{"doi":"10.1101/2020.12.03.408716","title":"Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity","abstract":"ABSTRACT In obesity, overexpression of the IRE1-regulated transcription factor XBP1s protects against metabolic dysfunction by stimulating adaptive remodeling of multiple tissues, most notably the liver. 1–5 This observation suggests that pharmacologically increasing IRE1/XBP1s signaling might be an attractive approach to mitigate pathologies in obesity and its associated complications. 6–8 Here, we tested this notion by treating diet-induced obese (DIO) mice with the pharmacologic IRE1/XBP1s activator IXA4. 9 We show that IXA4 treatment selectively activated protective IRE1/XBP1s signaling in livers of DIO mice without inducing obesity-linked pathologies associated with IRE1 hyperactivity, such as liver inflammation and fibrosis. 10,11 Chronic IXA4 treatment improved systemic glucose metabolism and feeding-induced insulin action in the liver of DIO mice. These improvements were linked to IRE1/XBP1s-induced remodeling of the liver transcriptome, which dampened glucose production and reduced hepatic steatosis. Further, we show that IXA4 treatment enhanced pancreatic β cell function and insulin homeostasis, indicating that systemic activation of IRE1/XBP1s signaling engendered multi-tissue benefits that integrated to mitigate systemic metabolic dysfunction in DIO mice. Our findings show that selective pharmacological activation of protective IRE1/XBP1s signaling reprograms multiple metabolic tissues, such as liver and pancreas, and represents a potential strategy to correct metabolic alterations in obesity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":119947,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":333478,"name":"Bernard P. Kok","orcid":"0000-0002-9073-9700","position":1,"is_corresponding":false},{"id":249868,"name":"Julia M. D. Grandjean","orcid":"0000-0002-9247-5841","position":2,"is_corresponding":false},{"id":556170,"name":"Verena Albert","orcid":"0000-0001-7676-5403","position":3,"is_corresponding":false},{"id":556171,"name":"Ara Sukiasyan","orcid":"0000-0001-9192-5276","position":4,"is_corresponding":false},{"id":556172,"name":"Bibiana Rius","orcid":"0000-0003-3325-2653","position":5,"is_corresponding":false},{"id":249873,"name":"Evan T. Powers","orcid":"0000-0001-8185-8487","position":6,"is_corresponding":false},{"id":556173,"name":"Andrea Galmozzi","orcid":"0000-0002-9411-7327","position":7,"is_corresponding":false},{"id":333485,"name":"Enrique Sáez","orcid":"0000-0001-5718-5542","position":8,"is_corresponding":false},{"id":141781,"name":"R. Luke Wiseman","orcid":"0000-0001-9287-6840","position":9,"is_corresponding":false},{"id":252756,"name":"Aparajita Madhavan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:14:13.002105Z","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":[]}