Cholecystokinin (Cck) is a multifunctional peptide hormone involved in the regulation of digestion, appetite and reproduction. In this study, we generated medaka (Oryzias latipes) knockout lines for three distinct Cck receptors (cck1r-/-, cck2ra-/-, and cck2rb-/-) and conducted phenotypic analysis to elucidate their physiological functions. The cck1r-/- fish exhibited markedly reduced digestive enzyme secretion and growth remained impaired until 98 days post-hatching (dph), indicating an essential role of Cck1r in digestive regulation and early development. The cck2ra-/- fish showed a slight reduction in reproductive capacity and a moderate increase in lipid accumulation, implicating its involvement in reproductive maturation and lipid metabolism. The cck2rb-/- fish exhibited complete female infertility, pronounced lipid accumulation, and enhanced somatic growth after 126 dph, suggesting a central role for Cck2rb in regulating lipid metabolism, reproduction, and body size. Transcriptome analysis further supported receptor-specific roles in lipid metabolism and growth regulation. These findings reveal novel functions of Cck receptors in lipid metabolism and somatic growth, extending beyond their established roles in digestion and reproduction. This study provides insights into endocrine-metabolic integration in vertebrates and represents the first functional characterization of all three Cck receptor subtypes within a single vertebrate model.
Murashita et al. (2026) studied this question.