Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice
Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice
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DOI：
10.1210/en.2016-1571
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发表时间：
2016-11-01
期刊：
影响因子：
4.8
通讯作者：
White, Anne
中科院分区：
文献类型：
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作者：
Sefton, Charlotte;Harno, Erika;White, Anne
由于下丘脑-垂体-肾上腺轴紊乱或外源性药物治疗引起的内源性糖皮质激素（Gc）过量被认为会引起不良的代谢副作用。Gc受体（GR）在全身广泛表达，包括下丘脑等大脑区域。然而，慢性Gcs对下丘脑Gc浓度的影响程度以及对GR和靶基因的影响尚不清楚。为了研究这一点，我们使用了皮质酮（Cort）诱导的小鼠肥胖模型，并分析了下丘脑的Cort水平和与Gc作用相关的基因表达。小鼠在饮用水中给予Cort （75 μ g/mL）或乙醇（1%，车辆）4周。皮质激素治疗小鼠的体重、食物摄入量和肥胖程度都有所增加。正如预期的那样，Cort增加了在授时时间1和授时时间13时的血浆Cort水平，消融了昼夜节律。液相色谱双串联质谱分析显示下丘脑皮质激素增加4倍，这与循环水平和其他脑区皮质激素浓度相关。尽管11 β -羟基类固醇脱氢酶（Hsd11b1）表达下降，但外排转运蛋白Abcb1 mRNA未发生改变。此外，虽然Cort使下丘脑GR（Nr3c1）表达降低2倍，但gc诱导的亮氨酸拉链（Tsc22d3） mRNA升高，表明GR激活升高。随着贪食和肥胖的发展，Cort增加了Agrp，但下丘脑Pomc、Npy或Cart mRNA没有变化。总之，慢性Cort治疗导致下丘脑Cort水平的慢性增加和Agrp的持续升高，Agrp是代谢紊乱发展的中介。
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamicpituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 mu g/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11 beta-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamicGR(Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.