{"doi":"10.1101/2022.02.26.482134","title":"A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity","abstract":"ABSTRACT Objective Obesity-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. Methods We 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. Results We 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. Conclusions Multi-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 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","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299063,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9458,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":519364,"name":"Gabrielle A. Dotson","orcid":"0000-0001-6624-5332","position":1,"is_corresponding":false},{"id":988946,"name":"H.G. Pugh","orcid":null,"position":2,"is_corresponding":false},{"id":337050,"name":"Alnawaz Rehemtulla","orcid":"0000-0001-8291-3978","position":3,"is_corresponding":false},{"id":520046,"name":"Indika Rajapakse","orcid":null,"position":4,"is_corresponding":false},{"id":319902,"name":"Lindsey A. Muir","orcid":"0000-0002-1756-0325","position":5,"is_corresponding":false},{"id":749985,"name":"Cooper Stansbury","orcid":"0000-0003-2413-8314","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T00:31:40.528568Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}