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RESEARCH PRODUCT

Lipid and homeostatic alterations in nervous tissues associated with aging and metabolic dysregulations: implication of gut microbiota and autophagy

subject

description

The retina and the brain are two nervous tissues rich in lipids. Aging and metabolic syndrome (MetS) are associated with functional and physiological alterations of these tissues as well as modifications in the composition of the gut microbiota. The global objective of this thesis work is to understand the lipid and homeostatic alterations in aging and MetS contexts in the retina and the brain. In a first study, we evaluated the impact of the modifications in the composition of the gut microbiota associated with aging on the lipid/fatty acid contents of the liver and the brain (cortex). We showed that colonization of germ-free mice with the gut microbiota of old mice modulated the hepatic expression levels of fatty acid biosynthesis enzymes and induced alterations in the lipid and fatty acid profiles in the liver (decrease in the cholesterol and polyunsaturated fatty acids (PUFA) of the omega-3 series contents and increase in the monounsaturated fatty acids (MUFA) content) and in the cortex (decrease in the cholesterol and PUFA contents, including docosahexaenoic acid (DHA) and increase in the MUFA content). In a second study, we evaluated the effect of chronic exposure of mice to a high fat diet (HFD) inducing a MetS on the fatty acid contents of the retina and the cortex. We showed that a HFD impacted the content of plasmalogens as well as the retinal contents of saturated fatty acids (SFA), MUFA and the relative proportion of the essential fatty acids (linoleic acid and ⍺-linolenic acid), without however modifying those of arachidonic acid (AA) and DHA, the two major retinal PUFA. Alterations in the fatty acid profile of the cortex (decrease in the content of MUFA and increase in that of PUFA including linoleic acid, AA and DHA) has also been highlighted in animals fed with a HFD. Enriching HFD with inulin, a prebiotic, helped limiting some of these cortical changes. In a third study, we characterized in the retinas of apoB100, LDLR-/- mice, a model reproducing some features of the aging retina (accumulation of lipid deposits at the basement of the retina/loss of the photoreceptor function) cellular processes involved in cellular and tissue homeostasis: autophagy and the inflammatory and antioxidant responses. We highlighted an increase in the expression of pro-inflammatory cytokines in the retinas of apob100, LDLR-/- mice from the age of 2 months and a decrease in the basal autophagic flux at the age of 12 months. In conclusion, we characterized the alterations affecting the fatty acid and/or the lipid profiles of the retina and the cortex in a MetS and aging contexts and showed that the gut microbiota is involved, at least in part, in the modifications of the lipid/fatty acid composition occurring in the cortex during aging. Finally, although our results deserve to be confirmed, our work opens perspectives on the use of apob100, LDLR-/- mice as a model to study the aging of the retina.