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Functional and Molecular Characterization of Centrally Expressed Genes Associated with Obesity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. (Neurovetenskap, Funktionell Fa)
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: urn:nbn:se:uu:diva-262479ISBN: 978-91-554-9338-7 (print)OAI: oai:DiVA.org:uu-262479DiVA: diva2:853969
Public defence
2015-11-20, BMC, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2015-10-12 Created: 2015-09-15 Last updated: 2015-10-27
List of papers
1. The Drosophila ETV5 homologue Ets96B: Molecular link between obesity and bipolar disorder
Open this publication in new window or tab >>The Drosophila ETV5 homologue Ets96B: Molecular link between obesity and bipolar disorder
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2016 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 6, e1006104Article in journal (Refereed) Published
Abstract [en]

Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. For instance, obese individuals are more impulsive and have heightened reward responsiveness, phenotypes associated with BD, while bipolar patients become obese at a higher rate and earlier age than people without BD; however, the molecular mechanisms of such an association remain obscure. Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. We identify a novel molecular link between obesity and bipolar disorder. The Drosophila ETV5 homologue Ets96B regulates the expression of cellular systems with links to obesity and behaviour, including the expression of a conserved endoplasmic reticulum molecular chaperone complex known to be neuroprotective. Finally, a connection between the obesity- linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level.

National Category
Other Natural Sciences
Identifiers
urn:nbn:se:uu:diva-262381 (URN)10.1371/journal.pgen.1006104 (DOI)000379347100023 ()27280443 (PubMedID)
External cooperation:
Funder
Swedish Research CouncilThe Swedish Brain FoundationCarl Tryggers foundation Stiftelsen Olle Engkvist Byggmästare
Available from: 2015-09-15 Created: 2015-09-15 Last updated: 2017-12-05Bibliographically approved
2. The obesity-linked Nudt3 Drosophila homolog Aps is associated with insulin signalling
Open this publication in new window or tab >>The obesity-linked Nudt3 Drosophila homolog Aps is associated with insulin signalling
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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.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-262478 (URN)10.1210/ME.2015-1077 (DOI)000365272700008 ()6168034 (PubMedID)
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
3. Implication of coronin 7 in body weight regulation in humans, mice and flies
Open this publication in new window or tab >>Implication of coronin 7 in body weight regulation in humans, mice and flies
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2015 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 16, 13Article in journal (Refereed) Published
Abstract [en]

Background: Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. Results: We performed genome wide DNA methylation profiling comparing normal-weight and obese 9-13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression. Conclusion: We conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.

Keyword
Coronin 7, Obesity, Homeostatic control, Gene expression
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-251425 (URN)10.1186/s12868-015-0151-9 (DOI)000351126000001 ()
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2017-12-04Bibliographically approved
4. Nutrition regulates evolutionary conserved obesity-associated genes in mouse, zebrafish and fruit fly
Open this publication in new window or tab >>Nutrition regulates evolutionary conserved obesity-associated genes in mouse, zebrafish and fruit fly
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(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-262476 (URN)
Available from: 2015-09-15 Created: 2015-09-15 Last updated: 2015-10-27

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