SAT276 Glucocorticoid Excess Elevates Metabolic Rate Via A 11b-HSD1 Dependent Mechanism In C57BL/6J Mice

Abstract

Abstract Disclosure: S. Heaselgrave: None. S. Heising: None. S.A. Morgan: None. A. Kabli: None. M. Sagmeister: None. C. Doig: None. R.S. Hardy: None. N.M. Morton: None. K. Tsintzas: None. G.G. Lavery: None. Introduction: Glucocorticoids are vital metabolic regulators. However, glucocorticoid excess (GE) causes severe metabolic dysfunction, ultimately leading to Cushing’s Syndrome. This dysfunction is often dependent on the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Whether GE also alters metabolic rate, and whether this is also dependent on 11β-HSD1, remains unclear and merits investigation in a mouse model of GE and 11β-HSD1 inhibition. Methods: Male and female wild type (WT) C57BL/6J and 11β-HSD1KO mice were treated with corticosterone or vehicle control ad libitum via drinking water for 3 weeks whilst being fed a standard chow diet (n=12). Mice were housed in a TSE Phenomaster system for the final week of treatment for comprehensive metabolic assessment. Results: Corticosterone treatment in WT mice resulted in a phenotype typical of GE, however female mice experienced greater fat accumulation and bodyweight gain compared to males. 11β-HSD1KO mice did not experience this phenotype. Corticosterone treatment elevated energy expenditure (EE) in female WT mice during the day alone (25±5.9%). Male WT mice did not experience a significant increase. Corticosterone did significantly elevate the respiratory exchange ratio (RER) towards 1 in both male (10.7±5.7%) and female (11.8±7.0%) WT mice during the day. RER remained elevated in female WT mice (7.6±4.8%) and moderately so in male WT mice (3.2±2.6%) at night, indicating a continued suppression of lipid oxidation in favour of carbohydrate oxidation. Activity, assessed in female WT mice only, was continually decreased by corticosterone treatment (-53.1±54.8%). Corticosterone treated WT mice became hyperphagic and polydipsic, continuously eating and drinking more than controls. Male and female 11β-HSD1KO mice treated with corticosterone did not experience these effects. Conclusion: These findings provide further insights into the metabolic consequences of GE as well as the dependency on 11β-HSD1 to facilitate them. Whilst elevations are seen in both male and female WT mice, they are greater in females. Activity is decreased meaning it is not responsible for the elevations. However, hyperphagia and the subsequent chemical energy cost of de novo lipogenesis might be responsible and merits further investigation. Presentation: Saturday, June 17, 2023