Low Dose DHT Impairs Glucose Metabolism Via Increased Hepatic Gluconeogenic Output and Decreased Adipose Tissue Glucose Uptake
Authors: Andrisse Stanley , Billings Katelyn , Ma Yaping , Xue Ping , Wolfe Andrew , Wu Sheng 
Published: November 2023

Background

Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is characterized by hyperandrogenism, oligo‐or ammenorhea, and polycystic ovaries, and is associated with type 2 diabetes and insulin resistance. Our previous studies introduced a low dose dihydrotestosterone (DHT) mouse model that recapitulated features of PCOS and that displayed differential tissue specific responses to insulin action – insulin resistance in liver and adipose tissue but maintained insulin action in the pituitary and ovary.

Objective

Here we seek to further characterize the low dose DHT mouse model and to determine molecular mechanisms involved in the differential tissue response to androgen/insulin action. We hypothesized that low dose DHT will result in hepatic and adipocyte dysfunction, differentially alter insulin‐stimulated glucose transport in energy storage compared to reproductive tissues, and augmented hepatic gluconeogenesis. Many DHT mouse models use concentrations 8‐fold that of normal female mice. We used a 4 mm DHT pellet which continuous release DHT and achieving serum DHT levels 1.7‐fold higher than controls, similar to the elevation of DHT seen in women with PCOS.

Methods

Reproductive tests (mouse estrous cyclicity, mating, and ovary histology), metabolic tests (PTT and GSIS) and blood sampling (hormonal assays: LH, FSH, insulin, leptin, Il‐6, and Tnfa) were performed. Radiolabeled ex vivo glucose transport assays, histological staining, quantitative real‐time PCR (qRT‐PCR), Luminex multiple ligand assay, and western blot immunostaining were performed on energy storage (liver and adipose tissue) and reproductive (pituitary and ovaries) tissues.

Results

Low dose DHT mice demonstrated unaltered LH and FSH serum levels, no weight gain, impaired pyruvate tolerance, hepatic steatosis and adipocyte hypertrophy compared to control mice. Mice implanted with DHT exhibited lower hepatic mRNA expression of enzymes used in glycolysis and glycogen synthesis compared to controls. Interestingly, gluconeogenic mRNA expression levels were unaltered but gluconeogenic protein levels were increased in DHT mice compared to controls. In addition, we assessed protein levels of intermediates in the insulin signaling pathways. DHT mice displayed lowered p‐AKT levels in the liver and WAT but in contrast maintained p‐AKT levels in the ovary and pituitary. However, insulin receptor protein levels were unaltered in all tissues compared to control mice.

Conclusion

These findings suggest that low dose DHT serves as a mouse model of lean PCOS and that the molecular mechanism by which low dose DHT impairs glucose metabolism is partly due to increased hepatic gluconeogenic output and decreased adipocyte glucose uptake. In addition, the impairment in the insulin signaling pathway is downstream of the insulin receptor. Tissue specific targeting of AR via compounds such as SARMs may serve as therapeutic interventions for PCOS related glucose metabolism dysfunction.

Support or Funding Information

5T32DK007751‐19 Wolfe (PI) 09/12/1997 ‐06/30/17 NIH/NICHD Direct Costs: $300,812 Interdepartmental training program in cellular and molecular endocrinology The goal of the Interdepartmental Training Program in Cellular and Molecular Endocrinology at Johns Hopkins is to expand the pool of well‐trained and productive investigators in the biomedical sciences related to endocrinology. Role: Trainee

R00HD068130 Wu (PI) 07/01/14‐06/30/17 NIH/NICHD Direct Costs: $226,790 Insulin and Androgen Interactions in the Infertility of Obesity We will attempt to define the complex interactions of insulin and androgens on the development of obesity induced infertility. We hope to uncover the mechanism that underlies the development of infertility in women with metabolic dysfunction such as frequently is observed in PCOS. Role: Trainee