PMON210 Ovariectomy of Middle-Aged Female Mice Leads to Decreased Fat Oxidation and Energy Expenditure Accompanied by Weight Gain and Dysregulated Blood Glucose

Abstract Introduction In humans, menopause brings upon total body weight gain with increased visceral adiposity and a resulting increase in cardiometabolic risk profile. Although well described, the specific sequence and underlying mechanisms for this remain elusive. Rodent ovariectomy (OVX) is routinely used as an animal model for the study of human menopause but is often performed in young reproducing specimen, failing to replicate the complex interaction of concomitant chronological aging with the loss of sex hormones observed in humans. In this study we used middle-aged ovariectomized mice to explore the effect of concomitant estrogen deficiency with chronological aging on key aspects of cardiometabolic health and energy expenditure. Methods 10-month-old C57BLj/6 female mice, were subjected to a SHAM or OVX procedure and followed for 6 weeks post-surgery (n=5 per group). Non-fasting blood glucose (BG) and body weight were measured weekly. Prior to sacrifice mice were observed in metabolic cages using the Promethion Metabolic Phenotyping System (Sable Systems International). Body composition including total body fat and lean mass were evaluated by EchoMRI. A Reduction in uterine weight was used to confirm successful OVX. Results Relative to baseline weight, OVX mice weighed 13% more than SHAM mice 6-weeks after surgery (p= 0.04; t-test) with no significant change in body composition. Non-fasting BG was consistently higher throughout the study period in OVX vs SHAM mice (p<0.01; ANOVA). OVX mice exhibited an increased respiratory quotient (0.84 vs 0.81; p<0.01; t-test) driven by a reduction in fat oxidation (24 vs 34 g/d/kgeff. mass p<0.000; t-test). OVX mice showed a 17% percent decrease in total energy expenditure in both the light and dark phases (p<0.01), driven by a 38% percent decrease in ambulatory activity (p=0.04) and close to a 3-fold decrease in wheel running (p<0.001). No significant change was observed in overall food or water intake between the groups. Discussion It is difficult to detangle the complex web of causes and effects relating to the deranged metabolic phenotype induced by menopause. Here we show that even without additional insults such as a high-fat-diet or genetic manipulation, the combination of chronological aging at middle-age with the sex hormone deficiency resulting from OVX, led to an increase in total body weight, a dysregulated glucose profile and a deranged energy expenditure pattern. Additional studies are warranted using similar animal models to tease out cause and effect as well explore novel therapeutics and biomarkers for the rapidly increasing population of post-menopausal women at risk for cardiometabolic disease. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.