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The obesity-linked Nudt3 Drosophila homolog Aps is associated with insulin signalling
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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2015 (English)In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 29, no 9, 1303-1319 p.Article in journal (Refereed) Published
Abstract [en]

Several genome-wide association studies have linked the Nudix hydrolase family member nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to obesity. However, the manner of NUDT3 involvement in obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3 mRNA and protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3 mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the insulin-producing cells (IPCs), induces hyperinsulinemia-like phenotypes, including a decrease in circulating trehalose levels as well as significantly decreasing all carbohydrate levels under starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these lipids during starvation. Also, loss of neuronal Aps expression caused a starvation susceptibility phenotype while inducing hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, llp6, and llp3, genes known to be inhibited by insulin signaling. These results point toward a role for this gene in the regulation of insulin signaling, which could explain the robust association with obesity in humans.

Place, publisher, year, edition, pages
2015. Vol. 29, no 9, 1303-1319 p.
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-262478DOI: 10.1210/ME.2015-1077ISI: 000365272700008PubMedID: 6168034OAI: oai:DiVA.org:uu-262478DiVA: diva2:853956
Funder
Swedish Research CouncilThe Swedish Brain FoundationCarl Tryggers foundation Stiftelsen Olle Engkvist Byggmästare
Available from: 2015-09-15 Created: 2015-09-15 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Functional and Molecular Characterization of Centrally Expressed Genes Associated with Obesity
Open this publication in new window or tab >>Functional and Molecular Characterization of Centrally Expressed Genes Associated with Obesity
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a complex disorder that has reached epidemic proportions in the Western world, currently affection more than two billion people. The evidence for the genetic influence on obesity has been estimated to be as high as 70% based on twin studies. Subsequent application of genome wide association studies has identified more than 90 genes to be associated with BMI. Despite great efforts the majority of the identified genetic variants have an unknown link to BMI and lack scientific basis explaining how they affect energy balance resulting in altered body weight. This thesis aims to characterize seven BMI-associated genes, Coronin 7, Etv5, Mtch2, Nudt3, Raptor, Sh2b1 and Vps13B by performing a molecular and functional profiling in mouse, zebrafish and fruit fly. A screen analysing the regulation of the selected genes under different dietary conditions revealed altered transcript levels in mouse, zebrafish and fruit fly including a conserved regulation in all species for some of the genes. Using genetic tools the Nudt3 homolog Aps in the Drosophila CNS was knocked down and showed that Aps has a role in the regulation of insulin signaling which could explain the robust association to obesity in humans. A comprehensive in situ hybridization revealed abundant Nudt3 mRNA and protein expression throughout the brain, including in reward and feeding related regions of the hypothalamus while Nudt3 mRNA expression was significantly up-regulated in the same region of food-deprived mice. Furthermore, we were able to identify a novel molecular link between obesity and bipolar disorder. The Drosophila homologue Ets96B regulates the expression of a cellular system with links to obesity and bipolar disorder, including the expression of a conserved endoplasmic reticulum molecular chaperone complex. A connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and bipolar disorder at the molecular level. Furthermore, as the BMI associated genetic variants does not fully explain the heritability of obesity we decided to perform a genome wide DNA methylation profile where we compared normal-weight and obese preadolescent children. We found a CpG site located near Coronin 7 to have significantly lower methylation levels in obese children. Further studies showed Coronin 7 to be highly expressed in important brain regions involved in energy balance. Strong immunostaining was also seen in locus coeruleus, the main site for noradrenergic production, and injecting mice with an appetite suppressant increased the number of Coronin 7 neurons within the very same brain region. An evolutionary conserved metabolic function in Drosophila was also demonstrated by knocking down the Coronin 7 homologue Pod1 in the fruit fly adult nervous system.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1134
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-262479 (URN)978-91-554-9338-7 (ISBN)
Public defence
2015-11-20, BMC, Husargatan 3, Uppsala, 10:00 (English)
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Available from: 2015-10-12 Created: 2015-09-15 Last updated: 2015-10-27

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Williams, MichaelEriksson, AndersVoisin, SarahFredriksson, RobertSchiöth, Helgi

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