Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism
Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism
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DOI：
10.2337/diabetes.54.6.1846
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发表时间：
2005-06-01
期刊：
影响因子：
7.7
通讯作者：
Bhanot, S
中科院分区：
文献类型：
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作者：
Watts, LM;Manchem, VP;Bhanot, S
糖皮质激素（GC）可增加肝脏糖异生，并在调节肝脏葡萄糖输出中发挥重要作用。虽然全身性 GC 抑制可以缓解啮齿动物和人类的高血糖，但它会导致肾上腺功能不全并刺激下丘脑-垂体-肾上腺轴。在本研究中，我们使用优化的反义寡核苷酸（ASO）引起肝脏和白色脂肪组织（WAT）中糖皮质激素受体（GCCR）的选择性减少，并评估了几种糖尿病啮齿动物模型中葡萄糖和脂质代谢的变化。用 GCCR ASO 治疗 ob/ob 小鼠 4 周，肝脏和 WAT 中 GCCR mRNA 表达分别减少了 75% 和 40%。与此同时，进食时血糖水平降低了 65%，空腹血糖水平降低了 30%，血浆胰岛素浓度降低了 60%，血浆抵抗素和肿瘤坏死因子-a 水平分别降低了 20% 和 35%。此外，GCCR ASO 减少了基础和地塞米松处理动物肝脏切片中的肝脏葡萄糖生成并抑制肝脏糖异生。在 db/db 小鼠中，GCCR 表达的类似降低导致进食和空腹血糖水平降低 40%，血浆甘油三酯降低 50%。在 ZDF 和高脂饮食喂养的链脲佐菌素 (HFD-STZ) 治疗的大鼠中，GCCR ASO 治疗导致肝脏和 WAT 中 GCCR 表达降低 60%，同时空腹血糖水平降低 40-70%，血浆甘油三酯、胆固醇和游离脂肪酸大幅降低。 GCCR ASO 治疗后，任何模型中循环皮质酮水平均未见变化。为了进一步证明 GCCR ASO 不会引起全身性 GC 拮抗作用，正常 Sprague-Dawley 大鼠在用 GCCR ASO 治疗后接受地塞米松攻击。地塞米松增加了肝脏中 GC 响应基因（如 PEPCK）的表达，并减少了循环淋巴细胞。 GCCR ASO 治疗完全抑制了地塞米松诱导的肝脏中 PEPCK 表达的增加，而不引起地塞米松诱导的淋巴细胞减少的任何变化。这些研究表明，ASO 的组织选择性 GCCR 拮抗作用可能是治疗代谢综合征的可行治疗策略。
Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in similar to 75 and similar to 40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by similar to 65% decrease in fed and similar to 30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and similar to 20 and 35% decrease in plasma resistin and tumor necrosis factor-a levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused similar to 40% decrease in fed and fasted glucose levels and similar to 50% reduction in plasma triglycerides. In ZDF and high-fat diet-fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused similar to 60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40-70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasone-induced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.