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

点击翻译按钮获取中文摘要

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.