Regulation of systemic energy metabolism by myokines

 描述（由申请方提供）：代谢综合征导致的心血管疾病仍然是全球范围内的主要健康负担，尽管有许多可用的治疗策略。全身能量稳态的紊乱是个体组织内代谢功能障碍以及组织间通信缺陷的结果。了解特定组织内和整个身体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稳态中的重要作用，从而建立了心脏能够进行组织间代谢通信以引起全球组织之间的燃料分配的先例。然而，从心脏发出的信号的分子细节和心脏代谢轴在疾病中的作用尚未探索。我们已经确定了2个未知的肌肉特异性脂质还原酶能够产生代谢物，可以赋予心脏这种能力。在本建议的第一个目标中，我们将询问每个人的功能， 这些酶在心肌细胞中使用获得和丧失功能的动物模型。本提案的最终目的是测试每种脂质还原酶在介导组织间通讯中的作用 从肌细胞到身体的其他组织。该提案的总体目标是测试心脏通过分泌脂质衍生的代谢物作为信号效应物向其他组织发出信号的假设，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，这些研究将提供新的见解，肌细胞内分泌信号和横纹肌的全身能量代谢的调节，并可能产生新的治疗策略，调节这些过程中的心脏代谢疾病的设置。

 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.