Role of fat-derived purple and homothorax in drosophila feeding

Abstract

Well-regulated feeding is critical to growth, reproduction, and survival. Several researches discovered feeding related genes, however, mechanism of feeding is still unclear. We performed a two-tiered miRNA and RNAi-based genetic screen in Drosophila to identify novel fat-derived regulators of feeding. Here we show that homeodomain-containing transcription factor, Homothorax(HTH), and the enzymatic co-factor tetrahydrobiopterin (BH4) inhibit feeding in Drosophila. First, we observed that fat body-specific knockdown of Homothorax (HTH) flies shows overeating phenotype, and fat body-specific knockdown of the known Homothorax binding partner Extradenticle (EXD) also enhances feeding. While feeding behavior is related to fat storage, hth loss of function in fat body does not affect fat morphology. This study suggests that enhanced feeding from loss of Hth is not an inhibitor of appetite function in the adult fat body but the secondary effect as a growth factor from development. BH4 biosynthesis requires the sequential action of the conserved enzymes Punch, Purple, and Sepiapterin Reductase (Sptr). Although we observed increased feeding upon loss of Punch and Purple in the adult fat body, loss of Sptr must occur in the brain. We found Sptr expression is required in four adult brain neurons that express NPF, the fly homologue of the vertebrate appetite regulator NPY. As expected, feeding flies BH4 rescues the loss of Punch and Purple in the fat body and the loss of Sptr in NPF neurons. Mechanistically, we found that BH4 deficiency reduces NPF levels, while excess BH4 increases NPF accumulation without altering its expression. We thus show that because of its physically distributed biosynthesis BH4 acts as a fat-derived signal that induces satiety by inhibiting the activity of the NPF neurons.