Insights from engraftable immunodeficient mouse models of hyperinsulinaemia

• Main Authors: Michelle L. Maugham, Patrick B. Thomas, Gabrielle J. Crisp, Lisa K. Philp, Esha T. Shah, Adrian C. Herington, Chen Chen, Laura S. Gregory, Colleen C. Nelson, Inge Seim, Penny L. Jeffery, Lisa K. Chopin
• Format: Article
• Language: English
• Published: Nature Publishing Group 2017-03-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-017-00443-x

Abstract Hyperinsulinaemia, obesity and dyslipidaemia are independent and collective risk factors for many cancers. Here, the long-term effects of a 23% Western high-fat diet (HFD) in two immunodeficient mouse strains (NOD/SCID and Rag1 −/−) suitable for engraftment with human-derived tissue xenografts, 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 ± 1.01 ng/ml, P = 0.01) and increased insulin resistance (6.70 ± 1.68 HOMA-IR, P = 0.01) compared to low-fat chow-fed mice (0.71 ± 0.12 ng/ml and 2.91 ± 0.42 HOMA-IR). This was not observed in the NOD/SCID strain. Hepatic steatosis was more extensive in Rag1 −/− HFD-fed mice compared to NOD/SCID mice. Intramyocellular lipid storage was increased in Rag1 −/− HFD-fed mice, but not in NOD/SCID mice. In Rag1 −/− HFD-fed mice, LNCaP xenograft tumours grew more rapidly compared to low-fat chow-fed mice. This is the first characterisation of the metabolic effects of long-term Western HFD in two mouse strains suitable for xenograft studies. We conclude that Rag1 −/− mice are an appropriate and novel xenograft model for studying the relationship between cancer and hyperinsulinaemia.