{"doi":"10.1016/j.molmet.2025.102097","title":"LGR4 is essential for maintaining β-cell homeostasis through suppression of RANK","abstract":"Loss of functional β-cell mass is a major cause of diabetes. Thus, identifying regulators of β-cell health is crucial for treating this disease. The Leucine-rich repeat-containing G-protein-coupled receptor (GPCR) 4 (LGR4) is expressed in β-cells and is the fourth most abundant GPCR in human islets. Although LGR4 has regenerative, anti-inflammatory, and anti-apoptotic effects in other tissues, its functional significance in β-cells remains unknown. We have previously identified Receptor Activator of Nuclear Factor Kappa B (NFκB) (RANK) as a negative regulator of β-cell health. In this study, we assessed the regulation of Lgr4 in islets, and the role of LGR4 and LGR4/RANK stoichiometry in β-cell health under basal and stress-induced conditions, in vitro and in vivo . We evaluated Lgr4 expression in mouse and human islets in response to acute (proinflammatory cytokines), or chronic (high fat fed mice, db/db mice, and aging) stress. To determine the role of LGR4 we employed in vitro Lgr4 loss and gain of function in primary rodent and human β-cells and examined its mechanism of action in the rodent INS1 cell line. Using Lgr4 fl/fl and Lgr4 fl/fl / Rank fl/fl x Ins1 -Cre mice we generated β-cell-specific conditional knockout (cko) mice to test the role of LGR4 and its interaction with RANK in vivo under basal and stress-induced conditions. Lgr4 expression in rodent and human islets was reduced by multiple stressors. In vitro , Lgr4 knockdown decreased proliferation and survival in rodent β-cells, while overexpression protected against cytokine-induced cell death in rodent and human β-cells. Mechanistically, LGR4 protects β-cells by suppressing RANK- Tumor necrosis factor receptor associated factor 6 (TRAF6) interaction and subsequent activation of NFκB. Lgr4 cko mice exhibit normal glucose homeostasis but increased β-cell death in both sexes and decreased β-cell proliferation and maturation only in females. Male Lgr4 cko mice under stress displayed reduced β-cell proliferation and a further increase in β-cell death. The impaired β-cell phenotype in Lgr4 cko mice was rescued in Lgr4 / Rank double ko (dko) mice. Upon aging, both male and female Lgr4 cko mice displayed impaired β-cell homeostasis, however, only female mice became glucose intolerant with decreased plasma insulin. These data demonstrate a novel role for LGR4 as a positive regulator of β-cell health under basal and stress-induced conditions, through suppressing the negative effects of RANK. • Lgr4 mRNA levels are reduced in islets/β-cells in response to acute (proinflammatory cytokines), or chronic (high fat diet, db/db mice, and aging) stress in mice and humans. • In vitro Lgr4 knockdown leads to increased β-cell death and decreased proliferation; LGR4 overexpression in vitro protects β-cells against proinflammatory cytokines. • LGR4 protects β-cells through inhibition of RANK/NFκB activation. • Lgr4 conditional knockout (cko) mice exhibit impaired β-cell proliferation survival and maturation, and female mice become glucose intolerant and have decreased plasma insulin with age. • Simultaneous deletion of Rank and Lgr4 in double ko mice rescues the impaired β-cell phenotype observed in Lgr4 cko mice, highlighting the importance of RANK/LGR4 stoichiometry in the maintenance of β-cell health.","journal":"Molecular Metabolism","year":2025,"id":538418,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"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":1425397,"name":"Zelda Cisneros","orcid":null,"position":1,"is_corresponding":false},{"id":937093,"name":"Sneha S. Varghese","orcid":"0000-0001-5526-5856","position":2,"is_corresponding":false},{"id":782834,"name":"Nancy Leon-Rivera","orcid":"0000-0003-0231-492X","position":3,"is_corresponding":false},{"id":320850,"name":"Peng Wang","orcid":"0000-0002-9031-9861","position":4,"is_corresponding":false},{"id":1172827,"name":"Randy B. Kang","orcid":"0000-0002-2541-4344","position":5,"is_corresponding":false},{"id":412295,"name":"Geming Lu","orcid":"0000-0002-1322-3997","position":6,"is_corresponding":false},{"id":409402,"name":"Yate‐Ching Yuan","orcid":"0000-0002-3698-9784","position":7,"is_corresponding":false},{"id":323901,"name":"Hung-Ping Shih","orcid":"0000-0003-3035-5841","position":8,"is_corresponding":false},{"id":434047,"name":"S. Bhattacharya","orcid":"0000-0003-0483-2149","position":9,"is_corresponding":false},{"id":486438,"name":"Sangeeta Dhawan","orcid":"0000-0002-1562-7899","position":10,"is_corresponding":false},{"id":310887,"name":"Adolfo Garcı́a-Ocaña","orcid":"0000-0002-6883-6176","position":11,"is_corresponding":false},{"id":1052314,"name":"Nagesha Guthalu Kondegowda","orcid":"0000-0003-1738-6176","position":12,"is_corresponding":false},{"id":823636,"name":"Rupangi C. Vasavada","orcid":"0000-0003-3228-9235","position":13,"is_corresponding":false},{"id":889599,"name":"Joanna Filipowska","orcid":"0000-0002-5721-5032","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T02:52:21.389196Z","pmid":"39788290","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":[]}