Objective

Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing's Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by the production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Thus, we sought to investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats.

Methods

Recombinant adeno-associated virus particles bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1), respectively, were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels.

Results

Compared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake.

Conclusions

Therefore ARC corticosterone, regulated by 11βHSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11βHSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders, and other conditions.

中文翻译：

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下丘脑弓状核内皮质酮对雄性大鼠食物摄入和体重的影响。

客观的

肥胖是发病率和死亡率的主要原因。很少有减肥药物可用，而且这些药物的功效有限。库欣综合征（由糖皮质激素水平升高引起）和肥胖具有相似的代谢特征。尽管肥胖患者的循环糖皮质激素水平没有升高，但组织特异性糖皮质激素水平与肥胖代谢表型的发展有关。组织糖皮质激素水平受 11β-羟基类固醇脱氢酶 1 型 (11βHSD1) 调节，其通过 11-脱氢皮质酮产生皮质酮来增加活性糖皮质激素的局部浓度。11βHSD1 在下丘脑弓状核 (ARC) 中表达，ARC 是一个主要的体重和食欲调节中心，因此代表了新型抗肥胖治疗药物的靶点。因此，

方法

分别将带有感觉 11βHSD1 (rAAV-S11βHSD1) 和小干扰 11βHSD1 (rAAV-si11βHSD1) 的重组腺相关病毒颗粒立体定向注射到成年雄性 Wistar 大鼠的 ARC（双侧）中。将 rAAV-GFP 注射到雄性 Wistar 大鼠的对照组中。每周测量 3 次食物摄入量和体重，持续 70 天。采集末端脑、血浆和肩胛内棕色脂肪组织 (iBAT) 样本用于测量 mRNA 表达和激素水平。

结果

与对照组相比，rAAV-S11βHSD1 注射导致更高的 ARC 皮质酮水平、食欲过盛和体重增加增加。相反，rAAV-si11βHSD1 注射（与对照组相比）导致较低的 ARC 皮质酮水平、较高的 iBAT 解偶联蛋白-1 mRNA 表达和较少的体重增加，尽管食物摄入量相似。

结论

因此受 11βHSD1 调节的 ARC 皮质酮可能在食物摄入和体重调节中发挥作用。这些数据对开发中枢作用的 11βHSD1 抑制剂具有重要意义，目前正在开发用于治疗肥胖、代谢紊乱和其他疾病的药物。