Ciliary Mchr 1 Signaling in Feeding Behavior and Obesity

项目摘要 肥胖是过早死亡的主要原因，这是由于其相关的合并症，如糖尿病， 心脏病和中风。在美国，三分之二的成年人超重，这给人们的生活带来了巨大的负担。 医疗保健系统。虽然曾经被认为是一个社会问题的过度放纵，现代科学已经 揭示了基因对体重的深远影响。人类和动物中罕见的单基因型肥胖 模型显示，能量平衡的调节是复杂的，涉及许多相互交织的信号 途径。 Bardet-Biedl综合征（BBS）和Alström综合征（ALMS）都是遗传性疾病， 随着饮食和肥胖的增加。这些罕见的综合征是纤毛病的例子，纤毛病是一类遗传性疾病， 以纤毛功能障碍为病因学基础的疾病。初级纤毛小，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令人惊讶的是， 在人类和动物模型中，功能障碍与肥胖有关。纤毛破坏，特别是在 小鼠的大脑导致与肥胖症相关的食欲过盛。最近的研究表明纤毛或其相关的 蛋白质在协调瘦素信号传导中的作用，尽管这仍然存在争议和不清楚。最近， 已经表明，几种G蛋白偶联受体优先定位于神经元的纤毛。如何将这些 纤毛受体和信号通路可能影响摄食行为，肥胖也仍然不清楚。的 该项目的目标是确定是否通过特定的睫状受体改变信号传导，该受体已知具有 在摄食行为中的作用，黑色素浓缩激素受体1，有助于肥胖表型。一 对纤毛和肥胖之间联系的深入了解可以开辟新的治疗方法， 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.