Abstract
ObjectivesEmerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock - molecular core circadian genes (CCG) in the generation of NAFPD.DesignFemale C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined.ResultsOffspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-β and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (−4.818, p<0.01), REV-ERB-α (−1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (−0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG.ConclusionsFetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.
Highlights
Non-alcoholic fatty pancreas disease (NAFPD) is a recently described disease entity associated with an obese and/or dysmetabolic phenotype [1,2]
Fetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in circadian genes (CCG) expression
In a rodent model, that diet induced maternal obesity can play a causative role in the development of NAFPD and that this is exacerbated if the offspring themselves are reared on the same obesogenic diet [1]
Summary
Non-alcoholic fatty pancreas disease (NAFPD) is a recently described disease entity associated with an obese and/or dysmetabolic phenotype [1,2]. NAFPD describes a phenotype ranging from deposition of fat in the pancreas to pancreatic inflammation, and resultant fibrosis This pancreatic phenotype is similar to that of obesity-induced liver disease, non-alcoholic fatty liver disease (NAFLD), which describes a spectrum from hepatic steatosis through steatohepatitis to cirrhosis, and possible hepatocellular carcinoma [2,3]. Given that the liver and pancreas have similar embryological origins, it is plausible, as suggested for NAFLD, that obesity may lead to pancreatic cancer through pancreatic steatosis [4,5] This hypothesis is corroborated by studies implicating NAFPD as a risk factor in pancreatic adenocarcinoma [6,7,8]. The prevalence of maternal obesity is increasing worldwide in parallel with adult obesity rates [9], and observational studies suggest an association between maternal obesity, and risk of childhood obesity [10,11], for which rates are rising with
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