Abstract 18360: Single-Cell Analysis Reveals Insights Into Visceral Adiposity in Mice With Diabetes-Associated Atherosclerosis

Abstract

Introduction: - Visceral white adipose tissue (vWAT), once considered passive and uniform, is a dynamic and heterogeneous tissue involved in glucose and lipid metabolism and immune response. Changes in adipose tissue morphology, physiology, and cellular composition occur in response to dietary fat and carbohydrates, associated with insulin resistance, dyslipidemia, and type 2 diabetes. vWAT also has implications for vascular diseases such as atherosclerosis. However, the connection between vWAT metabolism and atherosclerosis in mouse models remains to be fully elucidated. Methods: - vWAT from male Ldlr -/- mice fed either a chow diet or high fat, high sucrose containing (HFSC) diet for 24 weeks were harvested. Single cell RNA sequencing, histology and immunofluorescence were used to analyze the cellular and transcriptomic profiles in the chow and HFSC groups. Results: - We identified distinct subpopulations of vascular endothelial cells (ECs), immune cells, and adipose stem and progenitor cells (ASPCs), revealing differences between healthy and diseased groups. Notably, we observed a significant increase in immune cell composition, accompanied by a decrease in ECs and progenitor cells in HFSC-fed mice. Within the macrophage population, we noted increased activated macrophages, B-cell derived macrophages, and collagen-expressing macrophage subclusters. In ECs, we observed increased lymphatic and vascular EC subgroups. Furthermore, inflammation and altered metabolism pathways were found in both macrophage and ECs. We identified novel markers, such as Lyz2 and Trem2, that were highly associated with diabetes associated atherosclerosis in male Ldlr -/- mice. Through cell-cell interaction analysis (CellChat), we discovered distinct interactions patterns associated with enriched pathways such as chemokine, Wnt, and BMP signaling in multiple cell types, including macrophages, mesothelial cells, ASPCs, pericytes, SMCs, and ECs. Conclusion: Our scRNAseq atlas reveals interactions amongst adipose cell types in lean and obese states, with the chemokine pathway emerging as a prominent player. This dataset serves as a valuable resource for studying genes and cell types involved in vWAT function in diabetes-associated atherosclerosis.