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

IF 2.2 4区医学 Q3 BIOCHEMICAL RESEARCH METHODS

Molecular Imaging Pub Date : 2024-12-18 eCollection Date: 2024-01-01 DOI:10.1177/15353508241301584

Jason Bini, Jordan Strober, Michael Kapinos, Ming-Qiang Zheng, Songye Li, Jim Ropchan, Nabeel Nabulsi, Yiyun Huang, Rachel J Perry, Daniel F Vatner, Richard E Carson

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引用次数: 0

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 levels in vivo may be key to understanding obesity pathophysiology.

Objective: We used a Zucker Fatty (ZF) rat model and [¹⁸F]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 [¹⁸F]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 with ex vivo 11β-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 [¹⁸F]AS2471907 PET, which correlated with measures of glucose and fatty acid metabolism.

Conclusion: We demonstrate that [¹⁸F]AS2471907 PET can provide useful quantification of 11β-HSD1 levels in a rodent model of obesity.

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Zucker脂肪大鼠模型多器官11β-羟基类固醇脱氢酶1型酶水平的定量：PET成像研究

背景：在啮齿类动物中，11β-羟基类固醇脱氢酶1 （11β-HSD1）催化无活性的11-脱氢皮质酮转化为活性激素皮质酮。细胞内糖皮质激素作用失调与代谢性疾病有关。评估体内11β-HSD1酶水平可能是了解肥胖病理生理的关键。目的：我们采用Zucker Fatty （ZF）大鼠模型和[18F]AS2471907 PET成像确定合适的动力学建模方法，评估肥胖导致肝脏、白色和棕色脂肪组织（WAT/BAT）和大脑中11β-HSD1水平的变化。材料和方法：为了验证[18F]AS2471907 PET在临床前模型中的有效性，生成时间-活动曲线（TACs），并使用从多个位置提取的图像衍生输入函数（idif）进行动力学建模。将放射性配体结合的定量估计与体外11β-HSD1蛋白表达进行比较。然后使用经过验证的定量PET动力学建模方法来评估瘦和肥胖ZF大鼠之间11β-HSD1的差异。葡萄糖和脂肪酸代谢的稳定同位素示踪研究证实了代谢性疾病的状态。结果：通过[18F]AS2471907 PET检测，肥胖与大脑11β-HSD1水平降低相关，并与葡萄糖和脂肪酸代谢相关。结论：我们证明[18F]AS2471907 PET可以提供有效的定量肥胖啮齿动物模型中11β-HSD1的水平。

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来源期刊

Molecular Imaging Biochemistry, Genetics and Molecular Biology-Biotechnology

自引率

3.60%

发文量

期刊介绍： Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.