Pharmacological Evaluation of Adipose Dysfunction via 11β-Hydroxysteroid Dehydrogenase Type 1 in the Development of Diabetes in Diet-Induced Obese Mice with Cortisone Pellet Implantation
Pharmacological Evaluation of Adipose Dysfunction via 11β-Hydroxysteroid Dehydrogenase Type 1 in the Development of Diabetes in Diet-Induced Obese Mice with Cortisone Pellet Implantation
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DOI：
10.1124/jpet.113.210716
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Hanasaki, Kohji
中科院分区：
文献类型：
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作者：
Akiyama, Nobuteru;Akiyama, Yuko;Hanasaki, Kohji
据报道，来自细胞内糖皮质激素（GC）的信号通过脂肪组织中的1型11 β-羟基类固醇脱氢酶（11 β-HSD 1）充当放大器，导致与肥胖相关的葡萄糖代谢恶化。为了阐明在肥胖相关糖尿病的发展中通过11 β-HSD 1激活的脂肪功能障碍，我们通过在饮食诱导的肥胖（DIO）小鼠中植入可的松颗粒（CP）建立了新型糖尿病小鼠。可的松颗粒植入DIO小鼠（DIO/CP小鼠）表现出高血糖症，胰岛素抵抗，高脂血症和异位脂肪堆积，而可的松颗粒植入瘦小鼠不诱导高血糖症。DIO/CP小鼠在高血糖出现前，血浆甘油和非酯化脂肪酸（NEFAs）等脂解指标升高。此外，与假手术DIO小鼠相比，DIO/CP小鼠的脂肪11 β-HSD 1 mRNA水平上调。RU 486（米非司酮，11 β-[对-（二甲氨基）苯基]-17 β-羟基-17-（1-丙炔基）雌甾-4，9-二烯-3-酮），一种糖皮质激素受体拮抗剂，降低脂肪11 β-HSD 1和脂肪甘油三酯脂肪酶的mRNA水平。RU 486还改善DIO/CP小鼠的血浆NEFA、甘油和葡萄糖水平。这些结果表明，通过11 β-HSD 1由GC激活引起的脂肪组织中的脂解是具有异位脂肪积聚的糖尿病的触发因素。我们的研究结果还表明，GC信号通过脂肪组织中11 β-HSD 1上调的恶性循环的可能性，有助于葡萄糖代谢的恶化，导致糖尿病。我们的DIO/CP小鼠可能是通过11 β-HSD 1评估脂肪功能障碍的2型糖尿病的合适模型。
Signals from intracellular glucocorticoids (GCs) via 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) in adipose tissues have been reported to serve as amplifiers leading to deterioration of glucose metabolism associated with obesity. To elucidate adipose dysfunction via 11 beta-HSD1 activation in the development of obesity-related diabetes, we established novel diabetic mice by implanting a cortisone pellet (CP) in diet-induced obesity (DIO) mice. Cortisone pellet-implanted DIO mice (DIO/CP mice) showed hyperglycemia, insulin resistance, hyperlipidemia, and ectopic fat accumulation, whereas cortisone pellet implantation in lean mice did not induce hyperglycemia. In DIO/CP mice, indexes of lipolysis such as plasma glycerol and nonesterified fatty acids (NEFAs) increased before hyperglycemia appeared. Furthermore, the adipose mRNA level of 11 beta-HSD1 was up-regulated in DIO/CP mice compared with sham-operated DIO mice. RU486 (mifepristone, 11 beta-[p-(dimethylamino)phenyl]-17 beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), a glucocorticoid receptor antagonist, decreased adipose mRNA levels of 11 beta-HSD1 as well as adipose triglyceride lipase. RU486 also improved plasma NEFA, glycerol, and glucose levels in DIO/CP mice. These results demonstrate that lipolysis in adipose tissues caused by GC activation via 11 beta-HSD1 serves as a trigger for diabetes with ectopic fat accumulation. Our findings also indicate the possibility of a vicious circle of GC signals via 11 beta-HSD1 up-regulation in adipose tissues, contributing to deterioration of glucose metabolism to result in diabetes. Our DIO/CP mouse could be a suitable model of type 2 diabetes to evaluate adipose dysfunction via 11 beta-HSD1.