Now showing 1 - 1 of 1
  • Publication
    Modelling The Impact Of High Fat Diet Feeding And Intentional Weight Loss On Type 1 Endometrial Cancer In The BDII/Han Rat
    (University College Dublin. School of Medicine, 2021)
    Background Obesity is associated with endometrial cancer (EC). Metabolic surgery (MS) induces weight loss and reduces the risk of developing EC. The present study sought to examine whether high fat diet (HFD) and weight gain, as well as subsequent intentional weight loss alters EC tumour biology using the BD/II Han rat model of EC. There is minimal data on the natural history of tumour development in this model. Rat EC has never previously been imaged and an imaging protocol was required to assess the onset of tumour development and longitudinally track tumours. Aims The aims of this study were to validate an imaging protocol of rat EC and determine a suitable timepoint to institute a weight loss intervention; to assess whether feeding HFD could mimic obesity and accelerate EC burden in an animal model of spontaneous EC and to assess the effect of intentional weight loss on rats fed HFD. Methods A pilot study was performed to optimise visualisation of the uterine horns (UH) on computed tomography (CT) imaging in cadaveric female Wistar rats. Parameters assessed included position, energy setting, concentration/volume of intraperitoneal (IP) contrast. 7 BDII/Han rats were fed normal chow (NC) and 8 weight-matched rats fed HFD from 3 months of age. Longitudinal PET (positron emission tomography)-CT was conducted at 7, 9, 12 and 15 months. Abdominal visceral fat was analysed from L1-L5 on CT. Subsequently, an intervention study compared the 8 HFD Control rats to 8 weight-matched HFD-fed rats treated with Liraglutide from 12-15 months. PET-CT was performed at 12 and 15 months to assess disease progression. Analysis of histological, immunohistochemical and transcriptomic parameters were used to compare cohorts. All rats were euthanased at 15 months of age. Imaging was correlated with necropsy findings and histopathology. Results The pilot study demonstrated that the supine position, 50kV energy setting, 1:4 dilution of IP contrast and maximal volume were optimal. Imaging also demonstrated the importance of overnight fasting of animals to ensure good visualisation of the UHs. Identified parameters were used in CT imaging of live animals in subsequent studies. HFD rats had significantly more abdominal fat on CT imaging (8.6cm3±0.7vs4.0cm3±0.6; p<0.0005) and had 10% higher bodyweight than NC rats (232.5g±4.9vs209.4g±2.0; p=0.001) at the study end. Histopathology demonstrated that 57%(n=4) of NC and 50%(n=4) of HFD rats had EC. A standardised uptake value (SUV) cut-off of 2 was used for tumour hotspots and validated. A hotspot was identified at 7 months and PET-CT imaging demonstrated 47%(n=7) hotspots at 12 months across both diet groups. Correlation with histology demonstrated that PET-CT was 87.5% sensitive and 86% specific. Maximal mean percentage weight loss in the Liraglutide group was 16% at 35 days post intervention. Mean percentage weight loss prior to the cull was 11%. Liraglutide induced significant reduction in final body weight (208.3g±5.7vs232.5g±4.9; p=0.006) and reduction in visceral abdominal fat on CT compared to HFD control rats (4.4cm3±0.4vs8.6cm3±0.7; p=0.0001). 2 tumours were identified in the Liraglutide group (25%) compared to 4 in the HFD control rats (50%). GLP-1 receptor expression was not detected in BDII/Han UHs or EC using RT-PCR or immunohistochemistry. Conclusions This study has established a robust, safe, sensitive and specific imaging protocol for longitudinal assessment of EC progression in rats. This is the first study to provide data on the weight profile of BDII/Han rats fed NC and 60% HFD. The HFD intervention used did not accelerate EC burden. However, it did create an obese phenotype and gave new information on the pathological variations of EC in the BDII/Han rat. Liraglutide did reduce EC burden, which may be due to weight loss dependent actions. This novel study has provided a foundation for future studies assessing the effect of intentional weight loss in obesity related cancer