Transcriptome analysis reveals IGF-dependent and IGF-independent mechanisms affected by loss of IGF-binding...

In teleosts, insulin-like growth factor-binding protein-2b (IGFBP-2b) is the major carrier of serum insulin-like growth factor (IGF). A line of gene-edited rainbow trout (2bKO) was produced that lacks a functional IGFBP-2b and associated phenotypes of reduced serum IGF-1, increased appetite, and faster growth compared with wild-type controls (WT). Transcriptomic analysis was completed in liver and muscle from fed and feed-deprived fish from the 2bKO and WT line; the differentially expressed gene (DEG) profiles were used to identify biological functions and pathways affected by the loss of IGFBP-2b and predict IGF-dependent and IGF-independent mechanisms regulated by IGFBP-2b. In general, DEGs reflected downregulation of hepatic functions and signaling pathways in 2bkO liver, whereas an overall upregulation was observed in muscle. A predicted increase in IGF-1 signaling in muscle of fed fish likely facilitated an upregulation in myogenic mechanisms. IGF-independent responses in both liver and muscle are consistent with IGFBP-2b interacting with Type II, III, and IV nuclear receptors such as hepatocyte nuclear factor 4A, thyroid hormone receptor, liver X receptor, and pregnane X receptor, thus mediating changes in lipid, glucose, and sterol metabolism. In the liver, immune and cytokine systems were inhibited (tumor necrosis factor-α, nuclear factor-κB, and interleukin-1B), supporting that IGFBP-2b may play a central role to regulate the cross talk between systems that modulate the balance of energy between growth and immune function. In summary, through both enhanced IGF-1 signaling and regulation of IGF-independent mechanisms, it is predicted that the loss of IGFBP-2b increased muscle growth and regulated nutrient metabolism and cytokine signaling, providing insight into the functional role of IGFBP-2b in rainbow trout.NEW & NOTEWORTHY Gene expression profiles predict IGFBP-2b as a regulator of ligand-dependent nuclear receptors (LDNRs) in rainbow trout, supported by protein modeling that infers interactions between IGFBP-2b1 and specific LDNRs. Additional IGF-independent responses include upregulation of cytokine and transforming growth factor-B1 signaling in hepatic tissue. Through its dual control of IGF-dependent and IGF-independent processes, IGFBP-2b1 may be a mechanism for integrating signals that direct energy toward growth or divert energy to support an immune response.