{"doi":"10.1016/j.molmet.2024.101894","title":"β-cell Jagged1 is sufficient but not necessary for islet Notch activity and insulin secretory defects in obese mice","abstract":"Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin secretory defects in obese mice. We assessed expression of Notch pathway components in high-fat diet-fed (HFD) or leptin receptor-deficient (db/db) mice, and performed single-cell RNA sequencing (scRNA-Seq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, β cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets. Jag1 was the only Notch ligand that tracked with increased Notch activity in HFD-fed and db/db mice, as well as in metabolically-inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from HFD-fed and db/db mice potentiated GSIS ex vivo. To demonstrate if β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic (β-Jag1TG) and loss-of-function (iβ-Jag1KO) mice. While forced Jagged1 impaired glucose intolerance due to reduced GSIS, loss of β cell Jagged1 did not protect against HFD-induced insulin secretory defects. Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that β cells are not a likely source of the Jagged1 signal.","journal":"Molecular Metabolism","year":2024,"id":464740,"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":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":315356,"name":"Alberto Bartolomé","orcid":"0000-0002-3382-0553","position":1,"is_corresponding":false},{"id":571929,"name":"Jiani Liang","orcid":null,"position":2,"is_corresponding":false},{"id":458943,"name":"Jinsook Son","orcid":"0000-0002-0836-2626","position":3,"is_corresponding":false},{"id":283456,"name":"Yoko Yagishita","orcid":null,"position":4,"is_corresponding":false},{"id":226257,"name":"Christian W. Siebel","orcid":"0000-0003-4333-3756","position":5,"is_corresponding":false},{"id":104004,"name":"Domenico Accili","orcid":"0000-0002-6874-3949","position":6,"is_corresponding":false},{"id":491708,"name":"Hongxu Ding","orcid":"0000-0002-7846-9744","position":7,"is_corresponding":false},{"id":109694,"name":"Utpal B. Pajvani","orcid":"0000-0001-5991-2723","position":8,"is_corresponding":false},{"id":914878,"name":"Nina Suda","orcid":null,"position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:04:42.082401Z","pmid":"38311286","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":[]}