Yangtze sturgeon is an endangered fish species. After weaning, some Yangtze sturgeon fry refuse to consume any food, which causes a low survival rate during the artificial breeding period. This study showed that the body length and body weight of failed weaning Yangtze sturgeons were significantly lower than those of successful weaning sturgeons. Since the brain is the center of appetite regulation, RNA-seq of the brain was employed to analyze the differentially expressed genes and their biological functions in successfully and unsuccessfully weaned fry. After that, 82,151 unigenes and 3222 DEGs were obtained. Based on the results of RNA-seq, appetite factors, including