Obesity disrupts innate-adaptive immune network patterning in adipose tissue

Abstract

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 including Apoe, Lrp1, Lpl and App that 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 Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/482134v6_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1d7ac5borg.highwire.dtl.DTLVardef@74c5c7org.highwire.dtl.DTLVardef@64b722org.highwire.dtl.DTLVardef@33392e_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- 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