{"doi":"10.1101/2021.06.09.447759","title":"Hepatocyte androgen receptor in females mediates androgen-induced hepatocellular glucose mishandling and systemic insulin resistance","abstract":"Abstract Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in AR fl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (AR fl/fl ) and LivARKO (AR fl/fl ; Cre +/- ) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Further, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218844,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"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":239517,"name":"Mingxiao Feng","orcid":"0000-0002-7412-0481","position":1,"is_corresponding":false},{"id":63856,"name":"Zhiqiang Wang","orcid":"0000-0001-7186-7099","position":2,"is_corresponding":false},{"id":158793,"name":"Olubusayo Awe","orcid":null,"position":3,"is_corresponding":false},{"id":650404,"name":"Lexiang Yu","orcid":"0009-0004-2782-1025","position":4,"is_corresponding":false},{"id":816974,"name":"Haiying Zhang","orcid":"0000-0001-9592-8669","position":5,"is_corresponding":false},{"id":816975,"name":"Sheng Bi","orcid":"0000-0002-2441-0528","position":6,"is_corresponding":false},{"id":393486,"name":"Hongbing Wang","orcid":"0000-0002-6224-6888","position":7,"is_corresponding":false},{"id":816976,"name":"Linhao Li","orcid":"0000-0002-3207-9740","position":8,"is_corresponding":false},{"id":440680,"name":"Serene Joseph","orcid":null,"position":9,"is_corresponding":false},{"id":291283,"name":"Nicola Heller","orcid":"0000-0001-7247-2021","position":10,"is_corresponding":false},{"id":104951,"name":"Franck Mauvais‐Jarvis","orcid":"0000-0002-0874-0754","position":11,"is_corresponding":false},{"id":817452,"name":"Guang William Wong","orcid":null,"position":12,"is_corresponding":false},{"id":428046,"name":"James H. 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