Peroxisome function in insulin signalling: Vesicular trafficking and neuropeptide secretion

• Applicant: Dr. Margret Bülow
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417982926

Peroxisomes are vital organelles whose function declines with aging. This decline is associated with oxidative stress and an imbalance of lipids that are synthesized or metabolized by peroxisomes. Oxidative stress elicits lipotoxicity that damages the pancreatic beta-cells in diabetes type 2. Peroxisome dysfunction leads to a reduction in the density of insulin-containing granules and overall pancreatic insulin content in mice. Moreover, defects in peroxisome biogenesis induce a lipolytic program that leads to the accumulation of free fatty acids and damages mitochondria. Here I used a fly model to show that defects in peroxisome biogenesis impair the secretion of insulin-like peptides from the insulin-producing cells in the brain. Insulin-like peptide secretion is regulated by signals derived from adipose tissue. As a consequence of high lipolysis in mutants for the peroxisome biogenesis factor Pex19, adipose tissue is reduced and free fatty acids accumulate in the circulation and in non-lipid-storing organs. Alleviating lipotoxicity specifically in the insulin-producing cells restores insulin-like peptide secretion in Pex19 mutants and restores insulin signaling in peripheral tissues. However, this is a consequence of peroxisome dysfunction and does not solve how peroxisome contribute to normal insulin-like peptide secretion. In the proposed study, I will investigate if peroxisomes, by their metabolism, as a cellular structure, or by their interaction with other organelles, mediate insulin-like peptide secretion. I will analyze if functional, mature peroxisomes, Pex19-positive pre-peroxisomal vesicles, or the capacity of Pex19 in vesicle budding are required for insulin-like peptide release. Further, I will test if these structures interact with small GTPases of the Rab protein family in membrane trafficking. Pex19 interacts with a protein of the endoplasmic reticulum, Creld, that regulates hydrogen peroxide formation and thereby dopaminergic neuron function. To test if findings obtained on the role of Pex19 or peroxisomes on vesicle trafficking can be generalized to other neuron groups, I will analyze the interaction of Creld and Pex19 with endoplasmic reticulum and mitochondria. I will further test if this interaction modulates the secretion of insulin-like peptides and the activity of dopaminergic neurons. In summary, I aim at defining the mechanisms that allow peroxisomes and interacting organelles to mediate neuropeptide secretion.

• DFG Programme: Research Grants