Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells

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

doi:10.1016/j.cmet.2022.09.004

Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells

Cell Metab. 2022 Oct 4;34(10):1578-1593.e6. doi: 10.1016/j.cmet.2022.09.004.

Authors

Jiekun Yang¹, Maria Vamvini², Pasquale Nigro², Li-Lun Ho¹, Kyriakitsa Galani¹, Marcus Alvarez³, Yosuke Tanigawa¹, Ashley Renfro¹, Nicholas P Carbone², Markku Laakso⁴, Leandro Z Agudelo¹, Päivi Pajukanta⁵, Michael F Hirshman², Roeland J W Middelbeek², Kevin Grove⁶, Laurie J Goodyear⁷, Manolis Kellis⁸

Affiliations

¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
³ Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
⁵ Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Novo Nordisk Research Center, Seattle, WA, USA.
⁷ Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
⁸ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: [email protected].

Abstract

Exercise training is critical for the prevention and treatment of obesity, but its underlying mechanisms remain incompletely understood given the challenge of profiling heterogeneous effects across multiple tissues and cell types. Here, we address this challenge and opposing effects of exercise and high-fat diet (HFD)-induced obesity at single-cell resolution in subcutaneous and visceral white adipose tissue and skeletal muscle in mice with diet and exercise training interventions. We identify a prominent role of mesenchymal stem cells (MSCs) in obesity and exercise-induced tissue adaptation. Among the pathways regulated by exercise and HFD in MSCs across the three tissues, extracellular matrix remodeling and circadian rhythm are the most prominent. Inferred cell-cell interactions implicate within- and multi-tissue crosstalk centered around MSCs. Overall, our work reveals the intricacies and diversity of multi-tissue molecular responses to exercise and obesity and uncovers a previously underappreciated role of MSCs in tissue-specific and multi-tissue beneficial effects of exercise.

Keywords: circadian rhythm pathway; exercise; extracellular matrix remodeling; mesenchymal stem cell; multi-tissue crosstalk; obesity; single-cell atlas; skeletal muscle; white adipose tissue; within-tissue crosstalk.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adipose Tissue* / metabolism
Animals
Diet, High-Fat
Mesenchymal Stem Cells* / metabolism
Mice
Mice, Inbred C57BL
Muscle, Skeletal / metabolism
Obesity / metabolism

Abstract

Publication types

MeSH terms

Grants and funding