Impaired leptin A signaling disrupts hepatic lipid metabolism and growth in female medaka (Oryzias latipes).

Leptin is a central regulator of appetite and energy metabolism in vertebrates, and its deficiency in mammals typically results in hyperphagia and severe obesity. In fish, however, the physiological roles of leptin remain less clearly defined, partly due to the whole genome duplication (WGD) and divergent expression patterns. In this study, we generated a leptin A (lepa) loss-of-function mutant in medaka (Oryzias latipes) using CRISPR/Cas9 to investigate the function of leptin signaling. Phenotypic analysis revealed that female homozygous mutants exhibited significantly reduced body length and body weight compared with wild-type females, indicating growth impairment. Unexpectedly, despite their lean phenotype, the female mutants developed pronounced hepatic steatosis accompanied by the formation of spongiosis hepatis structures, while no obvious fibrosis was detected. To explore the molecular mechanisms underlying these abnormalities, transcriptomic profiling of mutant livers was performed. Differentially expressed genes were significantly enriched in pathways related to lipid metabolism, including Fatty acid metabolism and PPAR signaling pathway, suggesting a potential reduction in hepatic fatty acid β-oxidation capacity. In addition, genes involved in endoplasmic reticulum stress, autophagy, and apoptosis were altered, indicating transcriptional changes in cellular stress-response pathways under leptin A deficiency. Together, these findings suggest that leptin A may play an important role in coordinating growth and hepatic lipid metabolism in medaka and highlight potential differences in leptin-mediated metabolic regulation between fish and mammals.