Browsing by Author "Pereira, Adriana Arrulo"
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- Silencing of cypx gene in the hypothalamus and its impact on whole-body metabolismPublication . Pereira, Adriana Arrulo; Nóbrega, Clévio; Aveleira, CéliaCholesterol metabolism is tightly controlled in the brain, through an equilibrium of cholesterol de novo synthesis and cholesterol efflux. Most of the cholesterol in the brain is in myelin sheaths to insulate axons and to maintain their morphology and synaptic transmission. The importance of cholesterol in the brain is highlighted by the fact that dysfunctions in its metabolism homeostasis are correlated with different neurodegenerative disorders. The hypothalamus, specially the ARC, is the principal brain region in the control of whole-body energy homeostasis, having a crucial role in metabolic organ regulation. This project goal was to silence the expression of the Cyp46a1 mouse gene in the hypothalamus of C57BL/6J wild-type mice fed with Chow and HFD, and to investigate its impact in the whole-body metabolism homeostasis. As the ARC is implicated in the control of whole-body energy metabolism, and oxysterols levels are altered in obesity, we hypothesize that the silencing of Cyp46a1 gene could lead to an obesity and TIIDM phenotypes. In this study, C57BL/6J wild-type mice (n=45) were divided into two groups corresponding to two different diets. One group (n=24) had access to a Chow containing 10% of fat and the other group (n=21) had access to an HFD containing 60% of fat. This study was conducted during 12 weeks. In the 4th week, the two groups of mice (Chow and HFD) were divided into four subgroups, from which two were submitted to the stereotaxic injection delivering the AAV of the serotype 5, with the shRNA targeting the mouse Cyp46a1 gene in each side of the ARC and two remained non-injected, as control. The silencing of Cyp46a1 mouse gene in the ARC of mice fed with Chow and HFD leads to an increase of BW, changes in food and water intake, to a reduction of glucose tolerance, of insulin sensitivity and leads also to modifications in several metabolic organs, comparatively to the non-injected animals. In fact, in the Chow AAV5-shCyp46a1 animals, the impact of the silencing Cyp46a1 gene appears to mimic an HFD effect, whereas in HFD AAV5-shCyp46a1 mice this silencing exacerbates the phenotype of obesity. These results could suggest an important role of the cholesterol metabolism in the brain, specially of the Cyp46a1 enzyme in the control of whole-body homeostasis. Finally, additional studies are needed to continue this project and it would be interesting to perform the overexpression of Cyp46a1 in the ARC to investigate if this gene could be a potential target to further genetic therapies.