{"doi":"10.2337/db21-1131","title":"Systemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity","abstract":"The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates nonalcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting that LSD1 has a context-dependent role in promoting maladaptive changes in obesity. In analysis of insulin target tissues we identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.","journal":"Diabetes","year":2022,"id":255741,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":343330,"name":"Dennis P. Pollow","orcid":null,"position":1,"is_corresponding":false},{"id":809930,"name":"Han Zhu","orcid":"0000-0003-1896-7140","position":2,"is_corresponding":false},{"id":806000,"name":"Chelsea Nora","orcid":null,"position":3,"is_corresponding":false},{"id":324886,"name":"Austin R. Harrington","orcid":null,"position":4,"is_corresponding":false},{"id":904577,"name":"Ibrahim Che Omar","orcid":null,"position":5,"is_corresponding":false},{"id":106556,"name":"Philip L.S.M. Gordts","orcid":"0000-0001-7224-4328","position":6,"is_corresponding":false},{"id":324887,"name":"Matthew Wortham","orcid":null,"position":7,"is_corresponding":false},{"id":7364,"name":"Maike Sander","orcid":"0000-0001-5308-7785","position":8,"is_corresponding":false},{"id":511325,"name":"Bastian Ramms","orcid":"0000-0001-7238-8663","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T00:25:17.224217Z","pmid":"36162056","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":[]}