A Comparison Between 1‐Month vs. 2‐Months on a High Fat Diet on the impact on Glucose Metabolism in Male and Female Liver Androgen Receptor Knockout Mice

Abstract

Previous research has indicated that a lipid-independent pathogenic mechanism plays a role in androgen-induced hepatic insulin resistance where liver androgen receptors may play a role in modulating disease. Consequently, this study aims to investigate the pathophysiology of high fat diet (HFD) induced dysglycemia and hepatic insulin resistance in male and female liver androgen receptor knockout (LivARKO) mice. We performed insulin tolerance tests (ITT), glucose tolerance tests (GTT), and pyruvate tolerance tests (PTT) on LivARKO male and female mice fed a high fat diet (HFD) or a control diet (CD) (from Research Diets Inc) during months 1 or 2 after starting the diet. Two-months on the CD showed significantly enhanced glucose tolerance (EGT) compared to 1-month on CD in both male and female LivARKO mice. This EGT phenotype was the same and equally as significant in males vs females. Two-months on CD showed impaired insulin sensitivity (IIS) compared to 1-month on CD in male and female LivARKO mice. This IIS was significantly greater in female mice. Two-months on the CD displayed enhanced pyruvate tolerance compared to 1-month on the CD in male and female LivARKO mice. Two-months compared to 1-month on HFD displayed no significant difference in glucose tolerance in male and female LivARKO mice. Two-months on HFD showed impaired insulin sensitivity compared to 1-month in female but not male LivARKO mice. Pyruvate tolerance was not changed from 1- to 2-months on HFD in male or female LivARKO mice. In the CD mice, we see EGT but IIS. This suggests that insulin action is decreased. The enhanced pyruvate tolerance in CD mice suggests that the control diet lowers gluconeogenesis. Why the control diet is altering glucose metabolism from 1-2 months is still a question to be investigated. In conclusion, we show that 1- vs 2-months on HFD showed no change in glucose metabolism in male and a slight change in female LivARKO mice. Further research consists of molecular data to elucidate the metabolic results on a molecular level.