Time-Dependent Progression of Metabolic Dysfunction in a Mouse Model of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is closely linked to metabolic disorders such as obesity, dyslipidemia, systemic insulin resistance (IR), adipose IR and white adipose tissue (WAT) dysfunction. Hyperandrogenism is a clinical hallmark of PCOS, and it plays a fundamental role in the development of metabolic perturbations associated with PCOS. Androgen excess is linked to metabolic dysfunction in multiple tissues, including WAT, in PCOS women. However, data on the disease onset and progression of WAT dysfunction and associated metabolic derangements in PCOS women are lacking. Therefore, we aim to test the hypothesis that the androgen dihydrotestosterone (DHT) induces time-dependent progression of metabolic dysfunction on both the molecular and functional levels in PCOS. This hypothesis will be tested using a well-characterized DHT-induced PCOS mouse model after 2, 4, 8 and 12 weeks of DHT administration. Methods: Three-week old female mice (C57BL/6N) were implanted with Silastic tubes filled with DHT (8 mg, s.c.) or vehicle (n=6/grp) for 2, 4, 8 and 12 weeks. Weekly body weight (BW, gravimetry), body composition (EchoMRI), retroperitoneal fat (RPF) mass (gravimetry) were assessed. Serum leptin, adiponectin and insulin were measured by ELISA, while cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified free fatty acid (NEFA) were measured using a clinical chemistry analyzer. Adipose IR (insulin x NEFA) was calculated. RPF androgen receptor (AR), lipolytic marker adipose triglyceride lipase (ATGL), and adipogenesis marker peroxisome proliferator-activated receptor-γ (PPAR-γ) protein levels were assessed by Western blot. Results: DHT-treated mice showed significant (p<0.05) increases in BW (20.23±0.3 vs 17.63±0.1 g) and lean mass (17.77±0.5 vs 15.50±0.3 g) starting 2 weeks following DHT exposure where higher cholesterol (90.0±2.9 vs 70.0±5.8 mg/dL), insulin (0.51±0.08 vs 0.22±0.03 ng/mL) and adipo-IR (2.5-fold) as well as lower insulin-sensitizing adipokine adiponectin levels (4.9±0.2 vs 9.70±1.1 mg/mL) were also observed compared to vehicle. The increases in RPF mass (105.40±10.3 vs 32.78±1.6 mg) and total fat mass (2.43±0.5 vs 1.09±0.1 g) were only significant starting at weeks 4 and 8, respectively. DHT significantly increased NEFA (1.3- and 1.2-fold, 8- and 12-weeks post DHT, respectively) and leptin (1.5-fold, 12 weeks post DHT). Unexpectedly, DHT increased HDL-C (58.80±1.42 vs 41.40±1.2 mg/dL, 4 weeks post DHT), while decreasing triglycerides (76.17±5.4 vs 107.17±9.4 mg/mL) and LDL-C (6.5±0.8 vs 9.0±0.5 mg/mL) after 8 weeks post DHT. At the molecular level, DHT upregulated RPF AR expression (5-fold) and downregulated ATGL expression by 40% as early as 2 weeks post DHT, and downregulated PPARγ expression by 40% at 4 weeks post DHT indicating early onset of adipose tissue dysfunction. Conclusion and significance: Our findings suggest that some PCOS metabolic traits occur very early following the induction of hyperandrogenemia such as serum adiponectin, insulin and cholesterol, highlighting these markers as an early diagnosis potential biomarkers. The onset of WAT lipolysis and adipogenesis alterations as well as adipo-IR were also early events that may be drivers of disease progression. Therefore, actively screening and managing risk factors for metabolic derangements from early on in PCOS is critical for disease management. Supported by NIH-NIGMS P20GM121334 and NIH-NIMHD P50MD017338 grants and American Heart Association Predoctoral Fellowship 903804. 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.