ABSTRACT: Compared to age-matched men, pre-menopausal women are protected against cardiovascular disease (CVD), hepatic steatosis, diabetes, and obesity - findings that are widely attributed to estrogen action. However pre-menopausal women who use oral combined contraceptives (OC) have 2-fold higher risk of cardiovascular disease (CVD), and OC use compounds with metabolic risk factors such as dyslipidemia, hypertension, or diabetes to further increase CVD susceptibility. While mitochondrial function in metabolically important tissues such as the liver and skeletal muscle is an emerging mechanism by which estrogen may confer its protection, effects of OC use on mitochondrial function and whole body metabolism in the context of disease risk has not yet been explored. To answer this question, female C57Bl/6J mice were fed a high fat diet and treated with vehicle or OCs for 3, 12, or 20 weeks (n=6-12 per group). Liver and skeletal muscle mitochondrial function (respiratory capacity, H2O2, coupling) was measured along with clinical outcomes of cardiometabolic disease such as obesity, glucose tolerance, hepatic steatosis, and aortic atherosclerosis. Main findings include that regardless of duration of treatment, OCs induced robust increases in hepatic mitochondrial H2O2, likely due to diminished antioxidant capacity. Furthermore, OC use in female mice decreased wheel running, spontaneous physical activity, and total energy expenditure. Surprisingly, in the chronic studies (12, 20 wk) OC treated mice had lower adiposity and hepatic triglyceride content compared to control mice. Together, these studies describe tissue-specific effects of OC use on mitochondrial function as well as variable impacts on markers of metabolic disease susceptibility.
