Integrating lipid metabolism, pheromone production and perception by Fruitless and Hepatocyte Nuclear Factor 4

Sexual attraction and perception are crucial for mating and reproductive success. In Drosophila melanogaster, the male-specific isoform of Fruitless (Fru), Fru^M, is a known master neuro-regulator of innate courtship behavior to control the perception of sex pheromones in sensory neurons. Here, we show that the non-sex-specific Fru isoform (Fru^COM) is necessary for pheromone biosynthesis in hepatocyte-like oenocytes for sexual attraction. Loss of Fru^COM in oenocytes resulted in adults with reduced levels of cuticular hydrocarbons (CHCs), including sex pheromones, and show altered sexual attraction and reduced cuticular hydrophobicity. We further identify Hepatocyte nuclear factor 4 (Hnf4) as a key target of Fru^COM in directing fatty acid conversion to hydrocarbons. Fru or Hnf4 depletion in oenocytes disrupts lipid homeostasis, resulting in a sex-dimorphic CHC profile that differs from doublesex- and transformer-dependent CHC dimorphism. Thus, Fru couples pheromone perception and production in separate organs to regulate chemosensory communications and ensure efficient mating behavior.