Impairment of Peripheral Circadian Clocks Precedes Metabolic Abnormalities in ob/ob Mice
Impairment of Peripheral Circadian Clocks Precedes Metabolic Abnormalities in ob/ob Mice
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DOI：
10.1210/en.2010-1068
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发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Fujimura, Akio
中科院分区：
文献类型：
--
作者：
Ando, Hitoshi;Kumazaki, Masafumi;Fujimura, Akio
最近的研究已经证明了生物钟功能障碍和代谢异常的发展之间的关系，但鸡和蛋的问题仍然没有解决。为了解决这个问题，我们研究了肥胖、糖尿病ob/ob小鼠的因果关系。与对照C57 BL/6 J小鼠相比，10周龄ob/ob小鼠的肝脏和脂肪组织中时钟和时钟控制基因Clock、Bmal 1、Cry 1、Per 1、Per 2和Dbp的每日mRNA表达谱明显减弱，但下丘脑视交叉上核的表达谱没有减弱。在ob/ob小鼠中，4周的低热量饮食喂养和7天的瘦素给药在显著和相当的程度上减弱了观察到的代谢异常（肥胖、高血糖、高胰岛素血症和高胆固醇血症）。然而，只有瘦素治疗改善受损的外周时钟。此外，通过测量峰期前后Per 1、Per 2和Dbp mRNA水平评估的生物钟功能，在无明显代谢异常的3周龄ob/ob小鼠外周组织中也降低了。总的来说，这些结果表明，在ob/ob小鼠外周时钟的损害不导致代谢异常，但可能至少部分地由瘦素缺乏本身引起的。需要进一步的研究来阐明瘦素缺乏如何影响外周生物钟。（内分泌学152：1347-1354，2011）
Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of metabolic abnormalities, but the chicken-and-egg question remains unresolved. To address this issue, we investigated the cause-effect relationship in obese, diabetic ob/ob mice. Compared with control C57BL/6J mice, the daily mRNA expression profiles of the clock and clock-controlled genes Clock, Bmal1, Cry1, Per1, Per2, and Dbp were substantially dampened in the liver and adipose tissue, but not the hypothalamic suprachiasmatic nucleus, of 10-wk-old ob/ob mice. Four-week feeding of a low-calorie diet and administration of leptin over a 7-d period attenuated, to a significant and comparable extent, the observed metabolic abnormalities (obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia) in the ob/ob mice. However, only leptin treatment improved the impaired peripheral clocks. In addition, clock function, assessed by measuringlevels of Per1, Per2, and Dbp mRNA at around peaktimes, was also reduced in the peripheral tissues of 3-wk-old ob/ob mice without any overt metabolic abnormalities. Collectively these results indicate that the impairment of peripheral clocks in ob/ob mice does not result from metabolic abnormalities but may instead be at least partially caused by leptin deficiency itself. Further studies are needed to clarify how leptin deficiency affects peripheral clocks. (Endocrinology 152: 1347-1354, 2011)