Abstract
The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2α and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1α, and ATF6 pathways were affected differently following the obesogenic insults.
Highlights
Obesity-associated non-alcoholic fatty pancreas disease (NAFPD) is a pathological condition characterized by ectopic fat deposition in the pancreas
At day 21 postpartum, offspring were weaned onto either the control diet (Con) or the obesogenic diet (Ob) creating the following experimental groups: offspring of control weaned onto control diet (Con-Con), offspring of control weaned onto obesogenic diet (ConOb), offspring of obese weaned onto control diet (ObCon), and offspring of obese weaned onto obesogenic diet (Ob-Ob)
We have previously described in this experimental model that maternal obesogenic feeding alone predisposed offspring to a NAFPD phenotype, characterized by increased macrovesicular fat infiltration, worsened oral glucose tolerance test, and increased fibrogenic-related gene expression [1]
Summary
Obesity-associated non-alcoholic fatty pancreas disease (NAFPD) is a pathological condition characterized by ectopic fat deposition in the pancreas. In NAFPD, pancreatic stellate cells are abnormally activated, leading to excess collagen production and pancreatic fibrosis [39]. This can potentially lead to pancreatic cancer [25], and currently, pancreatic adenocarcinoma is one of the deadliest malignancies in developed countries, with a prevalence increasing in parallel with obesity rates [7]. Experimental models have demonstrated that maternal nutrition status during the perinatal period can directly modulate the risk of developing obesity [2], as well as obesity-associated metabolic diseases in offspring, such as non-alcoholic fatty liver disease (NAFLD) [3, 22], glucose intolerance [6], and hypertension [34]. Our research group has recently demonstrated that maternal obesity and subsequent obesogenic feeding in offspring can increase their triglyceride content and injury-related gene expressions in the pancreas [1]
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