Oral Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Insights from engraftable immunodeficient mouse models of hyperinsulinaemia (#81)

Michelle Maugham 1 2 3 4 , Patrick Thomas 1 2 3 , Gabrielle Crisp 1 3 , Lisa Philp 2 , Esha Shah 1 2 3 , Adrian Herington 1 2 , Chen Chen 5 , Laura Gregory 4 , Colleen Nelson 2 , Inge Seim 1 2 3 , Penny Jeffery 1 2 3 , Lisa Chopin 1 2 3
  1. Ghrelin research group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Please Select, Australia
  2. Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia
  3. Comparative and Endocrine Biology Laboratory, Translational Research Institute – Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
  4. Skeletal Biology and Forensic Anthropology Research Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
  5. School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, Queensland, Australia

Hyperinsulinaemia, obesity and dyslipidaemia are independent and collective risk factors for many cancers. The long-term effects of a 23% high fat diet (HFD) in two immunodeficient mouse strains (NOD/SCID and Rag1-/-), and the effect of diet-induced hyperinsulinaemia on human prostate cancer cell line xenograft growth, were investigated. Rag1-/- and NOD/SCID HFD-fed mice demonstrated diet-induced impairments in glucose tolerance at 16 and 23 weeks post weaning. Rag1-/- mice developed significantly higher fasting insulin levels (2.16 ± 1.01ng/ml, P = 0.01) and increased insulin resistance (6.70 ± 1.68 HOMA-IR, P = 0.01) compared to normal chow-fed controls (0.71 ± 0.12ng/ml and 2.91 ± 0.42 HOMA-IR), however, alterations in insulin resistance were not observed in the NOD/SCID strain. Hepatic steatosis and intramyocellular lipid storage was increased in Rag1-/- HFD-fed mice compared to NOD/SCID HFD-fed mice and absent in mice fed normal chow. Hepatic steatosis in HFD-fed mice was more extensive in Rag1-/- compared to NOD/SCID mice. In Rag1-/- HFD-fed mice, both PC3 and LNCaP xenograft tumour growth velocity was greater compared to chow-fed mice. Mice with PC3 xenografts developed significantly greater normalised wet tumour weight (485.16 ± 143.80% compared to 1562.69 ±338.20%, P = 0.032), tumour volume (485.16 ± 143.80% compared to 1562.69 ± 338.20%, P = 0.032) and velocity of proliferating Ki67+ PC3 tumour cells (36.08 ± 2.53% compared to 66.14 ± 8.514, P = 0.032) compared to mice fed normal chow. The percentage of mice surviving to ethical endpoint was significantly decreased in both HFD-fed groups compared to chow-fed mice (P = 0.0078 and P = 0.031). This is the first characterisation of the metabolic effects of long term HFD feeding in two strains of immunodeficient mice suitable for xenograft studies. Rag1-/- mice are an appropriate and novel xenograft model for studying the relationship between cancer and hyperinsulinaemia.