Exercise Training Remodels Inguinal White Adipose Tissue Through Adaptations in Innervation, Vascularization and the Extracellular Matrix

Abstract

Inguinal subcutaneous white adipose tissue (iWAT) is essential for conferring the beneficial effects of exercise training on metabolic health. Training alters adipocyte function, yet how the structural components of iWAT respond to training is not known. Using multi-omics approaches, we show that training in male mice results in iWAT remodeling, decreasing extracellular matrix (ECM) deposition, and increasing vascularization and innervation. We find adipose stem cells (ASC) to be the main ECM contributors and show an exercise-induced shift from hypertrophic to insulin sensitive adipocyte subpopulations. We demonstrate a critical role of the PRDM16 transcriptional complex in training-induced tissue remodeling, and propose a link between PRDM16 and neuronal growth regulator1 (NEGR1) in regulating neuritogenesis in trained iWAT. Combined, the major cellular and structural adaptations to iWAT induced by exercise training give rise to a remarkably flexible and multitasking tissue with a key role in modulating metabolic health.

Exercise Training and Cold Exposure Trigger Distinct Molecular Adaptations to Inguinal White Adipose Tissue

“…We utilized the 10x Genomics Visium Spatial Gene Expression platform (10x Genomics, Pleasanton, CA, USA) for our spatial transcriptomics analysis. As previously described, the experiment involved the utilization of paraffin-embedded inguinal white adipose tissue (iWAT) obtained from sedentary and trained mice 4 . The Visium Spatial Gene Expression procedure was conducted following the manufacturer’s instructions (10x Genomics, Pleasanton, CA, USA) with the following parameters: adipose tissue sections of 20 μm thickness were used, and hematoxylin and eosin (H&E) staining was performed by immersing the slides in isopropanol for 1 minute, followed by a 3-minute incubation in hematoxylin and a 30-second incubation in eosin (diluted at 1:20).…”

“…Additionally, the proteins were filtered to maintain an FDR of less than 1%. Protein quantification was performed exclusively on peptides with a summed signal-to-noise (SN) threshold greater than 200 and an MS2 isolation specificity of 0.5.The mass spectrometry proteomics data were previously deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD040894 4 .…”

“…As previously described 4 , for the analysis of the secretome, we employed Quantitative Immunoprecipitation (Quant-IP) analysis. To begin, 20 mg of inguinal white adipose tissue (iWAT) was subjected to three washes with 1X phosphate-buffered saline (PBS).…”

“…We utilized the 10x Genomics Visium Spatial Gene Expression platform (10x Genomics, Pleasanton, CA, USA) for our spatial transcriptomics analysis. As previously described, the experiment involved the utilization of paraffin-embedded inguinal white adipose tissue (iWAT) obtained from sedentary and trained mice 4 . The Visium Spatial Gene Expression procedure was conducted following the manufacturer's instructions (10x Genomics, Pleasanton, CA, USA) with the following parameters:…”

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

“…The findings by these authors emphasize the importance of physical activity in alleviating obesity (4). It has been shown that exercise acts as an effective stimulus of Inguinal white adipose tissue (iWAT) remodeling primarily through changes in extracellular matrix (ECM), vascularization, and innervation (5).…”