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The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder.

ABSTRACT: 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.

SUBMITTER: Williams MJ

PROVIDER: S-EPMC4900636 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder.

Williams Michael J MJ Klockars Anica A Eriksson Anders A Voisin Sarah S Dnyansagar Rohit R Wiemerslage Lyle L Kasagiannis Anna A Akram Mehwish M Kheder Sania S Ambrosi Valerie V Hallqvist Emilie E Fredriksson Robert R Schiöth Helgi B HB

PLoS genetics 20160609 6

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 ob ...[more]

PMID: 27280443

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Project description:Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N = 10,720-10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10-3) and BMI (P = 1.63 × 10-5); the circadian rhythm was associated with BMI (P = 1.28 × 10-3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P = 7.7 × 10-3; replication data P = 3.9 × 10-2)-a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.

Dataset Information

The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder.

Publications

The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder.

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