7169 Temporal Development of Adipose Tissue and Metabolic Dysfunction in a Mouse Model of Polycystic Ovary Syndrome

Abstract Disclosure: J. Basnet: None. S. Rezq: None. A.M. Huffman: None. L.L. Yanes Cardozo: None. D.G. Romero: None. Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS women often have increased body weight, white adipose tissue (WAT) dysfunction and insulin resistance (IR). Hyperandrogenism is prevalent in PCOS and is linked to metabolic dysfunction in multiple tissues, including WAT. 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 WAT and 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 wks of DHT administration. Methods: Three-wks old female mice (C57BL/6N) were implanted with Silastic tubes filled with DHT (8mg, s.c.) or vehicle (n=6/grp) for 2, 4, 8 and 12 wks. Weekly body weight (BW, gravimetry) and body composition (EchoMRI) were assessed. Serum leptin, adiponectin and insulin were measured by ELISA, and cholesterol by a clinical chemistry analyzer. Retroperitoneal fat (RPF), a WAT depot that contributes to visceral adiposity and systemic inflammation, was collected for molecular determinations. RPF androgen receptor (AR), the lipogenesis markers acetyl coA carboxylase (ACC) and fatty acid synthetase (FAS), the lipolytic markers adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL), fatty acid-binding protein 4 (FABP4) and adipogenesis marker peroxisome proliferator-activated receptor-γ (PPAR-γ) 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 (1.14-fold) starting 2 wks following DHT exposure where higher cholesterol (1.3-fold) and insulin (2.3-fold) as well as lower insulin-sensitizing adipokine adiponectin levels (50%) were also observed compared to vehicle. The increases in RPF mass (3.2-fold) and total fat mass (2.2-fold) were only significant starting at wks 4 and 8, respectively. DHT significantly increased leptin (1.5-fold) at 12 wks post-DHT. At the molecular level, DHT upregulated RPF AR expression (5-fold) and downregulated HSL, FAS, FABP4, ATGL and ACC expression by 15 – 60% as early as 2 wks post-DHT, and downregulated PPARγ expression by 40% at 4 wks post-DHT, indicating early onset of adipose tissue dysfunction. Conclusion and significance: Our findings suggest that WAT dysfunction and some of the associated metabolic traits in PCOS such as serum adiponectin, insulin and cholesterol occur very early following the induction of hyperandrogenemia 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. Presentation: 6/1/2024