Regulation of systemic energy metabolism by myokines

 描述(由申请人提供)：无论有多少可用的治疗策略，由代谢综合征引起的心血管疾病仍然是世界范围内的主要健康负担。全身能量平衡紊乱是单个组织内代谢功能障碍以及组织间沟通障碍的结果。了解特定组织和整个身体内的代谢协调将导致新的和改进的治疗途径。我们最近发现了心脏在全身能量动态平衡中的重要作用，从而建立了心脏能够在全球范围内组织间代谢通讯以引发组织之间的燃料分配的先例。然而，来自心脏的信号的分子细节以及这个心脏代谢轴在疾病中的作用还没有被探索。我们已经鉴定出两种未知的肌肉特异性脂肪还原酶，它们能够产生能够赋予心脏这种能力的代谢物。在本提案的第一个目标中，我们将审问每个 在获得和丧失功能的动物模型中，心肌细胞中的这些酶。这项提案的最终目的是测试每种脂肪还原酶在组织间通讯中的作用。 从肌细胞到身体的其他组织。这项提议的总体目标是检验这样一个假设，即心脏通过分泌充当信号效应器的脂类代谢物来向其他组织发出信号，并预测我们将发现横纹肌与其他组织沟通的新方式。总体而言，这些研究将为肌细胞内分泌信号和横纹肌对全身能量代谢的调节提供新的见解，并可能产生在心脏代谢性疾病背景下调节这些过程的新的治疗策略。

 DESCRIPTION (provided by applicant): Cardiovascular disease as result of metabolic syndrome continues to be a major health burden worldwide, regardless of the numerous available therapeutic strategies. Derangements in systemic energy homeostasis are the result of metabolic dysfunction within individual tissues as well as in defective communication between tissues. Understanding metabolic coordination within a particular tissue and throughout the body will lead to new and improved therapeutic avenues. We recently uncovered an important role of the heart in systemic energy homeostasis, thus establishing the precedent that the heart is capable of intertissue metabolic communication to elicit fuel partitioning between tissues globally. However, the molecular details of the signals emanating from the heart and the role of this cardiometabolic axis in disease are unexplored. We have identified 2 uncharacterized muscle-specific lipid reductase enzymes capable of generating metabolites that could confer the heart this ability. In the first aim of this proposal, we will interrogate the functions of each of these enzymes in cardiomyocytes using gain- and loss-of-function animal models. The final aim of this proposal will test the role of each lipid reductase in mediating inter-tissue communication from myocytes to other tissues of the body. The overall goal of this proposal is to test the hypothesis that the heart signals to other tissues by secreting lipid-derived metabolites that act as signaling effectors, with the prediction that we will uncover novel ways in which striated muscles communicate to other tissues. Overall, these studies will provide new insights into myocyte endocrine signaling and the regulation of systemic energy metabolism by striated muscle and may yield novel therapeutic strategies for modulating these processes in the settings of cardiometabolic disease.