{"doi":"10.1126/sciimmunol.adl4909","title":"Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis","abstract":"Regulatory T cells (T regs ) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT T regs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2 hi VAT T reg subsets. T reg -specific deletion of Srebf2 , the master regulator of cholesterol homeostasis, selectively reduced ST2 hi VAT T regs , increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2 hi VAT T reg subsets after Srebf2 deletion. Srebf2 -mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2 hi VAT T reg accumulation. However, long-term high-fat diet feeding disrupted VAT T reg cholesterol homeostasis and impaired clonal expansion of the ST2 hi subset. Restoring T reg cholesterol homeostasis rescued VAT T reg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for T reg -targeted therapies in obesity-associated metabolic diseases.","journal":"Science Immunology","year":2025,"id":510708,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1367814,"name":"Chengyu Ye","orcid":"0009-0005-4109-6971","position":1,"is_corresponding":false},{"id":493863,"name":"Pulavendran Sivasami","orcid":"0000-0002-9816-8527","position":2,"is_corresponding":false},{"id":1367815,"name":"Roy Neal Mulpur","orcid":"0000-0001-7900-7288","position":3,"is_corresponding":false},{"id":1264008,"name":"Pamela P. Diaz-Saldana","orcid":"0000-0002-6630-4328","position":4,"is_corresponding":false},{"id":1367816,"name":"Amy Peng","orcid":"0009-0000-3487-2745","position":5,"is_corresponding":false},{"id":1368459,"name":"Miaoer Xu","orcid":null,"position":6,"is_corresponding":false},{"id":703577,"name":"Yeun-po Chiang","orcid":"0000-0003-0054-596X","position":7,"is_corresponding":false},{"id":1367817,"name":"Samara Moll","orcid":"0009-0007-9553-5399","position":8,"is_corresponding":false},{"id":683820,"name":"Dormarie E. Rivera-Rodriguez","orcid":"0000-0002-2091-4104","position":9,"is_corresponding":false},{"id":805469,"name":"Luisa Cervantes‐Barragán","orcid":"0000-0003-1662-7345","position":10,"is_corresponding":false},{"id":623483,"name":"Tuoqi Wu","orcid":"0000-0002-4003-1034","position":11,"is_corresponding":false},{"id":722335,"name":"Byron B. Au‐Yeung","orcid":"0000-0002-6446-9102","position":12,"is_corresponding":false},{"id":270265,"name":"Christopher D. Scharer","orcid":"0000-0001-7716-8504","position":13,"is_corresponding":false},{"id":270266,"name":"Mandy L. Ford","orcid":"0000-0001-6736-4421","position":14,"is_corresponding":false},{"id":240995,"name":"Haydn Kissick","orcid":"0000-0001-7624-5598","position":15,"is_corresponding":false},{"id":667810,"name":"Chaoran Li","orcid":"0000-0001-8103-9596","position":16,"is_corresponding":false},{"id":334125,"name":"Cody Elkins","orcid":"0000-0002-9788-5233","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-19T02:47:50.575618Z","pmid":"39792637","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":[]}