which 11 putative transition regulators cooperate with IGF1 signaling to promote AP6-cell transdifferentiation toward fibroblastoid lineages. These data nominate testable targets for therapeutic modulation of obesity and its complications. Given the limited sample size, findings are descriptive and hypothesis-generating; definitive lineage inference awaits validation by fate mapping or RNA-velocity in larger cohorts.