Endocrine Abstracts

Steroid hormones and bile acids are potent regulators of metabolic phenotype. 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 AKR1D1KO mice had altered hepatic steroid (in vitro cortisone clearance: 100% [WT], 70% [KO]; in vitro 5α-cortisone/cortisol generation 100% [WT], 390% [KO]) and bile acid metabolism (hepatic bile 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 10 weeks, KO animals were the same weight as wildtype (WT) littermates with no differences in glucose tolerance. Mice were challenged with a further 20-weeks of high fat diet feeding whereon female, but not male, AKR1D1KO mice were protected from diet induced weight gain (weight gain males: 21.8 g±0.9 g [WT], 21.4 g±0.7 g [KO] P=ns; females: 27.2 g±0.5 g [WT], 15.8 g±1.2 g [KO] P<0.01), with reduced adipose tissue mass across all depots (gonadal: 4.0 g±0.2 g [WT], 2.4 g±0.4 g [KO] P<0.005; subcutaneous: 3.9 g±0.3 g [WT], 2.4 g±0.5 g [KO] P<0.05; mesenteric: 1.9 g±0.2 g [WT], 1.2 g±0.3 g [KO] P<0.05), but with preserved lean mass. Female AKR1D1KO mice were also protected from the metabolic consequences of the high fat diet, with improved glucose tolerance (ipGTT AUC females: 3216 mMol×min [WT], 2601 mMol×min [KO] P<0.05) and enhanced insulin sensitivity (ipITT AUC females: 1171 mMol×min [WT], 947 mMol×min [KO]).

AKR1D1KO mice display a sexually dimorphic metabolic phenotype, where female mice are protected from the adverse metabolic effects of a high fat diet. Although the underpinning mechanisms remain to be fully defined, AKR1D1 may represent a future novel therapeutic target for the treatment of metabolic disease.