SAT-573 - Hepatic Androgen Receptor siRNA Modulates Tissue-Specific Insulin Signaling in A Mouse Model of PCOS

Objective: To determine whether hepatic androgen receptor (AR) knockdown using siRNA improves insulin signaling in a low-dose dihydrotestosterone (DHT) mouse model of polycystic ovary syndrome (PCOS).

Background: PCOS is characterized by hyperandrogenism and metabolic dysfunction, yet therapeutic strategies targeting androgen-driven insulin resistance remain limited. Hepatocyte-specific AR knockout prevents glucose dysregulation in DHT-treated female mice, suggesting hepatic AR as a therapeutic target. Therefore, we investigated the therapeutic capacity of an siRNA against hepatic AR to rescue insulin resistance in female mice with low-dose DHT-induced PCOS.

Methods: A liver-targeted siRNA against androgen receptor, provided by Alnylam Pharmaceuticals, was used to achieve hepatocyte-specific AR knockdown in control and DHT-treated female mice. We used western-blot analysis to assess AKT signaling in white adipose tissue (WAT) and skeletal muscle (SKM) under basal and insulin-stimulated conditions following DHT treatment and gene knockdown.

Results: In WAT, insulin-stimulated AKT phosphorylation was reduced following hepatic AR knockdown, whereas in SKM, AR knockdown significantly enhanced insulin responsiveness relative to basal signaling.

Discussion: These findings demonstrate tissue-specific effects of hepatic AR knockdown, with enhanced skeletal muscle insulin sensitivity despite altered adipose insulin signaling, supporting hepatic AR as a viable therapeutic target in PCOS-associated insulin resistance. This data highlights that targeting hepatic AR using siRNA warrants further exploration as a potential treatment for PCOS, including higher end value.

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