OR02-06 Diet-induced Obesity Exacerbates Neuronal Inflammation and Behavioral Changes in Hyperandrogenic Female Mice: Implications for Brain Health in Women with Polycystic Ovary Syndrome

Abstract Disclosure: S. Rezq: None. J. Flaherty: None. J. Basnet: None. D.G. Romero: None. Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, characterized by oligo- or anovulation, hyperandrogenism, and polycystic ovaries. PCOS women experience memory and executive function impairments that are correlated with plasma androgen levels. Obesity, prevalent in 80% of women with PCOS, is a known risk factor for cognitive and neurodegenerative disorders such as Alzheimer’s disease (AD). However, the role of obesity in hyperandrogenemia-mediated behavior alterations and associated molecular changes in the brain remains unknown in PCOS. This study aims to test the hypothesis that hyperandrogenemia in females causes cognitive impairment by inducing pathological changes in brain regions associated with cognition that are exacerbated by an obesogenic diet. Methods: Three-week-old peripubertal female mice were implanted with Silastic tubes filled with the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle. Animals were fed either a high-fat diet (HFD; 60% kcal fat) or a low-fat diet (LFD; 10% kcal fat) for 90 days. Fat mass was measured by EchoMRI. Brain expression of androgen receptor (AR) and markers linked to cognitive disorders including tau hyperphosphorylation (phospho-Tau [Thr181, Thr205, Ser404], total Tau), apoptosis (Bax, Bcl-XL), and oxidative stress (NOX2) were assessed via Western blot, while inflammation (TNF-α) was evaluated by ELISA in the parietal cortex. Spatial memory, learning, and exploratory tendencies were assessed using the Barnes Maze and Y-maze behavioral assays. Results: DHT induced an increase in fat mass, which was exacerbated in HFD-fed mice (2.17- and 6.9-fold, respectively, p<0.05). In the parietal cortex, DHT significantly upregulated AR expression (3.7-fold), with a greater increase observed in HFD-fed PCOS mice (5-fold). HFD increased the expression of phospho-Tau (S404), with no further exacerbation by DHT. Apoptosis and oxidative stress markers remained unchanged across treatments. However, levels of the inflammatory marker TNF-α were elevated only in HFD-fed PCOS mice (6.1 ± 0.9 vs. 3.15 ± 0.5 pg/mg protein). Behavioral assessments revealed that PCOS mice showed higher latency to reach the target hole in the Barnes Maze, more pronounced in the HFD-fed group (1.4- and 1.7-fold, respectively), indicating spatial learning and memory impairment. Additionally, in the Y-maze test, only HFD-fed PCOS mice had decreased exploratory tendencies (increased frequency to center point). Conclusion and Significance: Our findings suggest that androgen excess induces neuronal inflammation and impairs spatial memory and learning, effects that are exacerbated with an obesogenic diet. This study highlights weight loss as a promising therapeutic approach to improve brain health and delay the onset and progression of cognitive dysfunction in PCOS. Presentation: Saturday, July 12, 2025