Sex-specific metabolic regulation by the Drosophila RNA-binding protein Nab2

Abstract

Conserved RNA binding proteins (RBPs) regulate key steps of gene expression including mRNA processing, export, localization, stability and translation. Human ZC3H14 is a conserved RBP that regulates pre-mRNA processing in neurons and loss of ZC3H14 leads to neurological defects. Studies of Nab2, the Drosophila orthologue of ZC3H14, have identified potential target RNAs involved in metabolism, suggesting Nab2 may influence neurometabolic circuitry. Here, we show a female-specific increase in dilp2 and dilp5 mRNA levels. The dilps encode insulin-like peptides that signal from the brain insulin producing cells (IPCs) to peripheral tissues. Nab2null females have enlarged lipid droplets in the fat body, a tissue analogous to human adipose tissue and liver. Notably, neuronal depletion of Nab2 increases lipid droplet size while neuronal expression of Nab2 in Nab2null female rescues this phenotype supporting a role for Nab2 in a neuronal circuit that regulates dilp levels. Furthermore, depletion of dilp2 or dilp5 from IPCs rescues the enlarged lipid droplet phenotype in Nab2null females indicating that elevated dilp2/dilp5 contributes to enlarged lipid droplets. Together, these data support a female-specific role for Nab2 in brain neurons to support insulin signaling and fat storage, expanding the known functions of RBPs linking neuronal function and metabolic homeostasis. Significance Statement Drosophila Nab2, orthologue of the human RBP ZC3H14, which is lost in an inherited form of intellectual disability, regulates a specific subset of neuronal RNAs. This study identifies a female-specific role for Nab2 in regulating systemic metabolism by maintaining insulin-like peptides dilp2 and dilp5 mRNA levels in the brain and lipid homeostasis in the fat body, a tissue analogous to human adipose tissue and liver. These findings suggest that Nab2 has a role in a female-specific circuit that helps to maintain metabolic homeostasis involving the insulin signaling pathway and lipid storage in the fat body.