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ObjectiveObesity-induced metabolic dysfunction, tissue remodelling, and chronic inflammation in visceral white adipose-tissue (WAT) are correlated with insulin resistance, type II diabetes, and metabolic disease pathogenesis [1]. In this work, we sought to establish spatio-temporal context of adipose tissue macrophage (ATM) reprogramming during obesity.MethodsWe captured single-cell RNA-sequencing, spatial transcriptomics, and histological imagining of murine WAT over the course of diet-induced obesity to study macrophage phenotype dynamics. We developed a straightforward mathematical approach to integrating multi-modal data to quantify obesityinduced changes to WAT organization. We aligned ATM phenotypes with crown-like structures (CLS) in early obesity and used spatial network analysis to uncover signalling mechanisms implicated in CLS formation.ResultsWe identified novel diversity of the lipid-associated macrophage (LAM) phenotype, whose transcriptional profile, signaling mechanisms, and spatial context serve as indicators of CLS formation in early obesity. We demonstrated that dysregulation of lipid-metabolic signalling is a critical turning point in the monocyte-LAM lineage and identified novel ligand-receptor mechanisms includingApoe, Lrp1, LplandAppthat serve as hallmarks of nascent CLS in WAT.ConclusionsMulti-modal spatio-temporal profiling demonstrates that LAMs disproportionately accumulate in CLS and are preceded by a transition-state macrophage phenotype with monocytic origins. We identified novel ligand-receptor interactions implicated in nascent CLS regions which may guide future cellular-reprogramming interventions for obesity-related sequelae.Graphical AbstractHighlights-We characterize a novel lipid-associated macrophage (LAM) phenotype along the monocyte-LAM lineage-Integrated imaging, single-cell sequencing and spatial transcriptomics data show that LAMs accumulate at nascent CLS-Analysis of spatial transcriptomics data reveals a novel set of ligands and receptors that implicate immature LAMs in shaping the CLS microenvironment in early obesity-We present a simple mathematical framework for studying dynamics of tissue-structure over time |
