Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice
Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice
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DOI：
10.1007/s00125-008-0929-8
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发表时间：
2008-02
期刊：
影响因子：
8.2
通讯作者：
H. Tsuneki;S. Murata;Y. Anzawa;Y. Soeda;Emi Tokai;T. Wada;I. Kimura;Masashi Yanagisawa;Takeshi Sa
中科院分区：
文献类型：
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作者：
H. Tsuneki;S. Murata;Y. Anzawa;Y. Soeda;Emi Tokai;T. Wada;I. Kimura;Masashi Yanagisawa;Takeshi Sa
目的/假说食欲素/下丘脑泌素是一种下丘脑神经肽，调节动机行为，如进食和唤醒，重要的是，也参与能量稳态。本研究的目的是揭示食欲素在调节胰岛素敏感性的葡萄糖metabolis.MethodsOrexin基因敲除小鼠禁食过夜进行口服葡萄糖耐量试验和胰岛素耐量试验的作用。食欲素缺乏对胰岛素信号传导的影响进行了研究，通过蛋白质印迹法测量Akt磷酸化水平及其上游和下游分子在下丘脑，肌肉和肝脏中的食欲素knockout mice.ResultsWe发现，食欲素缺乏引起的年龄相关的发展的葡萄糖耐量受损和胰岛素抵抗的雄性小鼠没有肥胖和雌性小鼠轻度肥胖，喂养正常的食物饮食。当维持高脂肪饮食时，这些异常仅在发展为严重肥胖的雌性食欲素敲除小鼠中变得更加明显。通过Akt的胰岛素信号传导在中年（9个月大）的外周组织中被破坏，但在正常饮食喂养的年轻成年（2至3个月大）的食欲素敲除小鼠中没有被破坏。此外，在所研究的每个年龄的食欲素敲除小鼠中，下丘脑Akt磷酸化的基础水平异常升高，并且胰岛素刺激未能增加磷酸化水平。观察到类似的异常，就在下丘脑和周围组织的中年食欲素基因敲除mice.Conclusions/interpretationOur结果表明食欲素在下丘脑胰岛素信号，这可能是负责防止外周胰岛素抵抗的发展与年龄的一种新的作用。
Aims/hypothesisOrexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism.MethodsOrexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice.ResultsWe found that orexin deficiency caused the age-related development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice.Conclusions/interpretationOur results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.