Single-cell dissection of obesity-exercise axis in adipose-muscle tissues

Abstract

Regular physical exercise has long been recognized to reverse the effects of diet-induced obesity, but the molecular mechanisms mediating these multi-tissue beneficial effects remain uncharacterized. Here, we address this challenge by studying the opposing effects of exercise training and high-fat diet at single-cell, deconvolution and tissue-level resolutions across 3 metabolic tissues. We profile scRNA-seq in 204,883 cells, grouped into 53 distinct cell subtypes/states in 22 major cell types, from subcuta-neous and visceral white adipose tissue (WAT), and skeletal muscle (SkM) in mice with diet and exercise training interventions. With a great number of mesenchymal stem cells (MSCs) profiled, we compared depot-specific adipose stem cell (ASC) states, and defined 7 distinct fibro-adipogenic progenitor (FAP) states in SkM including discovering and validating a novel CD140+/CD34+/SCA1-FAP population. Exercise- and obesity-regulated proportion, transcriptional and cell-cell interaction changes were most strongly pronounced in and centered around ASCs, FAPs, macrophages and T-cells. These changes reflected thermogenesis-vs-lipogenesis and hyperplasia-vs-hypertrophy shifts, clustered in pathways including extracellular matrix remodeling and circadian rhythm, and implicated complex single- and multi-tissue communication including training-associated shift of a cytokine from binding to its decoy receptor on ASCs to true receptor on M2 macrophages in vWAT. Overall, our work provides new insights on the metabolic protective effects of exercise training, uncovers a previously-underappreciated role of MSCs in mediating tissue-specific and multi-tissue effects, and serves as a model for multitissue single-cell analyses in physiologically complex and multifactorial traits exemplified by obesity and exercise training.

Single-cell analysis of white adipose tissue reveals the tumor-promoting adipocyte subtypes

“…Lastly, we asked whether transcription factors (TFs) contribute to the phenotypic state of these subpopulations (Figure 2H). It is reported that transcriptional diversity decreases during differentiation [27]. Our results con rmed that mA3 and mA4, rather than mA5 showed increased transcriptional diversity, consistent with their earlier differentiation state.…”

Organism-wide secretome mapping uncovers pathways of tissue crosstalk in exercise

“…Our studies suggest that many more cell types respond to exercise than previously recognized, including Pdgfra + cells distributed to multiple organ systems. Recent reports using single cell RNA-sequencing showed that exercise regulation in adipose was most strongly pronounced in adipose stem cells (Yang et al, 2021), which are defined by the expression of Pdgfra + (Shin et al, 2020). These adipose-resident fibroblasts may indeed correspond to a subset of the Pdgfra + cells identified in our secretome profling dataset.…”