Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals

PLoS Genet. 2012;8(8):e1002857. doi: 10.1371/journal.pgen.1002857. Epub 2012 Aug 2.

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, [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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Appetite Regulation / genetics*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / physiology
  • Eating / physiology*
  • Feeding Behavior / physiology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation*
  • Humans
  • Hypothalamus / physiology
  • Mammals / physiology
  • Mice
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / genetics*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism

Substances

  • Drosophila Proteins
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Neuropeptide Y
  • Neuropeptides
  • short neuropeptide F, Drosophila
  • Dyrk kinase
  • mnb protein, Drosophila
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1