Scientific Reports (2017-03-01)

Insights from engraftable immunodeficient mouse models of hyperinsulinaemia

  • 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

DOI
https://doi.org/10.1038/s41598-017-00443-x
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 10

Abstract

Read online

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.