Liver Androgen Receptor Knockout Delays the Onset of Diet Induced Metabolic Dysfunction in Female Mice Compared to Male Mice

Abstract

Polycystic ovarian syndrome (PCOS) is a hormonal disorder with insulin resistance (IR) and hyperandrogenism (HA) as drivers of the condition. Women diagnosed with PCOS have an increased risk of developing non-alcoholic fatty liver disease (NAFLD). Our lab explores the condition of NAFLD in PCOS through a mouse model with a liver androgen receptor (AR) knockout (LivARKO). The role of AR in high-fat diet (HFD) induced metabolic disease is not fully understood. We hypothesized that LivARKO would cause dysglycemia in males but protect from dysglycemia in females. To test the hypothesis, we collected data from male and female mice fed a HFD or a caloric adjusted control diet (CD) over the course of two months. We performed glucose tolerance (GTT), insulin tolerance (ITT), and pyruvate tolerance (PTT) tests. At 1-month, HFD female LivARKO mice displayed no difference in glucose tolerance compared to CD LivARKO female mice, suggesting that at one month LivARKO is protecting female mice from HFD-induced metabolic dysfunction. In contrast to females, at 1-month of diet, HFD male LivARKO mice displayed impaired glucose tolerance (IGT) compared to CD LivARKO mice. Thus, LivARKO was not protective against HFD-induced glucose metabolic dysfunction in male mice. At 2-months, HFD showed IGT compared to Control diet in male and female LivARKO mice, suggesting that LivARKO slowed the progression to metabolic disease in female mice but did not fully stop it. HFD male and female LivARKO mice did not display significant changes in insulin tolerance at 1-month compared to CD mice. HFD male and female LivARKO mice showed impaired pyruvate tolerance starting at 1-month and continuing at 2-months compared to CD LivARKO mice. The impairment was significantly greater in male mice. In conclusion, we found that it took LivARKO female mice longer to show dysglycemia from HFD than male LivARKO mice. Thus, in females, LivARKO slowed the progression to metabolic disease, but did not fully stop it. The impaired PTT suggests the effects of HFD may alter hepatic gluconeogenic regulation. Further molecular analysis is warranted.