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Hepatocyte androgen receptor in females mediates androgen-induced hepatocellular glucose mishandling and systemic insulin resistance

bioRxiv, ISSN: 2692-8205
2021
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Article Description

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 mice (adLivARKO). We observed normal metabolic function in littermate female Control (AR) and LivARKO (AR; 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.

Bibliographic Details

Stanley Andrisse; Mingxiao Feng; Zhiqiang Wang; Olubusayo Awe; Lexiang Yu; Andrew Wolfe; Sheng Wu; Serene Joseph; James Segars; Guang William Wong; Haiying Zhang; Sheng Bi; Nicola Heller; Rexford Ahima; Hongbing Wang; Linhao Li; Franck Mauvais-Jarvis; Sara Divall

Cold Spring Harbor Laboratory

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences; Immunology and Microbiology; Neuroscience; Pharmacology, Toxicology and Pharmaceutics

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