Forsøksdyr: Comparison of feeding of a high fat diet to Park7-/- zebrafish with wildtype zebrafish

Godkjenningsdato 15.03.2018

Godkjenningsperiode 16.03.2018-15.01.2020

Zebrafish are a popular animal model for studying a number of human diseases in particular neurodegenerative diseases such as Parkinson's Disease (PD). DJ-1, encoded by the Park7 gene, is a protein associated with the familial form of PD. DJ-1 is thought to protect cells from oxidative stress insults. In order to study the function of DJ-1 further we have previously produced a park7 knockout (KO) zebrafish line. We have been using our line to study the protein changes occurring in larvae in vivo during the induction of oxidative stress. Recent studies suggest that DJ-1 may additionally have roles in metabolic diseases and we to elucidate the function of DJ-1 in regard to metabolism. Previous studies in DJ-1 KO mice have shown a correlation between the upregulation of DJ-1 and high fat diets (1). Also, there appears to be an important role for DJ-1 in glucose metabolism, as DJ-1 deficient mice develop higher levels glucose intolerance and increased levels of B-cell dysfunction during aging compared to wild type (WT) mice (2). This may relate back to DJ-1's function as a regulator of overall reactive oxygen species (ROS).

We propose an experiment of feeding a high fat diet to WT and park7-/- adult zebrafish for a period of 10 weeks. We hypothesize that the KO fish will be protected from some of the obesity related traits as seen in mice. Additionally, a second trial using the same food supplemented with tetradecylthioacetic acid (TTA) will also be fed to WT and park7-/- adult zebrafish for a period of 10 weeks. TTA, CH3-(CH2)13-S-CH2-COOH, is a fatty acid synthesized by replacing the β-methyl group with a sulfur atom preventing β-oxidation or degradation from occurring. TTA acts as a triglyceride lowering compound. It induces mitochondrial proliferation and increases mitochondrial fatty acid oxidation in rats (3). Additionally, it has been seen that a TTA enriched high fat diet fed to rats protects them from diet induced obesity (4). Because DJ-1 is suspected to fulfill a similar function we are interested in seeing if the TAA is sufficient in the KO to give the same effect.

Before the initial feeding fish will be anesthetized briefly in order to measure their length and weigh them. During the feeding period we will observe fish for any changes in behavior in addition to weighing the fish every other week. At the conclusion of the 10 week feeding period, we will terminate the fish in order to study the histological and proteomic changes which have occurred due to the high fat diet or high fat supplemented diet when comparing the KO to the WT. The fish should experience limited distress from the diet change and will be ethically terminated for dissection and the completion of the project.

1. Waanders, L., et al. (2009) Proc National Acad Sci, 106, 18902–18907.
2. Jain, D.,et al. (2012) J Mol Cell Biol 4, 221–30.
3. Lindquist, C., et al. (2017) J. Lipid Res. 58, 1362–1373.
4. Madsen, L.,et al. (2002) J. Lipid Res. 43, 742–50.