Hypothalamic JNK1 and IKKβ Activation and Impaired Early Postnatal Glucose Metabolism after Maternal Perinatal High-Fat Feeding
Hypothalamic JNK1 and IKKβ Activation and Impaired Early Postnatal Glucose Metabolism after Maternal Perinatal High-Fat Feeding
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DOI：
10.1210/en.2011-1589
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
Doetsch, Joerg
中科院分区：
文献类型：
--
作者：
Rother, Eva;Kuschewski, Ruth;Doetsch, Joerg
下丘脑炎症已被证明是肥胖型2型糖尿病发病的一个重要机制。喂养怀孕和哺乳期的啮齿类动物，富含饱和脂肪酸的饮食一直被证明容易使后代患上肥胖症和糖代谢受损。然而，子代的下丘脑炎症还没有被认为是潜在的潜在机制。在这项研究中，处女C57BL/6小鼠从受孕开始接受高脂肪喂养，直到出生后21天断奶。在哺乳期间，后代的体重、体脂含量和血清瘦素浓度都有所增加。对出生后21天的后代下丘脑组织的分析显示，Toll样受体4信号级联的几个成员上调，随后激活了c-jun氨基末端激酶1和I-kappa B激酶-β炎症通路。有趣的是，后代的糖耐量测试显示出糖耐量受损的迹象，同时肝脏中关键的葡萄糖异生酶磷酸烯醇式丙酮酸羧酸激酶的表达增加。此外，肝脏和胰腺的PGC1a表达显著增加，表明交感神经在调节下丘脑炎症对外周的影响中发挥了作用。综上所述，我们的数据表明，下丘脑炎症在围产期高脂喂养后糖耐量异常的早期发病机制中起重要作用。(内分泌学153：770-781,2012)
Hypothalamic inflammation has been demonstrated to be an important mechanism in the pathogenesis of obesity-induced type 2 diabetes mellitus. Feeding pregnant and lactating rodents a diet rich in saturated fatty acids has consistently been shown to predispose the offspring for the development of obesity and impaired glucose metabolism. However, hypothalamic inflammation in the offspring has not been addressed as a potential underlying mechanism. In this study, virgin female C57BL/6 mice received high-fat feeding starting at conception until weaning of the offspring at postnatal d 21. The offspring developed increased body weight, body fat content, and serum leptin concentrations during the nursing period. Analysis of hypothalamic tissue of the offspring at postnatal d 21 showed up-regulation of several members of the toll-like receptor 4 signaling cascade and subsequent activation of c-Jun N-terminal kinase 1 and I kappa B kinase-beta inflammatory pathways. Interestingly, glucose tolerance testing in the offspring revealed signs of impaired glucose tolerance along with increased hepatic expression of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. In addition, significantly increased hepatic and pancreatic PGC1 alpha expression suggests a role for sympathetic innervation in mediating the effects of hypothalamic inflammation to the periphery. Taken together, our data indicate an important role for hypothalamic inflammation in the early pathogenesis of glucose intolerance after maternal perinatal high-fat feeding. (Endocrinology 153: 770-781, 2012)