Sexual identity of Akh neurons shapes Nucb1-dependent metabolic and reproductive plasticity.

Sex differences in metabolic physiology are widespread across species and are tightly linked to reproductive demands. Here, we identify nucleobindin 1 (Nucb1), a conserved calcium-binding protein, as a female-specific metabolic regulator in the adipokinetic hormone (Akh)-producing cells (APCs) of Drosophila melanogaster. APC-specific nucb1 knockdown increased energy storage and body mass in females but not in males. Cellular sex reversal experiments revealed these female-specific functions of Nucb1 to be dependent on the intrinsic sexual identity of the APCs, rather than the sex of the organism. Furthermore, under nutrient restriction, females lacking nucb1 in APCs failed to suppress oocyte maturation, indicating disrupted coupling between nutrient status and reproductive output. In contrast, we identified slowpoke-binding protein (Slob) in the APCs as a regulator of male-specific body fat storage. Together, these findings demonstrate that sex-specific metabolic and reproductive regulation arises from differential regulatory factors within the same neuroendocrine cell type.