Impaired leptin signaling disrupts lipid metabolism and causes growth disorders in female medaka (Oryzias latipes)

Leptin, a pivotal hormone secreted by adipose tissue, is a central regulator of appetite and energy metabolism in vertebrates. In this study, we generated a novel lepa loss-of-function mutant in medaka (Oryzias latipes) using CRISPR/Cas9 gene-editing to investigate its physiological roles. Phenotypic analysis revealed that homozygous lepa mutant females exhibited significantly stunted growth and a markedly reduced lifespan compared to their wild-type counterparts. These mutants developed pronounced age-associated phenotypes, including severe hepatic steatosis and accelerated liver aging, which progressively worsened after 6 months of age. Transcriptomic profiling of the liver further demonstrated that the expression patterns of differentially expressed genes (DEGs) involved in aging processes and lipid metabolism were consistent with the observed pathological phenotypes. Collectively, our findings indicate that Lepa plays a more indispensable and critical role in governing growth and metabolic homeostasis in teleosts than its mammalian leptin counterparts. This study establishes the lepa-deficient medaka as a valuable model for unraveling the conserved and divergent functions of leptin signaling in fish.