{"doi":"10.1210/endocr/bqae080","title":"Gut-specific Neprilysin Deletion Protects Against Fat-induced Insulin Secretory Dysfunction in Male Mice","abstract":"Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut-/-) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut-/- mice, and was similar in plasma, pancreas, and kidney in NEPGut-/- vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut-/- displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.","journal":"Endocrinology","year":2024,"id":473589,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"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":947636,"name":"Stephen M. Mongovin","orcid":null,"position":1,"is_corresponding":false},{"id":947155,"name":"Breanne M. Barrow","orcid":"0000-0002-5496-7474","position":2,"is_corresponding":false},{"id":445351,"name":"Sakeneh Zraika","orcid":"0000-0003-4831-7034","position":3,"is_corresponding":false},{"id":249039,"name":"Nathalie Esser","orcid":"0000-0003-1823-3817","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:06:04.967429Z","pmid":"38953181","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":[]}