{"doi":"10.1016/j.molmet.2025.102172","title":"Genetic depletion of adipose-derived Isthmin-1 causes hepatic steatosis","abstract":"OBJECTIVES: Adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis and result in lipid overflow and ectopic lipid deposition in the liver. We previously demonstrated that Isthmin-1 (Ism1) regulates glucose uptake into the adipose tissue and suppresses hepatic steatosis, but the role of adipose-derived Ism1 is unknown. Here, we investigate the role of adipose-derived Ism1 in metabolic health and its impact on hepatic steatosis and lipid metabolism. METHODS: In this study, we employed both a genetic knockout approach, selectively deleting Ism1 in adipose tissue of mice (AdipoQ-Ism1-KO), and a pharmacological approach by administering recombinant Ism1 protein to mice. These mice were subjected to a high fat-high fructose diet to simulate conditions that promote Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD). RESULTS: AdipoQ-Ism1-KO are of normal weight, but prone to severe hepatic steatosis in response to high fat-high fructose feeding. Lipidomic profiling through untargeted analyses in both gain-of-function and loss-of-function models was used to assess changes in hepatic lipid homeostasis. These results provide in vivo genetic support for the role of Ism1 as a regulator of the adipose-hepatic axis. CONCLUSIONS: Collectively, these data demonstrate that loss of adipose-derived Ism1 disrupts lipid homeostasis and accelerates the development of hepatic steatosis. This study provides a genetic basis for Ism1's involvement in metabolic regulation, suggesting a potential therapeutic target for treating metabolic disorders.","journal":"Molecular Metabolism","year":2025,"id":532429,"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":0.9588,"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":920870,"name":"Laetitia Coassolo","orcid":"0000-0003-2138-4819","position":1,"is_corresponding":false},{"id":348821,"name":"Meng Zhao","orcid":"0000-0002-5415-8335","position":2,"is_corresponding":false},{"id":1413978,"name":"Rajagopalan Narasimhan","orcid":null,"position":3,"is_corresponding":false},{"id":1365771,"name":"Aayan Patel","orcid":null,"position":4,"is_corresponding":false},{"id":1143763,"name":"Jameel Lone","orcid":"0000-0003-4571-1335","position":5,"is_corresponding":false},{"id":432242,"name":"Ewa Bielczyk-Maczyńska","orcid":"0000-0002-0558-1188","position":6,"is_corresponding":false},{"id":1413979,"name":"Niels Banhos Danneskiold-Samsoee","orcid":null,"position":7,"is_corresponding":false},{"id":959376,"name":"Taylor G. Brown","orcid":"0000-0001-9817-2094","position":8,"is_corresponding":false},{"id":348823,"name":"Zewen Jiang","orcid":"0000-0002-3852-8666","position":9,"is_corresponding":false},{"id":259635,"name":"Veronica L. Li","orcid":"0000-0001-8888-3853","position":10,"is_corresponding":false},{"id":348824,"name":"Katrin J. Svensson","orcid":"0000-0001-5376-5128","position":11,"is_corresponding":false},{"id":911168,"name":"Saranya Chidambaranathan Reghupaty","orcid":"0000-0001-6660-1296","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40436204","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":[]}