Genetic control of quantitative traits associated with the metabolic syndrome

描述（由申请人提供）：最近的生化和遗传证据有力地支持肥胖和相关代谢紊乱是由线粒体功能缺陷引起的。这些缺陷会产生由活性氧 (ROS) 介导的过量细胞氧化应激。似乎可以改善代谢紊乱结果的一种机制是线粒体质子泄漏，即线粒体中能量产生与呼吸的解偶联。据报道，解偶联蛋白 (UCP) 介导的线粒体呼吸中的轻度解偶联可减少动物的脂肪储存和 ROS 产生，并有利地改变胰岛素敏感性。使用 18 个不相关的黑腹果蝇野生型自交系，我们发现自然发生的遗传变异会影响骨骼肌中线粒体状态 4 呼吸速率（例如基础质子泄漏）的个体间变异。我们还表明，骨骼肌线粒体状态 4 呼吸速率的变化与脂肪储存的变化呈负相关。这意味着一些基因型具有较高的线粒体耦合效率并储存更多的脂肪，而其他基因型具有较低的耦合效率并需要更多的能量来维持其线粒体电化学梯度。这些观察结果提出了一个重要问题：为什么线粒体质子泄漏的变异（例如代谢效率低下）在自然群体中是进化保守的。我们推测，在我们的初步研究中观察到的线粒体状态 4 呼吸和脂肪储存之间的权衡反映了竞争性有机体功能之间有限资源的分配。我们的假设是，虽然具有高效线粒体耦合的个体可以成功地利用其脂肪储存来繁殖和应对环境挑战，例如对抗感染，但那些耦合效率较低的个体将需要使用更多的能量来维持线粒体电化学梯度，而以牺牲其他有机体功能为代价。然而，线粒体基础质子泄漏可能会减少 ROS 的产生，从而防止细胞退化和衰老。该项目的具体目标是：(1) 进行全基因组关联扫描，以绘制影响肌肉特异性线粒体生物能、ROS 产生、能量代谢特征、食物摄入、先天免疫反应和女性生育力自然发生变异的遗传变异。 (2)确定幼果蝇（3-5天龄）调节线粒体生物能性状的基因共表达网络。 (3) 验证目标 2 中进行的分析确定的 10 个“中心基因”是否负责线粒体生物能量的协调调节，并影响整个生物体的能量稳态和生命史特征。 (4) 调查先前目标中确定的 10 个果蝇候选基因的人类直系同源基因变异是否与人类肥胖和相关代谢结果的表型变异相关。这些研究将为线粒体偶联效率的遗传基础提供新的见解，因为它与代谢、免疫反应和生活史特征有关。

DESCRIPTION (provided by applicant): Recent biochemical and genetic evidence provides strong support that obesity and related metabolic disorders develop from defects in mitochondrial function. These defects produce excess cellular oxidative stress mediated by reactive oxygen species (ROS). One mechanism that appears to improve outcomes in metabolic disorders is mitochondrial proton leak, i.e., the uncoupling of energy production from respiration in the mitochondria. Mild uncoupling in mitochondrial respiration mediated by uncoupling proteins (UCPs) has been reported to decrease fat storage and ROS production in animals and favorably modifies insulin sensitivity. Using 18 unrelated wild-type inbred lines of D. melanogaster, we have shown that naturally occurring genetic variation affects inter-individual variability in mitochondrial state 4 respiration rates (e.g. basal proton leak) in skeletal muscles. We have also shown that variation in mitochondrial state 4 respiration rates in skeletal muscles is negatively correlated with variation in fat storage. This implies that some genotypes have higher mitochondrial coupling efficiency and store higher quantities of fat while other genotypes have lower coupling efficiency and require more energy for maintaining their mitochondrial electrochemical gradient. These observations raise the important question of why variation in mitochondrial proton leak (e.g. metabolic inefficiency) is evolutionary conserved in natural populations. We speculate that the trade-off between mitochondrial state 4 respiration and fat storage observed in our preliminary studies is a reflection of the allocation of finite resources between competing organismal functions. Our hypothesis is that while individuals with efficient mitochondrial coupling can successfully use their fat storage for reproduction and for coping with environmental challenges, such as fighting infection, those with less coupling efficiency will need to use more energy for maintaining their mitochondrial electrochemical gradient at the expense of other organismal functions. However, mitochondrial basal proton leak may decrease ROS generation and, therefore, protect against cellular degeneration and aging. The Specific Aims of this project are to: (1) Perform a genome-wide association scan to map genetic variants affecting naturally occurring variation in muscle-specific mitochondrial bioenergetics, ROS production, energy metabolism traits, food intake, innate immune response, and female fecundity. (2) Determine the gene co-expression network regulating mitochondrial bioenergetic traits in young flies (3-5 days old). (3) Verify whether 10 of the "hub genes" identified by the analyses performed in Aim 2 are responsible for the coordinated regulation of mitochondrial bioenergetics and also impact whole-organism energy homeostasis and life-history traits. (4) Investigate whether genetic variants in human orthologs of the 10 Drosophila candidate genes identified in the previous aims are associated with phenotypic variation in human obesity and related metabolic outcomes. These studies will provide new insights into the genetic basis of mitochondrial coupling efficiency as it relates to metabolic, immune response and life-history traits.