High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice
High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice
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DOI：
10.1152/ajpendo.00512.2012
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发表时间：
2013-05-01
影响因子：
5.1
通讯作者：
Oster, Henrik
中科院分区：
文献类型：
--
作者：
Barclay, Johanna L.;Shostak, Anton;Oster, Henrik
哺乳动物昼夜节律的扰动，无论是由环境影响，如轮班工作或遗传操作，已与代谢紊乱和肥胖症和糖尿病的发展。生物钟基于转录/翻译反馈环，包括正和负分量。虽然时钟基因机制的正臂缺失的代谢效应，如在时钟或Bmal 1缺陷小鼠中，已经得到很好的表征，周期基因（Per 1 -3）作为负臂的组成部分的失活对能量稳态具有更复杂的，有时是矛盾的影响。线粒体色素是PER的关键相互作用伙伴，同时缺失Cry 1和Cry 2导致行为和分子昼夜节律的不稳定性。我们发现，当用高脂肪饮食进行挑战时，Cry 1/2（-/-）小鼠迅速增加体重并超过野生型小鼠，尽管表现出食欲减退。白色脂肪组织的转录分析揭示了脂肪生成基因的上调表达，其中许多是胰岛素靶点。高脂饮食诱导的高胰岛素血症，作为增强胰岛素分泌的结果，加上Cry 1/2（-/-）小鼠脂肪组织中的选择性胰岛素敏感性，与脂质摄取增加相关。总的来说，这些数据表明，Cry缺乏导致对高脂肪饮食诱导的肥胖症的易感性增加，这可能是由脂肪组织中胰岛素分泌和脂质储存增加介导的。
Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes (Per1-3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and -2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2(-/-) mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals up-regulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2(-/-) mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.