Aging Research Centre, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
PLoS Genet. 2012;8(8):e1002857. doi: 10.1371/journal.pgen.1002857. Epub 2012 Aug 2.
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, [corrected] 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, and [corrected] 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.
摄食行为是动物最基本的活动之一，受神经内分泌因素的严格调节。果蝇短神经肽 F（sNPF）和哺乳动物功能同源物神经肽 Y（NPY）调节摄食。了解 sNPF 和 NPY 信号转导的分子机制对于阐明摄食调节至关重要。在这里，我们发现 minibrain（mnb）和哺乳动物同源物 Dyrk1a，sNPF 和 NPY 信号的靶基因，[校正]调节果蝇和小鼠的摄食。在果蝇神经元细胞和小鼠下丘脑细胞中，sNPF 和 NPY 通过 PKA-CREB 途径调节 mnb 和 Dyrk1a 的表达。增加的 Dyrk1a 激活 Sirt1 以调节 FOXO 的去乙酰化，从而增强 FOXO 诱导的 sNPF/NPY 表达，并反过来促进摄食。相反，AKT 介导的胰岛素信号抑制 FOXO 介导的 sNPF/NPY 表达，导致摄食减少。此外，人类 Dyrk1a 转基因小鼠表现出下丘脑中 FOXO 乙酰化减少和 NPY 表达增加，并[校正]增加摄食。我们的研究结果表明，Mnb/Dyrk1a 通过果蝇和哺乳动物中进化保守的 Sir2-FOXO-sNPF/NPY 途径调节摄食。
