{"doi":"10.1210/endocr/bqaf069","title":"12-Lipoxygenase Inhibition Improves Glycemia and Obesity-associated Inflammation in Male Human Gene Replacement Mice","abstract":"Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes. 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and promotes the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we used a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered male mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β-cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β-cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and type 2 diabetes.","journal":"Endocrinology","year":2025,"id":523028,"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":0.9498,"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":877624,"name":"Titli Nargis","orcid":"0009-0005-2823-0873","position":1,"is_corresponding":false},{"id":1178152,"name":"Kayla Figatner","orcid":null,"position":2,"is_corresponding":false},{"id":1268382,"name":"Jiayi Wang","orcid":"0009-0009-1818-3670","position":3,"is_corresponding":false},{"id":659646,"name":"Sarida Pratuangtham","orcid":"0000-0002-1105-1001","position":4,"is_corresponding":false},{"id":1178151,"name":"Advaita Chakraborty","orcid":null,"position":5,"is_corresponding":false},{"id":244407,"name":"Isabel Casimiro","orcid":"0000-0003-2833-1744","position":6,"is_corresponding":false},{"id":439667,"name":"Jerry L. Nadler","orcid":"0000-0002-4200-6991","position":7,"is_corresponding":false},{"id":605304,"name":"Matthew B. Boxer","orcid":null,"position":8,"is_corresponding":false},{"id":268309,"name":"David J. Maloney","orcid":"0000-0002-5607-4178","position":9,"is_corresponding":false},{"id":370038,"name":"Ryan M. Anderson","orcid":"0000-0003-3413-0121","position":10,"is_corresponding":false},{"id":244409,"name":"Raghavendra G. Mirmira","orcid":"0000-0002-5013-6075","position":11,"is_corresponding":false},{"id":244408,"name":"Sarah A. Tersey","orcid":"0000-0003-0667-2361","position":12,"is_corresponding":false},{"id":1258268,"name":"Kerim B. Kaylan","orcid":"0000-0001-7147-0614","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:49:58.707747Z","pmid":"40186458","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":[]}