Investigative Ophthalmology & Visual Science · 7 authors, 2 centres
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This study found 97 sex-different metabolites across mouse eye tissues (retina, RPE, lens), brain, and plasma, with 64 being tissue-specific. Pantothenic acid was consistently higher in females, while the lens and retina showed the most tissue-specific sex differences. These findings may explain sexual dimorphisms in eye physiology and disease susceptibility, such as higher cataract and AMD risk in women.
**Background:** Sexual dimorphisms are well-documented in visual physiology and ocular diseases (e.g., women have higher prevalence of AMD, cataract, and glaucoma), but the biochemical basis for these differences across eye tissues is unknown. The metabolome reflects interactions between genetics, diet, and environment, and may underlie tissue-specific metabolism. This study aimed to identify common and tissue-specific sex differences in the metabolome of the retina, RPE/choroid, lens, brain, and plasma under fed and fasted conditions.
**Methods:** Twelve-week-old C57BL/6J mice of both sexes were used. The fed group had ad libitum access to food; the fasted group had food removed for 18 hours. Retina, RPE/choroid, lens, whole brain, and plasma were harvested. Targeted metabolomics quantified 133 metabolites covering major metabolic pathways (glucose, amino acid, nucleotide, fatty acid, vitamin metabolism) using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Data were analyzed with partial least squares-discriminant analysis (PLSDA) and volcano plots (P < 0.05, fold change > 1.3 or < -1.3).
**Key Results:** Under fed conditions, 9 to 45 metabolites differed between sexes across tissues; under fasted conditions, 6 to 18 metabolites differed. Among 133 metabolites, 97 showed sex differences, with 33 changed in 2 or more tissues and 64 tissue-specific. Pantothenic acid, hypotaurine, and 4-hydroxyproline were the top commonly changed metabolites. The lens had the most sex-different metabolites (45 fed, 28 fasted), followed by the retina (35 fed, 8 fasted), RPE (19 fed, 9 fasted), brain (14 fed, 15 fasted), and plasma (9 fed, 7 fasted). In the female retina, pantothenic acid, trigonelline, aminoadipic acid, oxidized glutathione, NADP, NADPH, CDP, and GDP were among the top increased metabolites. In the female lens, glucose was higher but cystine, glutathione, and ascorbic acid were lower than in males. The female brain had more sex-different metabolites in glycolysis in the fed state and showed three times more metabolite changes after fasting than the male brain. Plasma had the fewest sex-different metabolites, with very few overlapping changes with tissues. Fasting increased 3-hydroxybutyrate and decreased trigonelline in all tissues. The female RPE and female brain were more sensitive to fasting, with more decreased metabolites in amino acid metabolism, TCA cycle, and glycolysis.
**Clinical Implications:** These findings demonstrate strong, tissue-specific sex differences in eye and brain metabolism, which may underlie sexual dimorphisms in ocular physiology and disease susceptibility. The higher pantothenic acid in females across tissues suggests a role in CoA synthesis and mitochondrial function. The lower antioxidant metabolites (glutathione, ascorbic acid) in the female lens may contribute to the higher prevalence of cataracts in women. The greater sensitivity of the female brain to fasting and its reliance on glucose metabolism may be relevant to sex differences in neurodegenerative diseases like Alzheimer's. The results highlight the need to include both sexes in metabolomics studies and suggest that eye metabolomics could serve as a window to brain metabolism and disease.