The immunometabolic role of mitochondrial dynamics in microglial cells in Obesity models

Abstract

The Obesity is commonly related to a high lipidic intake during the feeding, that reaches the bloodstream are capable of surpass the blood-brain barrier and get to the hypothalamus, the brain region responsible for controlling the metabolic homeostasis of the body. Once in the hypothalamus, high levels of fatty acids activate the resident innate immune cells, such as the microglia, leading to a secretion of proinflammatory cytokines and generating a hypothalamic inflammation that may compromise the metabolism of other organs and tissues of the body, contributing to the development of metabolic disorders. During Obesity, there's an expansion of microglial cells that precedes the weight gain and contributes for such event, in addition to their activation, secreting cytokines that acts on adjacent neurons enhancing their resistance to insulin and leptin, two signaling hormones involved with systemic metabolic regulation, or even leading neurons to apoptosis. It has also been shown that inhibition of the NFºB pathway in microglial cells decreases High Fat Diet (HFD) - induced Obesity, showing the great importance of these cells in the development of the Obesity. The processing of these lipids occurs mostly at the mitochondria, a highly dynamic organelle when it comes to its morphology, altering its structure accordingly to the cell metabolic needs. During low nutrients availability, for instance, mitochondria tend acquire a fused morphology. The opposite happens during a high caloric intake, leading the mitochondria fragmentation or fission. This dynamic characteristic of the mitochondria is extremely important to the metabolic state of the cell and cell activation. Two proteins possess a fundamental role in mitochondrial dynamics and act in two different ways. Drp1 acts during fission and the Mfn2 during fusion. Our aim is to determine the role of mitochondria dynamics in hypothalamic microglial cells upon HFD - induced Obesity. We will perform in vitro assays using pharmacological modulators, as well as in vivo experiments with genetically altered mice that doesn't express Drp1 and Mfn2 in microglia. We will determine the consequences of their absence for weight gain, microglia activation and the subsequent and hypothalamic inflammation. (AU)