1,25(OH)2D3 rescues obesity and impairment of lipid mobilization in Cyp27b1 deficient zebrafish

Cytochrome P450 family member 27b1 (Cyp27b1) is the key enzyme that converts vitamin D 3 into its bioactive form 1,25(OH) 2 D 3 . This conversion is achieved through 1α-hydroxylation of 25(OH)D 3 . Given the established importance of 1,25(OH) 2 D 3 in lipid metabolism, we generated a cyp27b1 knockout ( cyp27b1 −/− ) zebrafish model. This model was used to elucidate the specific roles of 1,25(OH) 2 D 3 and to identify potential therapeutic targets for obesity. Our findings indicated that cyp27b1 −/− zebrafish exhibit growth retardation, abdominal obesity, and altered lipid composition in adipose tissue. Furthermore, triglyceride (TG) catabolism was impaired in fasted knockout fish. Transcriptome analysis identified pnpla2 as a candidate gene associated with altered lipid mobilization in adipose tissue. pnpla2 encodes patatin-like phospholipase domain-containing protein 2 (Pnpla2, also known as adipose triglyceride lipase, ATGL), which is the rate-limiting enzyme that catalyzes the initial step of triglyceride hydrolysis. Specifically, both mRNA and protein expression levels of pnpla2 were significantly downregulated in the adipose tissue of cyp27b1 −/− zebrafish. Interestingly, treatment with 1,25(OH) 2 D 3 was found to upregulate pnpla2 protein expression, decrease TG content in adipose tissue, and rescue the defective phenotypes observed in the knockout fish. In summary, this study highlighted a crucial role for 1,25(OH) 2 D 3 in regulating lipid mobilization, which was associated with the regulation of pnpla2 expression. Our findings provided a novel insight into the function of 1,25(OH) 2 D 3 in lipid metabolism and its potential therapeutic applications in obesity management.