Interactions of leptin and PPAR delta in the control of POMC-expressing neurons

• Grant number: 19/12969-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: September 23, 2019
• End date: September 22, 2020
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Licio Augusto Velloso
• Grantee: Alexandre Moura Assis
• Supervisor: Jeffrey M Friedman
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Rockefeller University, United States
• Associated to the scholarship: 16/01245-5 - Evaluation of the involvement of TRIL in inflammation and apoptosis of POMC neurons in the hypothalamus of obese mice, BP.DR

Abstract

Obesity is one of the main health problems in Brazil and worldwide and the recent advances in the comprehension of its physiopathology has indicated the existence of a functional impairment of the hypothalamic-associated control over food intake. The hypothalamus integrates peripheral signals to complex neurocircuits and exerts a preponderant control over food intake and metabolism through AgRP- and POMC-expressing neurons in the arcuate nucleus. Depolarization and activation of POMC neurons triggered by uptake and oxidation of glucose involves increased intracellular ATP and the closure of ATP-dependent potassium channels (KATP). In addition, glucose oxidation also increases the reactive oxygen species (ROS) levels and its increase lead to POMC activation. Interestingly, ob/ob or high fat fed mice display abnormal reduction in POMC ROS levels and the concomitant increase in UCP2 expression seems to be involved in the uncoupled respiration that, in turn, decreases ATP and ROS availability for POMC neurons.The transcriptional control over hypothalamic UCP2 occurs, at least in part, by PPAR´ and its regulation seems to be associated to leptin. Therefore, the aim of this project is to determine if the anomalous regulation of POMC neurons might be associated with PPAR´ and if leptin would control POMC neurons toward the PPAR´-UCP2-ROS axis. To interrogate the role of PPAR´ in the POMC neurons, we will employ Cre-dependent adeno associated-virus to knockdown PPAR´ expression exclusively in POMC neurons, phenotyping mice using metabolic approaches, and analyze leptin and POMC activation through histological techniques. We aim to elucidate the molecular mechanisms associated with the functional impairment of POMC-expressing neurons, that is intimately connected to treatment refractoriness in obesity.