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Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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2014 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 9, e1004499- p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 10, no 9, e1004499- p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-229123DOI: 10.1371/journal.pgen.1004499ISI: 000343009600002OAI: oai:DiVA.org:uu-229123DiVA: diva2:735740
Available from: 2014-07-31 Created: 2014-07-31 Last updated: 2017-12-05Bibliographically approved
In thesis
1. The Molecular Mechanism of Aggression and Feeding Behaviour in Drosophila melanogaster
Open this publication in new window or tab >>The Molecular Mechanism of Aggression and Feeding Behaviour in Drosophila melanogaster
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a complex disorder which has become a growing health concern. Twin studies have demonstrated a strong genetic component to the development of obesity and genome wide association studies have identified several genetic loci associated with it. However, most of these loci are still poorly understood in a functional context. Interestingly, many of the hormones and neurobiological messengers responsible for regulating feeding behaviour and metabolism are also linked to controlling aggression, but it is still not understood how they interact to maintain metabolic homeostasis. In this thesis, the model organism Drosophila melanogaster was employed to dissect the molecular mechanisms of the genetic cascades regulating aggressive behaviour and metabolic homeostasis.

In paper I and II, the role of transcription factor AP-2 (TfAP-2) and Tiwaz Twz, Drosophila homologues of two human obesity-linked genes were investigated in aggression and feeding behaviour. Paper I demonstrated that TfAP-2 and Twz genetically interact in octopaminergic neurons to modulate male aggression by controlling the expression of genes necessary for octopamine (fly analogue of noradrenaline) production and secretion. Moreover, it was revealed that octopamine in turn regulates aggression through the Drosophila cholecystokinin (CCK) satiation hormone homologue Drosulfakinin (Dsk). Paper II revealed that TfAP-2 and Twz also initiate feeding through regulation of octopamine poduction and secretion. Octopamine then induces Dsk expression leading to inhibition of feeding.

Paper III established that the activity of the small GTPase Ras-related C3 botulinum toxin substrate 2 (Rac2) is required in Drosophila for the proper regulation of metabolic homeostasis, as well as overt behaviours. Rac2 mutants were starvation susceptible, had less lipids and exhibited disrupted feeding behaviour. Moreover, they displayed aberrant aggression and courtship behaviour towards conspecifics.

Paper IV studied Protein kinase D (PKD), the homologue of a third obesity-linked gene PRKD1, and another kinase Stretchin-Mlck (Strn-Mlck). Reducing PKD transcript levels in the insulin producing cells led to flies with increased starvation susceptibility, decreased levels of lipids and diminished insulin signalling compared to controls. Reduced Strn-Mlck expression resulted in a starvation phenotype and slight reduction in insulin signalling and lipid content. These findings imply a function for PKD and Strn-Mlck in insulin release.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 45 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1015
Keyword
Drosophila, aggression, obesity, homeostasis
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-229124 (URN)978-91-554-8985-4 (ISBN)
Public defence
2014-09-16, C8.301, Husargatan, 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2014-08-26 Created: 2014-07-31 Last updated: 2014-09-08Bibliographically approved

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Williams, MichaelGoergen, PhilipZheleznyakova, GalinaHägglund, MariaPerland, EmelieBagchi, SonchitaFredriksson, RobertSchiöth, Helgi

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