Obesity alters circadian expressions of molecular clock genes in the brainstem
Obesity alters circadian expressions of molecular clock genes in the brainstem
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DOI：
10.1016/j.brainres.2008.12.071
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发表时间：
2009-03-31
期刊：
影响因子：
2.9
通讯作者：
Katagiri, Hideki
中科院分区：
文献类型：
--
作者：
Kaneko, Keizo;Yamada, Tetsuya;Katagiri, Hideki
能量稳态的主要组成部分，包括摄食行为和糖脂代谢，都受到昼夜节律的影响。最近的研究表明，分子钟基因的功能障碍参与了肥胖和糖尿病的发展。为了研究代谢状态本身是否会改变中枢神经系统（CNS）的生物钟，我们分析了孤束尾侧脑干核（NTS）中核心时钟基因的每日mRNA表达谱。在瘦的C57 BL/6小鼠中，核心时钟基因（Npas 2、Bmal 1、Per 1、Per 2和Rev-erb alpha）的转录水平清楚地显示出24小时节律性。另一方面，Bmal 1和Rev-erba的表达谱在高脂饮食诱导的肥胖小鼠以及遗传性肥胖的KK-A（y）和ob/ob小鼠中减弱。Clock表达水平在高脂饮食诱导的肥胖小鼠中增加，而Cry 1表达水平在KK-A（y）和ob/ob小鼠中降低。此外，过氧化物酶体增殖物激活受体α（PPAR α），据报道，增加BMAL 1的转录水平，上调这些小鼠模型的肥胖和胰岛素抵抗的NTS，这表明在肥胖状态下的NTS的昼夜节律衰减的PPAR α参与。此外，生物钟基因下游靶点的昼夜节律表达谱，大电导钙激活的K（+）通道，在这些小鼠肥胖模型的NTS中受到干扰。这些扰动可能导致肥胖状态下的神经元功能障碍。这是第一个报告表明，肥胖扰乱了中枢神经系统的核心时钟基因的昼夜表达。(C)2009年由Elsevier B. V.出版
Major components of energy homeostasis, including feeding behavior and glucose and lipid metabolism, are subject to circadian rhythms. Recent studies have suggested that dysfunctions of molecular clock genes are involved in the development of obesity and diabetes. To examine whether metabolic states per se alter the circadian clock in the central nervous system (CNS), we analyzed the daily mRNA expression profiles of core clock genes in the caudal brainstem nucleus of the solitary tract (NTS). In lean C57BL/6 mice, transcript levels of the core clock genes (Npas2, Bmal1, Per1, Per2 and Rev-erb alpha) clearly showed 24-h rhythmicity. On the other hand, the expression profiles of Bmal1 and Rev-erba were attenuated in mice with high fat diet-induced obesity as well as genetically obese KK-A(y) and ob/ob mice. Clock expression levels were increased in mice with high fat diet-induced obesity and Cry1 expression levels were decreased in KK-A(y) and ob/ob mice. In addition, peroxisome proliferator-activated receptor alpha (PPAR alpha), which reportedly increases the BMAL1 transcriptional level, was up-regulated in the NTS of these murine models of obesity and insulin resistance, suggesting involvement of PPAR alpha in the attenuation of circadian rhythms in the NTS in obese states. Furthermore, a circadian expression profile of a downstream target of clock genes, the large conductance Ca2+-activated K(+)channel, was disturbed in the NTS of these murine obesity models. These perturbations might contribute to neuronal dysfunction in obese states. This is the first report showing that obesity perturbs the circadian expressions of core clock genes in the CNS. (C) 2009 Published by Elsevier B.V.