| First Author | Bell RMB | Year | 2021 |
| Journal | Mol Metab | Volume | 48 |
| Pages | 101225 | PubMed ID | 33785425 |
| Mgi Jnum | J:304452 | Mgi Id | MGI:6690335 |
| Doi | 10.1016/j.molmet.2021.101225 | Citation | Bell R, et al. (2021) Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice. Mol Metab :101225 |
| abstractText | OBJECTIVE: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20beta-dihydrocorticosterone (20beta-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to the cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue, and impacts glucose homeostasis in the lean and obese state. METHODS: The actions of 20beta-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. RESULTS: 20beta-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect which was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20beta-DHB and absent in female mice with higher baseline adipose 20beta-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. CONCLUSIONS: Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue which influences glucose homeostasis in lean mice. |
