Regulation of Insulin Signaling by Matrix Metalloproteinase 2 in Drosophila melanogaster



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Insulin sensitivity declines progressively with age in mammals, potentially leading to diseases such as metabolic syndrome, obesity, and type 2 diabetes. The mechanisms underlying this decline are not well understood. Matrix metalloproteinases or MMPs are multifunctional Zn2+-dependent protease enzymes that play key roles in tissue development, cell organization, cell cycle control, and response to stimuli and signaling in a wide variety of animals, including mammals and the model organism Drosophila melanogaster. Many MMPs are attached to the cell membrane by the protein glycosylphosphatidylinositol (GPI), which enables them to interact with the cell’s extracellular matrix (ECM) (Cieplak & Strongin, 2017). Previous studies of MMPs in D. melanogaster indicate that MMP1 and MMP2 work cooperatively and distinctly to degrade ECM components, particularly type IV collagen and laminin, during tissue remodeling of the larval fat bodies (Jia et al., 2014, 2017). MMP2 overexpression causes premature fat body remodeling in larvae and is both necessary and sufficient to induce fat body dissociation in D. melanogaster (Bond et al., 2011). I investigated the role of MMP2 in insulin signaling using D. melanogaster, which is a great model organism with a short life cycle that requires minimal culturing effort. Despite the fruit fly having low genetic redundancy, it still has a 75% similarity to all human genes implicated in disease. This makes it an ideal model organism to study the insulin signaling pathway. Previous studies show the indirect involvement of MMP2 in insulin signaling in D. melanogaster, and overexpression of an MMP (MT1-MMP/MMP14) in mouse hepatic (liver) tissue showed direct cleavage of the insulin receptor, thus suppressing insulin signaling (Guo et al., 2022). I hypothesized that in D. melanogaster, MMP2 has direct involvement in the insulin signaling pathway through cleavage of the insulin receptor. In my investigation - inspired by the mouse study - I overexpressed MMP2 in the fat body of transgenic flies and quantified the effect on insulin signaling via western blot analysis. Quantification of the western blot by downstream protein biomarkers of autophagy, Atg8a proteins, resulted in a surprising decrease in autophagy in the fat bodies of MMP2 overexpressing transgenic flies compared to the control group. Despite that outcome, it was notable that early fat body remodeling occurred in MMP2 overexpressed flies, which is consistent with the findings of Bond et al., (2011). In future studies, more western blots should be performed to gain a higher n value, and tissue samples should also be taken from feeding 3rd instar larvae when insulin signaling is at its highest (Chen, 2020).



insulin, matrix metalloproteinase, MMP2, signaling, Drosophila, autophagy, fat body