Regular physical exercise is critical for the prevention and treatment of obesity. Dissecting the underlying molecular mechanisms that mediate these beneficial effects of exercise has been challenging because of the technical barriers to simultaneously investigate heterogeneous responses on the molecular, cell type-specific, and cross-tissue levels. Here, we address this challenge by studying the opposing effects of exercise training and high-fat diet induced obesity 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 subcutaneous and visceral white adipose tissue (WAT), and skeletal muscle (SkM) in mice with diet and exercise training interventions. Despite the complex responses observed, we identify a prominent role of mesenchymal stem cells (MSCs) in mediating the exercise and obesity-induced adaptations in each tissue. Adipose stem cells (ASCs, the MSCs for WAT), show distinct profiles for scWAT compared to vWAT in terms of transcriptional diversity and regulons. In SkM we identify seven distinct fibro-adipogenic progenitors (FAPs, MSCs for SkM) including discovery and validation of a novel SCA1- FAP population. Among the pathways regulated by exercise and high-fat diet in MSCs across the three tissues, extracellular matrix remodeling and circadian rhythm are the most prominent. Cell-cell interactions also implicate complex within- and multi-tissue crosstalk centered around MSCs. Overall, our work reveals the intricacies and diversity of multi-tissue molecular responses to exercise training and obesity and uncovers a previously underappreciated role of MSCs in mediating tissue-specific and multi-tissue effects.
Jiekun Yang, Maria Vamvini, Pasquale Nigro, Li-Lun Ho, Kyriakitsa Galani,
Marcus Alvarez, Yosuke Tanigawa, Ashley Renfro, Nicholas P. Carbone, Markku
Laakso, Leandro Z. Agudelo, Päivi Pajukanta, Michael F. Hirshman, Roeland J.W.
Middelbeek, Kevin Grove, Laurie J. Goodyear, Manolis Kellis,
Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues
implies a critical role for mesenchymal stem cells, Cell
Metabolism, Volume 34, Issue 10, 2022, Pages 1578-1593.e6, ISSN 1550-4131,
This webpage was made using ShinyCell