Tissue-specific sex difference in mouse eye and brain metabolome under fed and fasted states

Abstract

Purpose: Visual physiology and various ocular diseases demonstrate sexual dimorphisms; however, how sex influences metabolism in different eye tissues remains undetermined. This study aims to address common and tissue-specific sex differences in metabolism in the retina, retinal pigment epithelium (RPE), lens and brain under fed and fasted conditions. Methods: After ad libitum fed or deprived of food for 18 hours, mouse eye tissues (retina, RPE/choroid, and lens), brain, and plasma were harvested for targeted metabolomics. The data were analyzed with both Partial least squares-discriminant analysis (PLS-DA) and Volcano Plot analysis. Results: Among 133 metabolites that cover major metabolic pathways, we found 9-45 metabolites that are sex-different in different tissues under the fed state and 6-18 metabolites under the fasted state. Among these sex-different metabolites, 33 were changed in two or more tissues, and 64 were tissue-specific. Pantothenic acid, hypotaurine and 4-hydroxyproline were the top commonly changed metabolites. Lens and retina had the most tissue-specific sex-different metabolites enriched in the metabolism of amino acid, nucleotide, lipids and TCA cycle. Lens and brain had more similar sex-different metabolites than other occular tissues. Female RPE and female brain were more sensitive to fasting with more reduced metabolites in amino acid metabolism, TCA cycle and glycolysis. The plasma had the least sex-different metabolites with very few overlapping changes with tissues. Conclusion: Sex has a strong influence on eye and brain metabolism in tissue-specific and metabolic state-specific manners. Our findings may implicate the sexual dimorphisms in eye physiology and susceptibility to ocular diseases.

The role of epigenetic changes in the pathology and treatment of inherited retinal diseases

“…A better understanding of how HDAC inhibitors affect people with different genotypes will facilitate future clinical translation of these types of drugs. There may also be sex differences in epigenetic regulation and drug metabolism that need to be considered (Gegenhuber and Tollkuhn, 2019;Li et al, 2019;Oliva et al, 2020;Saravanan et al, 2023). Clearly, interaction between each of these epigenetic regulators are very complex, with functional relationships via diverse molecules and intracellular pathways.…”