Ciliary Mchr 1 Signaling in Feeding Behavior and Obesity

项目总结 肥胖是过早死亡的主要原因，因为它与糖尿病等并发症相关， 心脏病和中风。美国三分之二的成年人超重，这增加了美国人的负担 医疗保健系统。尽管曾被认为是过度放纵的社会问题，但现代科学已经 揭示了基因对体重的深刻影响。人类和动物罕见的单基因肥胖症 模型表明，能量平衡的调节是复杂的，涉及到许多相互交织的信号。 小路。 Bardet-Biedl综合征(BBS)和阿尔斯特伦综合征(ALMS)均为遗传性疾病 随着进食量和肥胖症的增加。这些罕见的综合征是纤毛病的例子，纤毛病是一种遗传性疾病 以纤毛功能障碍为病因的疾病。初生纤毛很小，单生，以微管为基础。 长期以来被认为是退化细胞器的细胞附属物。因此，令人惊讶的是，他们的 在人类和动物模型中，功能障碍都与肥胖有关。纤毛的破坏特别是在 小鼠的大脑会导致与过度吞噬相关的肥胖。最近的研究表明纤毛或与其相关的 蛋白质在协调瘦素信号中的作用，尽管这一点仍然存在争议和不清楚。它最近也 已有研究表明，几种G蛋白偶联受体优先定位于神经元纤毛。这些是如何 纤毛受体和信号通路可能会影响摄食行为，肥胖症也尚不清楚。这个 该项目的目标是确定通过特定的纤毛受体改变的信号是否具有 在进食行为中的作用，黑色素浓缩激素受体1，有助于肥胖表型。一个 对纤毛和肥胖之间的联系的深入理解可能会打开新的治疗方法 解决影响美国民众健康的最重要的临床问题之一。

PROJECT SUMMARY Obesity is a major cause of premature mortality due to its associated co-morbidities such as diabetes, heart disease and stroke. Two-thirds of adults in the United States are overweight, adding immense costs to the healthcare system. Although once considered to be a social issue of overindulgence, modern science has revealed a profound effect of genetics on body weight. Rare monogenetic forms of obesity in humans and animal models have revealed that the regulation of energy balance is complex, involving numerous intertwined signaling pathways. Both Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are genetic disorders that present with increases in eating and obesity. These rare syndromes are examples of ciliopathies, a class of genetic disorders that have cilia dysfunction as their etiological basis. Primary cilia are small, solitary, microtubule based cellular appendages that were long thought to be vestigial organelles. Thus, it was surprising that their dysfunction was associated with obesity in both humans and animal models. Disruption of cilia specifically within the brain of mice results in hyperphagia associated obesity. Recent work has implicated cilia or their associated proteins in coordinating leptin signaling, although this remains controversial and unclear. It has also recently been shown that several G-protein coupled receptors preferentially localize to the cilia of neurons. How these ciliary receptors and signaling pathways may impact feeding behavior and obesity also remains unclear. The goal of this project is to determine if altered signaling through a specific ciliary receptor that is known to have a role in feeding behavior, melanin concentrating hormone receptor 1, contributes to the obesity phenotype. A strong understanding of the connection between cilia and obesity could open new therapeutic approaches to address one of the most clinically important issues impacting the health of the American populace.