A fat-derived metabolite regulates a peptidergic feeding circuit in <i>Drosophila</i>

다국어 초록 (Multilingual Abstract)

<▼1><P>Here, we show that the enzymatic cofactor tetrahydrobiopterin (BH4) inhibits feeding in <I>Drosophila</I>. BH4 biosynthesis requires the sequential action of the conserved enzymes Punch, Purple, and Sepiapterin Reductase (Sptr). Although we observe 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 neurons that express neuropeptide F (NPF), the fly homologue of the vertebrate appetite regulator neuropeptide Y (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 BH4 deficiency reduces NPF staining, likely by promoting its release, 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.</P></▼1><▼2><P><B>Author summary</B></P><P>As the primary site of energy storage, adipose tissue must somehow monitor energy reserves and communicate this information to the brain. The brain must then modulate feeding behavior to maintain energy balance; however, the mechanisms underlying this communication between fat cells and the brain remain poorly understood. Here, we perform a targeted genetic screen in <I>Drosophila melanogaster</I> and identify a role for the enzymatic cofactor tetrahydrobiopterin (BH4) in regulating ad libitum feeding behavior in fruit flies. We show that three highly conserved enzymes—Punch, Purple, and Sepiapterin Reductase (Sptr)—are required for the biosynthesis of BH4. Fat body-specific knock-down of either Punch or Purple increases feeding, and this increase can be rescued by BH4. We find that rather than also being required in the fat body, Sptr is required in brain neurons that express neuropeptide F (NPF), the fly homologue of the vertebrate appetite regulator neuropeptide Y (NPY). BH4 also rescues the increase in feeding caused by NPF neuron-specific knock-down of Sptr. Although the exact mechanism remains unclear, our results suggest that BH4 inhibits signaling through NPF neurons by blocking their release of NPF. Based on its novel function in feeding and its physically distributed biosynthesis, BH4 may, therefore, represent one of the elusive signals that communicates energy status from the adipose tissue to the brain.</P></▼2>