A Double-Hit Model of Early-Life Stress and High-Fat Feeding Reveals Enhanced Exocrine Pancreatic Remodeling

Adverse childhood experiences are associated with long-term metabolic disturbances, yet their effects on the exocrine pancreas remain poorly understood. Using maternal separation (MS) as a model of early-life stress, this study examined whether MS modifies the exocrine pancreatic response to a post-weaning high-fat diet (HFD) in male C57BL/6 mice. Animals were exposed to MS or standard rearing conditions and fed a control diet or HFD for 16 weeks. Body and pancreatic mass, plasma amylase and lipase activities, exocrine pancreatic histopathology, and apoptosis were assessed. HFD increased body mass and reduced the pancreas-to-body mass ratio independently of MS, without altering absolute pancreatic mass. Lipase activity increased significantly in response to both MS and HFD, whereas amylase showed a non-significant upward trend. Histopathological analysis revealed condition-dependent exocrine pancreatic remodeling, including acinar hypertrophy, autophagic vacuolization, focal necrosis, vascular alterations, interstitial edema, and ductal changes. These alterations were mild in HFD-only mice but more pronounced in MS-exposed animals, particularly when combined with HFD. Apoptosis was strongly influenced by early-life stress and modulated by diet, with significant effects of MS and the MS × diet interaction. Overall, early-life stress induces persistent structural and functional alterations in the exocrine pancreas, increasing susceptibility to nutritional challenges in adulthood.