Divergent Roles of Zebrafish IGF1 Receptor a and b in Glucose and Lipid Metabolism

Insulin-like growth factor 1 (IGF-1) signaling plays a complementary role to insulin signaling in glucose metabolism homeostasis. This study characterized the physiological roles of the IGF1 receptor A (Igf1ra) and B (Igf1rb) in zebrafish. The transcripts of igf1ra and igf1rb were detected in multiple zebrafish tissues, including the liver, muscle, and brain. Zebrafish lacking igf1ra or igf1rb were generated using CRISPR/Cas9 technology. Both igf1ra^-/- and igf1rb^-/- zebrafish exhibited stunted growth. Reduced BMI was found in igf1ra^-/- zebrafish, while BMI increased in igf1rb^-/- zebrafish. Hyperglycemia and increased hepatic glycogen were observed in igf1ra^-/- zebrafish, while blood glucose levels in igf1rb^-/- zebrafish were normal. No significant difference in whole-body or hepatic triglyceride content was observed in igf1ra^-/- zebrafish, while the whole-body and hepatic triglyceride content of igf1rb^-/- zebrafish increased compared to their wild-type control siblings. Further analyses of the expression patterns of key genes involved in glucose and lipid metabolism were conducted on igf1r mutants. Decreased levels of genes involved in glucose absorption and glycolysis and increased levels of genes involved in gluconeogenesis and glycogen synthesis were observed in igf1ra^-/- zebrafish, but not in igf1rb^-/- zebrafish. Conversely, significantly decreased levels of transcripts involved in lipolysis and increased levels of transcripts involved in the lipogenesis process were observed in igf1rb^-/- zebrafish, but not in igf1ra^-/- zebrafish. Restricted cell growth and protein synthesis signaling, including AKT and mTOR activation, was also detected in igf1ra^-/- zebrafish, while a moderate elevation in AKT and mTOR activity was seen in igf1rb^-/- zebrafish. Taken together, our results suggest that functional divergence occurred after the duplication of the zebrafish igf1r gene, with igf1ra primarily modulating glucose absorption and utilization, and igf1rb primarily affecting lipid metabolism in the somatotropic axis.