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

The Drosophila RNA-binding protein Nab2 regulates key steps of gene expression, such as mRNA processing, export, localization, stability, and translation. In humans, ZC3H14 is a conserved RBP that influences pre-mRNA processing in neurons; its absence leads to neurological issues. Research on Nab2, the Drosophila equivalent of ZC3H14, has uncovered potential target RNAs involved in metabolism, implying Nab2 might impact neurometabolic circuits.

The study reveals a female-specific rise in dilp2 and dilp5 mRNA levels, with dilps encoding insulin-like peptides that transmit signals from brain insulin-producing cells (IPCs) to peripheral tissues. When Nab2 is absent in females, fat body cells exhibit larger lipid droplets, akin to human adipose tissue and liver. Interestingly, neuronal loss of Nab2 heightens lipid droplet size, while neuronal expression of Nab2 in Nab2-deficient females rectifies this issue, underscoring Nab2's role in a neuronal circuit that governs dilp levels.

Moreover, removal of dilp2 or dilp5 from IPCs alleviates the enlarged lipid droplet phenotype in Nab2-deficient females, indicating that heightened dilp2/dilp5 levels contribute to the enlarged lipid droplets. Collectively, these findings highlight a female-specific function for Nab2 in brain neurons to facilitate insulin signaling and fat storage, broadening the known roles of RBPs in connecting neuronal function with metabolic equilibrium.