Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice
Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice
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DOI：
10.1073/pnas.1210192110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Yoder, Bradley K.
中科院分区：
文献类型：
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作者：
Berbari, Nicolas F.;Pasek, Raymond C.;Yoder, Bradley K.
虽然初级纤毛被认为是重要的感觉和信号结构，但它们在大多数组织中的功能仍不清楚。肥胖是纤毛功能障碍的一些症状相关的特征，如Bardet-Biedl综合征(BBS)和Alstrom综合征，以及在几种纤毛突变小鼠模型中。最近的数据表明，BBS突变小鼠的肥胖是由于瘦素受体运输和瘦素抵抗的缺陷所致。此外，诱导瘦素反应的前阿片黑素皮质素原神经元纤毛丢失导致肥胖，暗示下丘脑神经元上的纤毛调节摄食行为。在这里，我们直接测试纤毛作为瘦素反应的中介的重要性。与目前的教条相反，对条件Ift88纤毛突变小鼠在不同肥胖状态下的纵向研究表明，只有当突变小鼠肥胖时，才会出现瘦素抵抗。我们的研究表明，卡路里限制会导致预期进食行为的改变，这种行为暂时取消了瘦素的厌食作用，尽管循环中的瘦素水平正常。有趣的是，肥胖前期Bbs4突变小鼠对瘦素的厌食作用有反应，并且没有表现出与瘦素信号缺陷相关的其他表型。此外，纤毛突变小鼠的体温调节和活动测量与先前观察到的瘦素缺乏ob/ob小鼠的表型不一致。总之，这些数据表明纤毛并不直接参与瘦素的反应，瘦素信号轴的缺陷并不是导致纤毛功能障碍的过度吞噬和肥胖的始动事件。
Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alstrom syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.