Role of PEDF/ATGL signalling in the central control of energy homeostasis

在中枢神经系统中，下丘脑通过整合循环代谢和激素信号在调节能量摄入和消耗方面起着关键作用。这些信号直接调节下丘脑神经元的活动，以协调适当的行为和生理反应，以维持能量稳态。脂肪酸（FA）在下丘脑细胞中起调节摄食和葡萄糖稳态的作用。然而，所涉及的机制仍然难以捉摸。除了循环脂肪酸，中性甘油脂脂肪酶的作用，从细胞内甘油三酯（TG）储存在能量平衡的调节中产生脂肪酸尚未探讨。 * 我们研究计划的主要目的是表征神经元脂肪酸甘油三酯脂肪酶（ATGL）在下丘脑控制能量稳态中的作用，ATGL是催化外周组织中TG水解的第一步和关键步骤的关键细胞内酶。此外，我们将研究色素上皮衍生因子（PEDF），一种通过ATGL调节外周组织脂质代谢的循环脂肪因子，是否在下丘脑中作为能量充足的信号，通过神经元ATGL维持能量平衡。基于支持下丘脑神经元中PEDF-ATGL信号传导在能量平衡控制中起关键作用的新概念的有希望的初步发现，我们提出1-研究中枢PEDF对能量稳态的影响，鉴定PEDF激活的下丘脑神经元网络并表征ATGL在脑中的区域和细胞表达模式，2-使用靶向神经元ATGL功能丧失策略和ATGL的药理学抑制来确定神经元下丘脑ATGL对能量稳态和PEDF的中枢作用的作用，3-表征下丘脑神经元中由PEDF经由ATGL调节的信号传导和代谢途径，并使用脂质组学鉴定由PEDF-ATGL途径产生的脂质衍生的信号，并鉴定潜在的下游靶标。* 中性甘油脂脂肪酶在细胞生理学和信号传导的基本方面的作用越来越被认识到。然而，它们在神经元FA信号传导和能量稳态控制中的贡献仍然未知。因此，这项研究计划将提供重要的见解ATGL的基本作用和信号通过PEDF-ATGL通路在下丘脑神经元和其功能的神经元调节能量稳态。通过结合分子和细胞方面以及综合模型来研究小鼠的代谢生理学和神经元回路，我们的计划将提供高水平，多学科的HQP培训。

In the central nervous system, the hypothalamus plays a key role in regulating energy intake and expenditure by integrating circulating metabolic and hormonal signals. These signals directly modulate the activity of hypothalamic neurons to coordinate appropriate behavioural and physiological responses to maintain energy homeostasis. Fatty acids (FA) act in hypothalamic cells to regulate feeding and glucose homeostasis. However, the mechanisms involved remain elusive. Besides circulating FA, the role of neutral glycerolipid lipases that generate FA from intracellular triglycerides (TG) stores in the regulation of energy balance has not been explored. *** The main objective of our research program is to characterize the role of neuronal Adipose Triglyceride Lipase (ATGL), a key intracellular enzyme catalyzing the first and committed step of TG hydrolysis in peripheral tissues, in the hypothalamic control of energy homeostasis. In addition, we will investigate if Pigment Epithelium-Derived Factor (PEDF), a circulating adipokine that regulates lipid metabolism in peripheral tissues via ATGL, acts in the hypothalamus as a signal of energy sufficiency to maintain energy balance via neuronal ATGL. Based on promising preliminary findings supporting the novel concept that PEDF-ATGL signalling in hypothalamic neurons plays a key role in the control of energy balance, we propose to 1-investigate the impact of central PEDF on energy homeostasis, identify PEDF-activated hypothalamic neuronal networks and characterize the regional and cellular expression pattern of ATGL in the brain, 2-determine the role of neuronal hypothalamic ATGL on energy homeostasis and central effects of PEDF using a targeted neuronal ATGL loss-of-function strategy and pharmacological inhibition of ATGL and, 3- characterize the signalling and metabolic pathways modulated by PEDF via ATGL in hypothalamic neurons and identify lipid-derived signals generated by the PEDF-ATGL pathway using lipidomics and identify potential downstream targets. ***The role of neutral glycerolipid lipases in fundamental aspects of cell physiology and signalling is becoming more and more recognized. However, their contribution in neuronal FA signalling and control of energy homeostasis remains unknown. Thus, this research program will provide important insights on the fundamental role of ATGL and signalling via the PEDF-ATGL pathway in hypothalamic neurons and its function in the neuronal regulation of energy homeostasis. By combining molecular and cellular aspects as well as integrative models to study metabolic physiology and neuronal circuitry in mice, our program will provide high level, multidisciplinary training of HQP.