Adipose Tissue Plasticity and Cellular Crosstalk at Single-Cell Resolution during Regression of Obesity

Obesity with its comorbidities constitutes one of the largest global health issues, with the prevention of weight regain being a key challenge. Mounting evidence suggests that breakdown of white adipose tissue (WAT) function is a key driver of obesity comorbidities. However, it remains unclear to what extent the obesity-induced changes in WAT are reversible through weight loss or if persistent cellular and molecular signatures of obesity affect adipose tissue function and health after weight loss. 


The overarching aim of this PhD project was to gain in-depth insight into the cellular and molecular dynamics of WAT depots during obesity development and regression, and to identify potential lingering signatures of the obese state. Using a mouse model of dietinduced obesity and subsequent weight loss, we applied an integrated approach that included metabolic profiling, histological and cytological analyses, bulk RNA-seq, and snRNA-seq to investigate the plasticity of epididymal and inguinal WAT (eWAT and iWAT).


By employing snRNA-seq on nuclei isolated from eWAT of lean and obese mice, we conducted the first comprehensive single-cell-resolved study of all WAT cell types. This enabled the identification of novel subtypes of mature adipocytes and revealed obesityinduced shifts in cellular compositions and gene expression profiles, particularly increased inflammatory responses and altered adipocyte subpopulations. Crucially, we were able to reconstruct a transcriptional trajectory of in vivo adipogenesis.


We developed a robust protocol for isolating nuclei from both fresh and frozen WAT, applicable across different depots and obesity states. This protocol is a valuable resource for unbiased single-cell genomic profiling of adipose cell types.


Our weight loss study showed that, although obesity-induced changes in the metabolic phenotype were largely restored by weight loss, a low level of inflammation persisted within eWAT even after sustained weight loss. This was observed both as elevated CLS density, inflammatory gene expression, and shifts in macrophage subpopulations. Interestingly, the degree of eWAT inflammation varied among mice and correlated with adiposity levels, particularly the weight of iWAT.


The work presented in this thesis provides novel insights into the cellular and molecular dynamics of WAT plasticity during obesity development and regression. Our findings highlight the complexity of tissue remodelling in response to weight gain and loss and reveal persistent signatures of the obese state.