Islet Proteome Remodeling and Proteostasis Disruption in HFSC-Fed Mice

Chronic overnutrition promotes metabolic syndrome and imposes substantial stress on pancreatic tissue, yet the early molecular alterations within pancreatic islets remain incompletely understood. High-fat, simple-carbohydrate (HFSC) diets have previously been shown to induce pancreatic steatosis, acinar atrophy, and islet hypertrophy in C57BL/6J mice. To investigate molecular responses underlying HFSC-induced pancreatic remodeling, we analyzed proteomic alterations in collagenase-isolated pancreatic islets from male C57BL/6J mice fed a laboratory-formulated HFSC diet for 150 days (n = 3 per group). Islet proteins were profiled using label-free ESI-nanoLC-MS/MS, resulting in the identification of 386 proteins. After applying peptide-based filtering criteria (≥2 peptides, ≥1 unique peptide) and statistical thresholds (fold change ≥ 1.5 and false discovery rate (FDR)-adjusted q-value ≤ 0.05), 30 proteins were identified as differentially expressed, including 19 upregulated and 11 downregulated proteins in HFSC islets compared with controls. Functional enrichment analysis revealed significant upregulation of pathways related to cytoplasmic translation, ribosomal biogenesis, and endoplasmic reticulum (ER) protein-folding processes, indicating increased biosynthetic activity and activation of proteostasis mechanisms. In contrast, downregulated proteins were enriched in carbohydrate and lipid metabolic pathways, suggesting metabolic remodeling within pancreatic islets. Notably, stress-responsive proteins, including MANF, HYOU1, SDF2L1, and HSP90B1, were downregulated, supporting the presence of ER stress-associated proteostasis alterations under HFSC-dietary conditions. Together, these findings provide proteomic evidence of molecular adaptations associated with metabolic stress in pancreatic islets, highlighting potential pathways involved in early islet dysfunction during diet-induced metabolic syndrome.