# Understanding the pathogenesis of elevated androgen induced metabolic dysfunction in females

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $536,530

## Abstract

Project Summary
 Androgen receptor (AR) signaling plays a crucial role in androgen induced metabolic dysfunction in states
of elevated androgen in females. However, how AR in the liver contribute to metabolic dysfunction in states of
androgen excess, such as in polycystic ovary syndrome (PCOS), is unknown. Hyperandrogenemia is one of the
defining features of PCOS, and is often accompanied by hyperinsulinemia and obesity making it difficult to
discern the role of androgen signaling in the development of metabolic dysfunction not secondary to impaired
metabolic function. Therefore, a model that can isolate the pathophysiological effects of hyperandrogenemia
from metabolic changes resulting from obesity is warranted. We observed that elevated androgen through
androgen receptor in the liver contributes to impaired metabolic function. We hypothesized that in a
setting of high androgen levels: 1) androgen/AR interacts with proteins upstream of AKT to interfere with
insulin signaling, thus inhibiting the phosphorylation of forkhead box O1 (FOXO1), leading to increased
gluconeogenesis; 2) androgen/AR regulates the cAMP-PKA (glucagon) pathway to increase activity of cAMP
response element binding protein (CREB), and leading to increased glucose production; 3) AR acts as a
transcription factor regulating Foxo1 and Creb gene expression to increase gluconeogenesis; 4) induced
metabolic pathology can be corrected or improved by acute deletion of AR thus pointing the way to therapeutic
interventional strategies.
We will focus on the role of pathophysiological androgen levels acting via AR in the liver. Approaches will use
genetic deletion of AR developmentally or acutely in liver in elevated androgen mouse models. Aim1 will focus
on the liver (mouse and human hepatocytes) by defining the role of hepatocyte extranuclear AR in androgen
induced metabolic dysfunction. Aim 2 will determine whether nuclear AR is required for androgen induced
gluconeogenesis. Aim 3 will focus on whether metabolic dysfunction associated with androgen excess can be
corrected or rescued by acute deletion of hepatic AR.
Together these Aims will elucidate the role of AR in mediating the pathogenic effects of androgen excess in
contributing to female metabolic dysfunction.

## Key facts

- **NIH application ID:** 10415165
- **Project number:** 5R01HD095512-05
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Sheng Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $536,530
- **Award type:** 5
- **Project period:** 2018-08-10 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415165

## Citation

> US National Institutes of Health, RePORTER application 10415165, Understanding the pathogenesis of elevated androgen induced metabolic dysfunction in females (5R01HD095512-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10415165. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*