{"doi":"10.1101/2021.04.21.440732","title":"Suppression of Fatty Acid Oxidation by Thioesterase Superfamily Member 2 in Skeletal Muscle Promotes Hepatic Steatosis and Insulin Resistance","abstract":"ABSTRACT Thioesterase superfamily member 2 (Them2) is highly expressed in oxidative tissues where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 ( Them2 -/- ) are protected against diet-induced obesity, insulin resistance and hepatic steatosis, liver-specific Them2 -/- mice remain susceptible. To explore the contribution of Them2 in extrahepatic tissues, we created mice with Them2 deleted in skeletal muscle ( S-Them2 -/- ), cardiac muscle ( C-Them2 -/- ) or adipose tissue ( A-Them2 -/- ). When fed a high-fat diet, S-Them2 -/- but not C-Them2 -/- or A-Them2 -/- mice exhibited reduced weight gain. Only S-Them2 -/- mice exhibited improved glucose homeostasis together with improved insulin sensitivity in skeletal muscle. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2 -/- mice were reflected in alterations in skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and the pentose phosphate pathway. Protection from diet-induced hepatic steatosis in S-Them2 -/- mice was attributable to increased VLDL triglyceride secretion rates in support of demands of increased muscle fatty acid utilization. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of diet-induced obesity, insulin resistance and hepatic steatosis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223845,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":303563,"name":"Hayley T. Nicholls","orcid":null,"position":1,"is_corresponding":false},{"id":423886,"name":"Michele Alves‐Bezerra","orcid":"0000-0003-4430-6434","position":2,"is_corresponding":false},{"id":761088,"name":"Yingxia Li","orcid":"0000-0001-6782-8740","position":3,"is_corresponding":false},{"id":761089,"name":"Anna Ivanova","orcid":"0000-0002-6221-6240","position":4,"is_corresponding":false},{"id":74596,"name":"Eric A. Ortlund","orcid":"0000-0001-8855-3029","position":5,"is_corresponding":false},{"id":302665,"name":"David E. Cohen","orcid":"0000-0001-9827-6926","position":6,"is_corresponding":false},{"id":573783,"name":"Norihiro Imai","orcid":"0000-0002-5865-3245","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:14.760456Z","pmid":null,"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":[]}