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Study of cellular factors that affects energy balance through AgRP neurons: role of connexin 43 and mTORC1 pathway

Grant number: 20/15262-4
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2023
Effective date (End): February 28, 2025
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Jose Donato Junior
Grantee:Gabriel Orefice de Souza
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:20/01318-8 - Central nervous system as a target of growth hormone for the regulation of multiple biological functions, AP.TEM

Abstract

The hypothalamus is one of the main brain areas responsible for energy metabolism regulation. The arcuate nucleus of hypothalamus (ARH) plays a crucial role in this regulation due to the presence of AgRP and POMC neurons, which are vital for the regulation of food intake and energy expenditure. Loss of function or deletion of some cellular and signaling factors from these neurons can impact energy homeostasis, leading to the development of metabolic disorders such as obesity and diabetes. Thus, it is imperative to fully understand the cellular mechanisms and signaling pathways that are capable of influencing the activity of these neuronal populations. Evidence shows that one important signaling pathway for AgRP functionality is the mTORC1 pathway. However, there is still some aspects needing more investigation. Besides, it was demonstrated that AgRP neurons express connexins, proteins that form gap junctions and allow neuronal communication through electrical synapses. Previous studies from our laboratory had shown AgRP neurons are hyperpolarized by connexin blockage, which may indicate a role of electrical synapses in AgRP neurons activity. Therefore, the present study aims to investigate the role of two cellular factors - mTORC1 and connexin 43 (CX43) - in the functionality of AgRP neurons. For this purpose, we will use Cre-LoxP technology to generate genetically modified mice with deletion of mTORC1 and CX43 exclusively on AgRP neurons, to investigate basal energy metabolism and glycemic homeostasis and how metabolic challenges such as food restriction, chronic high fat diet consumption and fasting are affected by mTORC1 and CX43 deletion on AgRP neurons. This study has the potential to discover new factors involved on the central energy metabolism control, identifying possible new pharmacological targets for the treatment of metabolic disorders.

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