Quantification of Multi-Organ 11β-Hydroxysteroid Dehydrogenase Type 1 Enzyme Levels in a Zucker Fatty Rat Model: A PET Imaging Study.

Abstract

BACKGROUND: In rodents, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the conversion of inactive 11-dehydrocorticosterone to the active hormone corticosterone. Dysregulation of intracellular glucocorticoid action is implicated in metabolic diseases. Assessing 11β-HSD1 enzyme levelsmay be key to understanding obesity pathophysiology. OBJECTIVE: We used a Zucker Fatty (ZF) rat model and [F]AS2471907 PET imaging to determine appropriate kinetic modeling methods and assess changes in 11β-HSD1 levels due to obesity in the liver, white and brown adipose tissue (WAT/BAT), and brain. MATERIAL AND METHODS: To validate [F]AS2471907 PET in preclinical models, time-activity curves (TACs) were generated and kinetic modeling was performed with image-derived input functions (IDIFs) extracted from multiple locations. Quantitative estimates of radioligand binding were compared with11β-HSD1 protein expression. Validated quantitative PET kinetic modeling methods were then used to assess differences in 11β-HSD1 between lean and obese ZF rats. Metabolic disease status was confirmed with stable isotopes tracer studies of glucose and fatty acid metabolism. RESULTS: Obesity is associated with decreased brain 11β-HSD1 levels, measured by [F]AS2471907 PET, which correlated with measures of glucose and fatty acid metabolism. CONCLUSION: We demonstrate that [F]AS2471907 PET can provide useful quantification of 11β-HSD1 levels in a rodent model of obesity.