MTOR signaling is a promising therapeutic target in a subset of human pancreatic ductal adenocarcinomas

Abstract

s / Pancreatology 13 (2013) e1–e20 e8 University College London, Institute of Liver and Digestive Health, Royal Free Hospital Guy's and St Thomas’ NHS Foundation Trust, London, Department of Gastroenterology King's College London and King's Health Partners, Division of Women's Health University College London, Department of Pathology University College London, HPB & Liver Transplant Unit, Royal Free Hospital Category: Benign and Inflammatory Background and aims: Some 35% of women of reproductive age are obese. Emerging evidence suggests that maternal obesity(MO) may predispose offspring to an increased risk of obesity and its related disorders, including Non-Alcoholic Fatty Pancreas Disease(NAFPD), a newly described disease entity which may link obesity and pancreatic adenocarcinoma. We have investigated the impact of MO on the pathogenesis of NAFPD using a pathophysiologically relevant model and mechanistically explored a role for altered expression of circadian genes(CG). Methods: Female C57BL6 mice were fed standard or obesogenic diet(OD) for 6 weeks prior to and throughout pregnancy and lactation. Litters were standardised to a minimum of 6 pups and offspring then weaned onto either standard or OD to produce 4 groups before sacrifice at 6 months. We assessed biochemical, histological and pro-inflammatory/profibrogenic markers associated with the NAFPD phenotype and the expression of CG in the pancreas. Results and Interpretation: Offspring exposed to MO and OD had increased bodyweights (p<0.001), pancreas tissue triglycerides (p<0.001) alongside an increased expression of TNF-a (p<0.0001), IL-6 (p<0.001), aSMA (p<0.0001), TGF-b (p<0.001) and collagen (p<0.0001) when compared to controls. Additionally, cosinor analysis of CG demonstrated a phase shift in CLOCK (p<0.01), REV-ERB-a (p<0.05) and PER2(p<0.05). 2-way ANOVA further demonstrated CLOCK (p< 0.005), PER1 (p< 0.005) and PER2 (p< 0.05) to display a significant interaction between MO and post-weaning diet. Summary: Our results show that MO and a post-natal OD interact to induce offspring NAFPD. The mechanisms through which MO programs offspring NAFPD may be through a perturbation of CG. Take-home message: Maternal obesity in conjunction with a postweaning obesogenic diet may interact to induce offspring NAFPD, potentially through pertubation of core circadian genes. Abstract previously presented? no (Although it is due for poster presentation at UEGW in October) Any disclosures? no ()