High Fructose Diet (HFrD) Induced Hepatic Insulin Resistance Is Not Present in Liver Androgen Receptor Knockout (LivARKO) Male Mice

Abstract

Background: Hyperandrogenism (HA), a common symptom of polycystic ovary syndrome (PCOS), involves action of the androgen receptor (AR) and can induce insulin resistance among 35-80% of PCOS women (PMID 35432749: Amisi 2022). The liver plays an essential role in the metabolism of insulin and androgen signaling. HA has been shown to increase insulin resistance in women and female mice. Previous studies have suggested that knocking out liver AR can lead to improvements in metabolic and reproductive functions of PCOS (PMID 34547140: Andrisse 2021). Hypothesis: We hypothesized that liver androgen receptor knockout (LivARKO) mice on a high fructose diet would exhibit increased insulin resistance compared to controls, as measured by expression of phospho-Akt (p-Akt) and phospho-FoxO1 (p-foxo1), proteins involved in insulin signaling. Methods: LivARKO mice were divided into groups based on an assigned diet (Control or High Fructose; Con, Research Diets Inc, RDI D12450J, Protein (20%), Carbs (70%, corn starch-50%, sucrose-maldextrin-20%, fructose-0%), Fat 10% (lard)) and High Fructose (HFrD, RDI D02022704, Protein (20%), Carbs (70%, corn starch-9%, sucrose-maldextrin-1%, fructose-60%), Fat 10% (lard)). The mice were sacrificed and liver tissue samples were extracted for western blotting analysis examining p-Akt S473 and p-foxo1 S256 levels. Results: LivARKO male mice fed the control diet for one month displayed a significant increase in p-AKT expression when stimulated with insulin compared to basal controls. Similarly, LivARKO male mice fed the high fructose diet for one month displayed a significant increase in p-AKT expression when stimulated with insulin compared to basal mice on the same diet. After one month, LivARKO male mice on a control diet stimulated with insulin displayed significantly decreased p-Foxo1 expression compared to non-stimulated basal control. A similar trend was seen between basal and insulin-stimulated groups in the LivARKO-HFrD male mice, though this trend was not significant. Discussion: These findings suggested that the HFrD did not induce hepatic insulin resistance in LivARKO male mice. Here, we observed a similar pattern of increased insulin stimulated p-AKT to what is seen in WT mice on a chow diet (PMCID PMC3296881: Lu 2012); and this suggested that LivARKO did not disrupt insulin signaling in the liver of male mice when fed a control diet, which was similar to what was seen previously (DOI: 10.1002/hep.22252, Lin 2008, insulin increased PI3K activity in chow diet LivARKO male mice). Our data suggested that the HFrD induced hepatic insulin resistance seen in some WT models (such as PMCID PMC3131094: Nagai 2009) is not present in LivARKO male mice.This also suggested that unlike HFD, HFrD did not cause insulin resistance in LivARKO male mice. These results illuminate LivARKO as a potential therapeutic target for insulin resistance. This project was supported by the following grants to Dr. Stanley Andrisse. (1) NIH 1R01DK126892; (2) NIH 1T34GM142610; and (3) NSF 1931045. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.