Steroid hormones and bile acids are potent regulators of metabolism. The enzyme 5β-reductase (AKR1D1) has a crucial role in bile acid synthesis and also generates 5β-reduced dihydrosteroid metabolites, regulating intra-cellular steroid availability though the clearance of cortisol, testosterone, androstenedione, and progesterone. As AKR1D1 sits at the interface of bile acid synthesis and steroid metabolism, we have hypothesised that it plays a key role in metabolic homeostasis and have generated and characterised an entirely novel, global AKR1D1 knockout (KO) mouse. As expected AKR1D1 KO mice had altered hepatic steroid (in vitro cortisone clearance: 100% (WT), 70% (KO); in vitro 5α-cortisone/cortisol metabolite generation increased 3.9-fold (KO)) and bile acid metabolism (hepatic bile acid concentration males: 1164±626 pmol/mg (WT), 122±42 pmol/mg (KO) P<0.05; females: 310±67 pmol/mg (WT), 113±23 pmol/mg (KO) P<0.01). At 30 weeks male, but not female, AKR1D1KO animals were lighter than wildtype (WT) littermates (males: 35.6±0.9 g (WT), 33.2±0.6 g (KO) P<0.05; females: 25.3±0.6 g (WT), 24.9±0.4 g (KO) P=ns) with lower total (9.7±0.7 g (WT), 7.4±0.5 g (KO) P<0.05) and % (29±1.4% (WT), 24±1.5% (KO) P<0.05) fat mass, as determined by DEXA. At termination, male AKR1D1 KO mice had smaller subcutaneous adipose depots (1.0±0.1 g (WT), 0.7±0.1 g (KO) P<0.05) and, despite no difference in body weight or composition, female KO animals had smaller gonadal fat depots (0.5±0.1 g (WT), 0.3 g±0.03 g (KO) P<0.05). Both male and female AKR1D1KO mice had enhanced insulin sensitivity (ipITT AUC males: 793 mMol min (WT), 647 mMol min (KO); ipITT AUC females: 663 mMol min (WT), 568 mMol min (KO)), without changes in glucose tolerance. AKR1D1 KO mice display a sexually dimorphic metabolic phenotype. Whereas both male and female AKR1D1 KO mice have increased insulin sensitivity, only male AKR1D1 KO mice have a lean phenotype. Although the underpinning mechanisms remain to be fully defined, AKR1D1 may represent a future novel therapeutic target for the treatment of metabolic disease.
20 - 23 May 2017
European Society of Endocrinology