Minibrain/Dyrk1a Regulates Food Intake through the Sir2-FOXO-sNPF/NPY Pathway in Drosophila and Mammals

Abstract

Feeding behavior is one of the most essential activities in animals, which is tightly regulated by neuroendocrine factors. Drosophila melanogaster short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. Here, we found that minibrain ( mnb) and the mammalian ortholog Dyrk1a target genes of sNPF and NPY signaling and regulate food intake in Drosophila melanogaster and mice. In Drosophila melanogaster neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, as well as increased food intake. Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals.

Author Summary

Feeding behavior is one of the most essential activities in animals. Abnormal feeding behaviors cause metabolic syndromes including obesity and diabetes. Neuropeptides regulate feeding behavior in animals from nematode to human. Here, we presented molecular genetic evidences of how neuropeptides regulate food intake using fruit fly and mouse model systems. Drosophila short neuropetide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) are produced from neurons in the brain of fruit fly and mouse, respectively. These neuropeptides turned on the minibrain, in mammals also called Dyrk1a, a target gene through the PKA-CREB pathway. Then, this Mnb/Dyrk1a enzyme activated Sir2/Sirt1 enzyme, which activated FOXO transcriptional factor, turning on the expression of a sNPF/NPY target gene. The increased sNPF/NPY increased food intake in fruit flies and mice. On the contrary, increased food intake induced insulin and activated insulin signaling. When insulin signaling is activated, FOXO transcriptional factor inhibited expression of a sNPF/NPY target gene. The inhibited sNPF/NPY reduced food intake. These findings indicate that FOXO transcription factor acts as a gatekeeper for fasting–feeding transition by regulating sNPF/NPY expression in Drosophila and mammals.