Androgen excess predisposes females to type 2 diabetes. Using mouse models, we reported that androgen excess causes insulin resistance via activation of the androgen receptor (AR) in the brain. Neurons of the arcuate nucleus of the hypothalamus (ARC) regulate hepatic glucose production (HGP). Thus, we hypothesized that in female mice, androgen excess in neurons of the ARC causes peripheral insulin resistance by increasing HGP. To test this, we injected AaV-Cre-GFP or AaV-GFP into the ARC of ARlox/lox female mice to generate ARC-specific AR knockout (ARC-ARKO) and control mice, respectively. When exposed to a Western diet, control female mice chronically treated with dihydrotestosterone (DHT) developed insulin resistance and fasting hyperglycemia compared to vehicle-treated control mice. In contrast, DHT-treated ARC-ARKO mice remained insulin sensitive and normoglycemic compared to vehicle-treated ARC-ARKO mice. During a hyperinsulinemic-euglycemic clamp, insulin’s ability to suppress HGP was blunted in DHT-treated control mice. In contrast, insulin was still able to suppress HGP in DHT-treated ARC-ARKO females. Additionally, during the clamp, DHT-treated control mice showed no alteration in hepatic activation of AKT, a marker of hepatocyte insulin sensitivity, but exhibited reduced activation of hepatic STAT3, a marker of hypothalamic insulin sensitivity. In contrast, in DHT-treated ARC-ARKO mice activation of hepatic STAT3 was increased. Together these results suggest that in female mice exposed to a Western diet, androgen excess causes insulin resistance in ARC neurons via action at the AR leading to impairments in the brain-IL6-STAT3 pathway which results in unsuppressed HGP.
J. Morford: None. F. Mauvais-Jarvis: None.
National Institutes of Health (R01DK074970, R01107444); U.S. Department of Veterans Affairs (BX003725)