The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder.
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.
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Michael J
MJ
Williams
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Anica
0000-0002-4750-2193
A
Klockars
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Anders
A
Eriksson
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Sarah
S
Voisin
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Rohit
0000-0002-2699-0087
R
Dnyansagar
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Lyle
L
Wiemerslage
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Anna
A
Kasagiannis
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Mehwish
0000-0002-1442-7174
M
Akram
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Sania
S
Kheder
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Valerie
V
Ambrosi
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Emilie
E
Hallqvist
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Robert
R
Fredriksson
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Helgi B
HB
Schiöth
D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics*; D015992:Body Mass Index; D002843:Chromatin / Q000378:metabolism; D003433:Crosses, Genetic; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics*; D005786:Gene Expression Regulation; D015723:Gene Library; D020868:Gene Silencing; D006801:Humans; D008297:Male; D009765:Obesity / Q000235:genetics*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D002843:Chromatin; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C086680:ETV5 protein, human; C000615825:Ets96B protein, Drosophila; D014157:Transcription Factors; D004298:Dopamine