title: Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster.
abstract: In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Philip
authors.initials: P
authors.lastname: Goergen
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Jayasimman
authors.initials: J
authors.lastname: Rajendran
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Galina
authors.initials: G
authors.lastname: Zheleznyakova
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Hägglund
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Perland
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Sonchita
authors.initials: S
authors.lastname: Bagchi
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Argyro
authors.initials: A
authors.lastname: Kalogeropoulou
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Khan
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.affiliation: Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism* / Q000502:physiology*; D005246:Feedback; D005247:Feeding Behavior / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D062407:Meals / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology*; D009655:Octopamine / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D015221:Potassium Channels; D050656:Transcription Factor AP-2; D009655:Octopamine