Tankyrases regulate glucoregulatory mechanisms and somatic growth via the central melanocortin system in zebrafish...

The central melanocortin system is a key regulator of energy homeostasis. Recent studies indicate that tankyrases (TNKSs), which poly(ADP-ribosyl)ate target proteins and direct them toward proteasomal degradation, affect overall metabolism, but the exact molecular mechanisms remain unclear. We used zebrafish larvae as a model to study the mechanisms by which TNKS1b, the zebrafish ortholog of mammalian TNKS1, regulates glucose homeostasis and somatic growth. In situ hybridization revealed that TNKS1b mRNA is prominently expressed in the hypothalamus and pituitary of the embryonic and larval brain. In the pituitary, TNKS1b is coexpressed with pro-opiomelanocortin a (pomca) gene in corticotropes and melanotropes. Knockdown of TNKS1b reduced the linear growth of the larvae, stimulated insulin gene and glucose transporter 4 protein, and suppressed gluconeogenic phosphoenolpyruvate carboxykinase 1 gene. This result indicates rapid glucose utilization and reduction of gluconeogenesis in TNKS1b-deficient larvae. Knockdown of TNKS1b down-regulated pomca expression and diminished α-melanocyte-stimulating hormone in the pars intermedia. Furthermore, down-regulation of TNKS1b suppressed the expression of melanocortin receptor 3 and increased the expression of melanocortin receptor 4. The collective data suggest that TNKS1b modulates glucoregulatory mechanisms and the somatic growth of zebrafish larvae via the central melanocortin system.