The influence of microglial mitochondrial homeostasis on hypothalamic neurons in a saturated fat acid excess environment

• Grant number: 22/01332-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: November 01, 2022
• End date: October 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Eduardo Rochete Ropelle
• Grantee: Renata Rosseto Braga
• Supervisor: Daria Mochly-Rosen
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Institution abroad: Stanford University, United States
• Associated to the scholarship: 19/21171-4 - The role of mitonuclear imbalance and hypothalamic UPRmt on the control of food intake of obese mice, BP.DD

Abstract

Obesity is classified as a low-grade chronic inflammation, accompanied by resistance to insulin and leptin, hormones directly associated with energy homeostasis. Mitochondrial activity in hypothalamic arcuate nucleus neurons is closely related to the control of food intake and energy homeostasis. Mitochondria is a dynamic organelle and changes its conformation according to cellular energetic demands and nutrient availability. Although the majority of studies focus on neuronal activity when studying energy homeostasis, there is a non-neuronal cell type, the glial cells, such as microglia, that also senses changes in the healthy brain environment. Microglia provides structural and metabolic support for neurons and is considered the immune system of the brain, considering that it releases inflammatory mediators in response to a stress signal, such as high-fat diet consumption. An interesting study reported that transferring microglia activated media to cultured primary neurons promoted neuronal damage through extracellular DRP1-mediated fragmented mitochondrial release and lead to inflammation and mitochondrial dysfunction in neurons. These data suggest that mitochondrial dysfunction increases the inflammatory potential and deleterious signal from microglia toward to hypothalamic neurons. Mitochondrial metabolism of microglia in neurons seems to be critical for the control of energy homeostasis. It is well stablished that Nicotinamide Adenosine Dinucleotide (NAD+) is a coenzyme that plays an important role in mitochondrial activity. However, the role of microglial NAD+ synthesis pathway in the control of mitochondrial function in neuron tissue is unknown. The development of this project may provide new insights into the role of microglial NAD+ pathway in mitochondrial activity and neuron homeostasis. (AU)