Inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake.
Inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obesity by causing a reduction in food intake.
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DOI：
10.1371/journal.pone.0014605
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发表时间：
2011-01-27
期刊：
影响因子：
3.7
通讯作者：
Murata Y
中科院分区：
文献类型：
--
作者：
Sun XY;Hayashi Y;Xu S;Kanou Y;Takagishi Y;Tang YP;Murata Y
肥胖是一个严重的国际健康问题，它增加了几种与饮食有关的慢性疾病的风险。导致肥胖的遗传因素尚不清楚。Rcan 2最初被鉴定为甲状腺激素反应基因。在小鼠中，已经鉴定出具有不同组织特异性表达模式的两种剪接变体：Rcan 2 -3主要在脑中表达，而Rcan 2 -1在脑和其他组织如心脏和骨骼肌中表达。在这里，我们表明Rcan 2在年龄和饮食诱导的肥胖症的发展中起着重要作用。我们发现，尽管Rcan 2功能的丧失在出生后的前几周内减缓了小鼠的生长，但它也通过减少食物摄入而不是增加能量消耗来显着改善小鼠的年龄和饮食诱导的肥胖。Rcan 2表达在支配能量平衡的下丘脑腹内侧核、背内侧核和室旁核最为突出。禁食和再喂养实验表明，禁食仅上调下丘脑Rcan 2 -3 mRNA的表达，Rcan 2的缺失显著减弱了饥饿引起的摄食反应。使用双突变（Lepob/ob Rcan 2 −/−）小鼠，我们也能够证明Rcan 2和瘦素通过不同的途径调节体重。我们的研究结果表明，可能存在Rcan 2依赖性机制，该机制通过瘦素非依赖性途径调节食物摄入并促进体重增加。这项研究为控制小鼠体重提供了新的信息，并应提高我们对人类肥胖机制的理解。
Obesity is a serious international health problem that increases the risk of several diet-related chronic diseases. The genetic factors predisposing to obesity are little understood. Rcan2 was originally identified as a thyroid hormone-responsive gene. In the mouse, two splicing variants that harbor distinct tissue-specific expression patterns have been identified: Rcan2-3 is expressed predominately in the brain, whereas Rcan2-1 is expressed in the brain and other tissues such as the heart and skeletal muscle. Here, we show that Rcan2 plays an important role in the development of age- and diet-induced obesity. We found that although the loss of Rcan2 function in mice slowed growth in the first few weeks after birth, it also significantly ameliorated age- and diet-induced obesity in the mice by causing a reduction in food intake rather than increased energy expenditure. Rcan2 expression was most prominent in the ventromedial, dorsomedial and paraventricular hypothalamic nuclei governing energy balance. Fasting and refeeding experiment showed that only Rcan2-3 mRNA expression is up-regulated in the hypothalamus by fasting, and loss of Rcan2 significantly attenuates the hyperphagic response to starvation. Using double-mutant (Lepob/ob Rcan2 −/−) mice, we were also able to demonstrate that Rcan2 and leptin regulate body weight through different pathways. Our findings indicate that there may be an Rcan2-dependent mechanism which regulates food intake and promotes weight gain through a leptin-independent pathway. This study provides novel information on the control of body weight in mice and should improve our understanding of the mechanisms of obesity in humans.
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