Abstract
ObjectiveCarbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to 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 lean and obese states. MethodsThe actions of 20β-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. Results20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that 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 20β-DHB and absent in female mice with higher baseline adipose 20β-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. ConclusionsCarbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.
Highlights
Glucocorticoids act through widely expressed glucocorticoid receptors (GR) and the more tissuespecific mineralocorticoid receptor (MR) to modulate fuel metabolism, the immune system and salt and water balance
Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue which influences glucose homeostasis in lean mice
We recently showed that the cytosolic enzyme Carbonyl Reductase 1 (Cbr1) is a novel regulator of tissue glucocorticoid metabolism, converting cortisol/corticosterone into 20β-dihydrocortisol (20βDHF) or 20β-corticosterone (20β-DHB), both of which are weak agonists of the human and murine GR [15]
Summary
The mass spectrometer was operated at 600oC with polarity switching in multiple reaction mode in negative mode (-4.5 kV) for Aldosterone at m/z 359.0 → 188.9 at -24V, 359.0 → 331.1 at -22V and d8Aldo at m/z 367.1 → 193.9 at -26V and in positive mode (5.5 kV) for B, 20β-DHB at m/z 347.1 → 121.1 at 29V, 347.1 → 90.0 at 75V, 365.2 → 269.1 at 25V and 365.2 → 121.0 at 33V and m/z 355.3 → 125.1 at 31V for d8-B They eluted at 2.3, 2.3, 2.5, 3.4 and 3.3 mins. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit. Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit on the NextSeq 550 platform (Illumina Inc). Following identification of putatively differentially-expressed genes, the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways [1] and Gene Ontology (GO) terms [2] were assessed for pathway enrichment using a hypergeometric test.
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