RF33 | PSAT92 Glucocorticoid Excess Alters Metabolic Rate in Male and Female C57BL/6J Mice

Abstract Introduction Glucocorticoids are vital for regulating metabolic processes, as well as use in medical treatments. However glucocorticoid excess is known to cause negative metabolic effects including hyperglycaemia, muscle atrophy and fat accumulation, ultimately leading to Cushing's Syndrome. The effect on energy metabolism and metabolic rate remains undefined and merits investigation in both male and female mice. Methods 24 male and 24 female C57BL/6J mice were randomly assigned to a corticosterone (100mg/L, approximately 300µg/day) or a vehicle control group. Mice were treated ad libitum via drinking water for 3 weeks, whilst being fed a standard chow diet. Mice were placed into a TSE Phenomaster system for the final week of treatment for indirect calorimetry assessment. Results Corticosterone treatment resulted in a typical phenotype of glucocorticoid excess, however female mice experienced significantly greater fat accumulation and bodyweight gain compared to males. Females treated with corticosterone exhibited increased energy expenditure (EE, 25±5.9%), oxygen consumption (21.7±10.0%) and carbon dioxide production (36.4±14.3%) during the day compared to controls, but males did not. However, corticosterone did significantly elevate the respiratory exchange ratio (RER) towards 1 in both males (10.7±5.7%) and females (11.8±7.0%) during the day. At night, when mice are naturally more active and EE increases, female corticosterone mice no longer had elevated EE, oxygen consumption and carbon dioxide production compared to controls. However, RER remained elevated in females (7.6%±4.8%) and moderately so in males (3.2±2.6%), staying close to or exceeding 1 in both. Corticosterone treated mice were hyperphagic and polydipsic throughout, eating and drinking significantly more than controls during both night and day, with intake peaking at night. Subsequent metabolomic analysis of tissue samples (skeletal muscle, liver, gonadal fat) revealed significant treatment and sex differences. Conclusion and further investigation: These findings provide further insights into the metabolic consequences of glucocorticoid excess in male and female mice. Whilst energy metabolism and metabolic rate are altered in both (especially during the day), the metabolic effects of glucocorticoid excess might be exaggerated in females. Further investigation will determine whether these changes are driven simply by increased animal activity, increased feeding and drinking or another mechanism. Additionally, we will determine whether 11β-HSD1 KO prevents these changes, as it does with other negative metabolic effects associated with glucocorticoid excess. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:06 p.m. - 1:11 p.m.