Effects of activation of the Unfolded Protein Response in Drosophila melanogaster
Using Drosophila melanogaster as a model, I studied the role of the three branches of the unfolded protein response by their ectopic activation. Overexpression of XBP1s and of PERK in the fat body induced striking structural changes in cell shapes and nucleus sizes, while overexpression of IRE1 and ATF6 had only minor effects. Activation of XBP1s and of PERK in the trachea was lethal. Moreover, it could be found that ectopic activation of XBP1s and of PERK, both in trachea and in the fat body induced expression of the antimicrobial peptide genes drosomycin. Insulin-like peptides (ILPs) act as key effectors regulating lifespan, metabolism, growth, development, reproduction, stress resistance and feeding behaviors in multicellular organisms. In this part, the focus was on the role of ectopic activation of the UPR in regulation of DILPs in Insulin producing cells (IPCs). In these experiments, obvious phenotypic changes of IPCs were observed in the adult brain, comprising of a decreased size of the IPC cluster in the pars intercerebralis, in animals experiencing specific XBP1s and PERK overexpression in the IPC. This reduction was more pronounced in PERK overexpressing flies. The level of circulating DILP2 in XBP1s overexpressing flies was decreased, both in females and males, exactly as the level of total DILP2. The insulin level was associated with hyperglycemia, attenuated ability of glucose clearance, and an extension of life span. Conversely, in PERK-overexpressing flies, a marked down-regulation of total insulin level was detected compared to the control flies, but a normal level of circulating insulin and an unimpaired ability of glucose clearance was seen. In addition, a developmental delay and smaller body sizes were observed only in PERK-overexpressing flies. ORMDL flies possess a good capacity of glucose clearance after oral feeding of glucose, compared to control flies although the glucose levels were slightly higher.