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

We studied the opposing effects of exercise training and high-fat diet at single-cell resolution to reveal changes in cell type abundance, cell-type-specific gene expression/pathway/regulatory network changes, and changes in cell-cell communication both within and across tissues. We profiled scRNA-seq in 204,883 cells, grouped into 53 distinct cell sub-types/states across 22 major cell types, from subcutaneous white adipose tissue, visceral white adipose tissue, and skeletal muscle across 16 lean and 15 obese mice with both diet and exercise interventions. Changes in both cell proportion and transcriptional state were most strongly pronounced in adipose stem cells in fat, consistent with roles of adipogenesis in thermogenesis-vs-lipogenesis and hyperplasia-vs-hypertrophy in obesity. For immune cells, exercise training decreases obesity-associated inflammatory tissue-resident cell populations, including myeloid and regulatory T cells, and promotes beige-cell-inducing populations, including NKT cells. These changes clustered in common pathways across tissues for both exercise and obesity, including extracellular matrix remodelling and circadian rhythm in mesenchymal stem cells and cell activation/migration in immune cells. Overall design: Single-cell mRNA profiles of three metabolic tissues from 6-week old C57BL/6JN mice with 6-week high-fat diet and 3-week exercise training interventions