Multi-omics profiling reveals liver–retina axis in high-fat diet-induced early retinopathy

Diabetic retinopathy (DR), a leading cause of blindness in the working-age population, is a severe complication of type 2 diabetes mellitus (T2DM). The global increase in T2DM due to high-fat diets necessitates urgent research into the pathogenesis and precision treatments for high-fat-induced DR. Emerging clinical evidence of liver-retina crosstalk offers new mechanistic insights, while the underlying network of metabolites and secreted proteins within the liver-retina axis in high-fat diets induced retinopathy remains unclear. Here, we induced early retinopathy in mice with high-fat diet for 5 weeks, resulting in shortened retinal rods and elevated inflammatory factors, increased activation of microglia and shortened retinal rods. Integrated analysis of RNA-seq data from the retina and liver showed coordinated changes in retinol metabolism pathway and gene networks. Metabolomics and hepatokine analysis suggest that certain liver metabolites (e.g., betaine) and factors (e.g., FGF21) exhibit shared change profiles with the retina under retinal inflammation, uncovering a potential hepatic-ocular network in high-fat-induced DR. This study provides novel insights into distant organ regulation network and identifies potential therapeutic targets for early retinopathy associated with diet-induced metabolic stress, advancing precision treatments strategies.