{"doi":"10.2337/db22-0444","title":"Adipocyte-Secreted IL-6 Sensitizes Macrophages to IL-4 Signaling","abstract":"Complex bidirectional cross talk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies have suggested that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflammation. Here, we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue immune cells. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. We report that in this context, adipocyte-secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow-derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in adipose tissue are complex and context specific. These results suggest that cAMP-driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.","journal":"Diabetes","year":2022,"id":244119,"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":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"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":646181,"name":"Benyamin Dadpey","orcid":"0000-0002-6253-7167","position":1,"is_corresponding":false},{"id":877940,"name":"Jessica Zaid","orcid":null,"position":2,"is_corresponding":false},{"id":877941,"name":"Pania E. Bridge-Comer","orcid":null,"position":3,"is_corresponding":false},{"id":646180,"name":"Julia H. DeLuca","orcid":"0000-0001-5765-6834","position":4,"is_corresponding":false},{"id":716505,"name":"Wenmin Xia","orcid":"0000-0002-8963-4338","position":5,"is_corresponding":false},{"id":877294,"name":"Joshua Castle","orcid":"0000-0002-6006-5397","position":6,"is_corresponding":false},{"id":267913,"name":"Shannon M. Reilly","orcid":"0000-0003-0412-2446","position":7,"is_corresponding":false},{"id":510045,"name":"Danny Luan","orcid":"0000-0002-1167-1307","position":0,"is_corresponding":true}],"reference_count":22,"raw_metadata":null,"created_at":"2026-07-19T00:23:25.718788Z","pmid":"36449000","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":[]}