Effects of exercise training on subcutaneous adipose tissue cellular heterogeneity in adults with obesity - PROJECT SUMMARY Obesity is associated with impaired lipid storage in abdominal subcutaneous adipose tissue (ASAT), leading to excessive fatty acid release, ectopic fat accumulation, and insulin resistance. Identifying mechanisms that contribute to impaired lipid storage and developing strategies to enhance ASAT function are critical for improving metabolic health in individuals with obesity. While endurance training has been shown to induce beneficial adaptations in adipose tissue and improve lipid storage capacity, the cellular and molecular mechanisms remain unclear. My preliminary findings from single-nucleus RNA sequencing (snRNAseq) have identified a unique adipocyte subtype, Adipocyte-2, enriched with insulin-responsive and lipogenic genes and associated with improved metabolic health markers, including lower ectopic fat and higher endothelial cell abundance. Additionally, my ex vivo data demonstrate adipocyte heterogeneity in insulin-stimulated lipid uptake, suggesting that Adipocyte-2 may be a metabolically favorable subtype with enhanced lipid storage capacity. Building upon these findings, this project will determine whether a 3-month endurance training intervention, independent of weight loss, improves Adipocyte-2 abundance, transcriptional profile, and spatial localization, contributing to improved lipid storage and cardiometabolic health in adults with obesity. Aim 1 will assess the relationship of Adipocyte-2 abundance, transcriptional profile, and spatial localization with insulin sensitivity, along with its ex vivo lipid uptake capacity, using ASAT microdialysis during a hyperinsulinemic clamp and functional adipocyte assays. Aim 2 will investigate whether 3 months of endurance training increases Adipocyte-2 abundance and transcriptional profile and alters its spatial positioning within ASAT, specifically in relation to endothelial cells, pericytes, and macrophages, and how these adaptations contribute to improved cardiometabolic health. By integrating clinical exercise interventions with advanced molecular techniques, including snRNAseq, spatial transcriptomics, and functional assays, this project will define the role of adipocyte heterogeneity in exercise-induced metabolic adaptations. Under the mentorship of Dr. Lauren Sparks, an expert in human translational metabolism, and a collaborative team of specialists in metabolism and bioinformatics, this training plan will provide me with the skills and expertise necessary to establish an independent research career focused on exercise, adipose tissue function, and cardiometabolic health.
