title: Insights from engraftable immunodeficient mouse models of hyperinsulinaemia.
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.
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.|Skeletal Biology and Forensic Anthropology Research Laboratory, Cancer Program, School of Biomedical Sciences, Translational Research Institute (TRI), Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Maugham
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Patrick B
authors.identifier: 0000-0002-3649-7923
authors.initials: PB
authors.lastname: Thomas
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Gabrielle J
authors.initials: GJ
authors.lastname: Crisp
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Philp
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Esha T
authors.initials: ET
authors.lastname: Shah
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Herington
authors.affiliation: School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, Queensland, Australia.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Skeletal Biology and Forensic Anthropology Research Laboratory, Cancer Program, School of Biomedical Sciences, Translational Research Institute (TRI), Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Gregory
authors.affiliation: 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.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.|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.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Inge
authors.initials: I
authors.lastname: Seim
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia. p.jeffery@qut.edu.au.|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. p.jeffery@qut.edu.au.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. p.jeffery@qut.edu.au.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Jeffery
authors.affiliation: Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia. l.chopin@qut.edu.au.|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. l.chopin@qut.edu.au.|Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. l.chopin@qut.edu.au.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Chopin
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology* / Q000276:immunology / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000378:metabolism; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; C064658:RAG-1 protein