SAT390 Western Diet Exacerbates Colonic Mitochondrial Dysfunction in the Hyperandrogenemic Female Rat Model of Polycystic Ovary Syndrome

Disclosure: K. Edwards: None. N. Hoang: None. K. Brooks: None. R.M. Quin: None. K. Davenport: None. N.M. Shawky Elsayed: None. Introduction: Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women with approximately 80% suffering from hyperandrogenemia. Hyperandrogenemia causes PCOS women to suffer from additional comorbidities such as irritable bowel syndrome (IBS), a result of sub-acute gastrointestinal (GI) inflammation. Diet plays a role in the severity of symptoms. Mitochondrial dysfunction is associated with development of inflammation. Excess androgens can also alter mitochondrial function. This study aims to investigate the mechanisms linking PCOS and diet with the development of IBS. Methods: The hyperandrogenemic female (HAF) rat model exhibits characteristics similar to PCOS women such as increased body weight, fat mass, and food intake. At 4 weeks of age, female rats received dihydrotestosterone (DHT, 7.5mg/90 days, s.c.) pellets and were started on either a control diet (CD; n=9) or a western diet (WD: 17% protein, 43% carbohydrates mainly sucrose, and 40% fat; n=9-11). Two parallel groups of control rats (placebo pellets) were also fed either CD or WD. At 22 weeks of age, colon tissues were collected for mitochondrial isolation. Complex I-driven respiration, complex II-driven respiration or fatty acid oxidation were measured simultaneously with mitochondrial reactive oxygen species (mtROS) using the Oroboros O2k-FluoRespirometer. Data was normalized to mitochondrial content using citrate synthase. Results: In the colons from HAF rats, we observed a significant decrease in mitochondrial complex I-driven respiration (33%, p=0.0174), complex II-driven respiration (34%, p=0.0022), LCFA oxidation (35%, p=0.0309), and MCFA oxidation (47%, p=0.0016) compared to controls. In control females, WD significantly decreased complex I-driven respiration (54%, p=0.0004), complex II-driven respiration (50%, p<0.0001), LCFA oxidation (45%, p=0.006), and MCFA oxidation (58%, p=0.0001). In the HAF rats, WD further decreased complex I-driven respiration (30%, p=0.0144), while all other respirations rates were decreased by 10%. Regardless of substrate provided, colon mtROS was significantly increased in both control (2.6-fold; p=0.0028) and HAF (1.9-fold; p=0.0104) on WD. HAF rats showed a significant increase in in mtROS production compared to controls (1.3-fold increase, p=0.0164). Conclusion: Both hyperandrogenemia and WD consumption induce distinct forms of mitochondrial dysfunction that is exaggerated by the combination of both factors. This suggests that WD consumption could increase the severity in IBS symptoms in hyperandrogenemic PCOS women. This study highlights a potential avenue to the development of strategies to re-establish normal mitochondrial function that would provide options for preventive and therapeutic interventions for IBS where there are limited treatment options in PCOS women. Funding: P20GM121334 (KE, NMS), AHA CDA 938320 (NMS). Presentation Date: Saturday, June 17, 2023