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

PEDF/ATGL信号在能量稳态中央控制中的作用

• 批准号: RGPIN-2017-04798
• 负责人: Alquier, Thierry
• 金额: $ 2.33万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710766
• 关键词: Role; PEDF; ATGL; signalling; central

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.

在中枢神经系统中，下丘脑通过整合循环代谢和荷尔蒙信号来调节能量摄入和支出，在调节能量摄入和支出中起关键作用。这些信号直接调节下丘脑神经元的活性协调适当的行为和生理反应以维持能量稳态。脂肪酸（FA）在下丘脑细胞中作用于调节喂养和葡萄糖稳态。但是，涉及的机制仍然难以捉摸。除了循环FA外，尚未探索从细胞内甘油三酸酯（TG）存储中产生FA的中性甘油脂肪酶在能量平衡调节中的作用。 我们的研究计划的主要目的是表征神经脂蛋白甘油三酸酯脂肪酶（ATGL）的作用，这是一种关键的细胞内酶，催生了外周种组织中TG水解的第一个和承诺的步骤，在能量稳态的下丘脑控制中。此外，我们还将调查色素上皮衍生因子（PEDF）是一种循环脂肪因子，可通过ATGL调节外周组织中的脂质代谢，在下丘脑中起作用，是通过神经元ATGL维持能量平衡的能量信号。 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. 中性甘油脂肪酶在细胞生理和信号传导基本方面的作用越来越公认。但是，它们在神经元FA信号传导和能量稳态的控制中的贡献仍然未知。因此，该研究计划将提供有关ATGL和通过PEDF-ATGL途径在下丘脑神经元中的基本作用和信号传导的重要见解及其在能量稳态的神经元调节中的功能。通过结合分子和细胞方面以及整合模型来研究小鼠的代谢生理和神经元电路，我们的程序将提供高水平的HQP多学科培训。