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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE183288 | GEO | 2022/10/13

REPOSITORIES: GEO

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Project description:Background and aim: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C (PKC) signaling by converting DAG to phosphatidic acid (PA). We have reported that downregulation of DGKδ (type II isozyme) causes peripheral insulin resistance, metabolic inflexibility, and obesity. Our aim was to determine whether overexpression of DGKδ protects against the development of metabolic impairments and obesity. Methods: We generated a transgenic mouse model overexpressing the human DGKδ2 isoform under the myosin light change promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG and wild-type mice fed chow or high-fat diet. Mice were also given free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes. Results: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance, increased glycogen storage in skeletal muscle, and enhanced glucose uptake in white adipose tissue. Moreover, DGKδ TG mice were protected against high fat diet (HFD)-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat pad weight, and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulates the beneficial effects exercise on metabolic outcomes. DGKδ overexpression and exercise have a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle confirmed an overlap between genes associated with exercise and DGKδ overexpression. Gene ontology signatures of exercise and DGKδ overexpression were related to lipid storage, extracellular matrix, and glycogen biosynthesis pathways. Conclusion: We identify a role for DGKδ in glucose and energy homeostasis. Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against high fat diet-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.

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

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