Department of Cell, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7796-801. doi: 10.1073/pnas.1210192110. Epub 2013 Apr 18.
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 Alström 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.
虽然初级纤毛作为重要的感觉和信号结构已经得到很好的证实，但它们在大多数组织中的功能仍然未知。肥胖是与纤毛功能障碍综合征相关的特征之一，如 Bardet-Biedl 综合征 (BBS) 和 Alström 综合征，以及几种纤毛突变小鼠模型。最近的数据表明，BBS 突变小鼠的肥胖是由于瘦素受体转运和瘦素抵抗的缺陷。此外，诱导瘦素反应性 proopiomelanocortin 神经元中的纤毛丢失会导致肥胖，这表明下丘脑神经元上的纤毛参与调节摄食行为。在这里，我们直接测试纤毛作为瘦素反应中介的重要性。与当前的教条相反，对不同肥胖状态下条件性 Ift88 纤毛突变小鼠的纵向研究表明，只有当突变体肥胖时才存在瘦素抵抗。我们的研究表明，热量限制会导致预期性摄食行为发生改变，尽管循环瘦素水平正常，但暂时消除了瘦素的厌食作用。有趣的是，预肥胖 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传导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在瘦素缺乏 ob/ob 小鼠中观察到的表型不一致。总的来说，这些数据表明纤毛不直接参与瘦素反应，并且瘦素信号轴的缺陷不是导致与纤毛功能障碍相关的过度摄食和肥胖的起始事件。
