A fat-derived metabolite regulates a peptidergic feeding circuit in Drosophila

Here, we show that the enzymatic cofactor tetrahydrobiopterin (BH4) inhibits feeding in Drosophila. 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.

本研究证实，酶辅助因子四氢生物蝶呤（tetrahydrobiopterin, BH4）可抑制果蝇（Drosophila）的摄食行为。BH4的生物合成依赖保守酶Punch、Purple以及分离蝶呤还原酶（Sepiapterin Reductase, Sptr）的依次催化作用。尽管我们观察到成虫脂肪体中Punch与Purple缺失会导致摄食增加，但Sptr的功能缺失需发生于大脑中。我们发现，Sptr的表达仅在四类表达神经肽F（neuropeptide F, NPF，即脊椎动物食欲调节因子神经肽Y（neuropeptide Y, NPY）的果蝇同源物）的成虫神经元中是必需的。如预期一致，向果蝇饲喂BH4可挽救脂肪体中Punch、Purple缺失以及NPF神经元中Sptr缺失所引发的摄食异常表型。从机制层面来看，BH4缺乏会降低NPF的染色信号，这可能是通过促进NPF的释放实现的；而过量BH4则会增加NPF的积累，但不会改变其表达水平。综上，由于BH4的生物合成具有空间分布特性，其可作为一种脂肪来源信号，通过抑制NPF神经元的活性来诱导果蝇产生饱足感。