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Akr1d1-/- mice have a sexually dimorphic metabolic phenotype with reduced fat mass, increased insulin sensitivity and hypertriglyceridemia in males

By Laura L Gathercole, Nikolaos Nikolaou, Anastasia Arvaniti, Shelley E Harris, Toryn Poolman, Jonathan M Hazlehurst, Denise V Kratschmar, Marijana Todorcevic, Ahmad Moolla, Niall Dempster, Ryan C. Pink, Michael F Saikali, Liz Bentley, Trevor M Penning, Claes Ohlsson, Carolyn L Cummins, Matti Poutanen, Alex Odermatt, Roger D Cox, Jeremy W Tomlinson

Posted 02 Feb 2021
bioRxiv DOI: 10.1101/2021.02.02.429227

Background: Steroid 5{beta}-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. Methods: Akr1d1-/- mice were generated on a C57BL/6 background. Liquid chromatography / mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. Male Akr1d1-/- mice were challenged with a 60% high fat diet. Results: Akr1d1-/- mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, Akr1d1-/- mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male Akr1d1-/- mice were not protected against diet induced obesity and insulin resistance. Conclusion: This study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.

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