Skip to main content

Pathophysiology and Genetics of Obesity and Diabetes in the New Zealand Obese Mouse: A Model of the Human Metabolic Syndrome

  • Protocol
  • First Online:
Animal Models in Diabetes Research

Part of the book series: Methods in Molecular Biology ((MIMB,volume 933))

Abstract

The New Zealand Obese (NZO) mouse is one of the most thoroughly investigated polygenic models for the human metabolic syndrome and type 2 diabetes. It presents the main characteristics of the disease complex, including early-onset obesity, insulin resistance, dyslipidemia, and hypertension. As a consequence of this syndrome, a combination of lipotoxicity and glucotoxicity produces beta-cell failure and apoptosis resulting in hypoinsulinemia and diabetic hyperglycemia. With NZO as a breeding partner, several adipogenic and diabetogenic gene variants have been identified by hypothesis-free positional cloning (Tbc1d1, Zfp69) or by combining genetic screens and candidate gene approaches (Pctp, Abcg1, Nmur2, Lepr). This chapter summarizes the present knowledge of the NZO strain and describes its pathophysiology as well as the known underlying genetic defects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Leiter EH (2009) Selecting the “right” mouse model for metabolic syndrome and type 2 diabetes research. Methods Mol Biol 560:1–17

    Article  PubMed  CAS  Google Scholar 

  2. Bielschowsky M, Bielschowsky F (1953) A new strain of mice with hereditary obesity. Proc Univ Otago Med School 31:29–31

    Google Scholar 

  3. Bielschowsky M, Goodall CM (1970) Origin of inbred NZ mouse strains. Cancer Res 30:834–836

    PubMed  CAS  Google Scholar 

  4. Bielschowsky F, Bielschowsky M (1956) The New Zealand strain of obese mice; their response to stilboestrol and to insulin. Aust J Exp Biol Med Sci 34:181–198

    Article  PubMed  CAS  Google Scholar 

  5. Ortlepp JR et al (2000) A metabolic syndrome of hypertension, hyperinsulinaemia and hypercholesterolaemia in the New Zealand obese mouse. Eur J Clin Invest 30:195–202

    Article  PubMed  CAS  Google Scholar 

  6. Festing M (1997) Inbred strains of mice. Mouse Genome 95:519–686

    Google Scholar 

  7. Koza RA et al (2004) Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity. Metabolism 53:799–808

    Article  PubMed  CAS  Google Scholar 

  8. Herberg L, Coleman DL (1977) Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 26:59–99

    Article  PubMed  CAS  Google Scholar 

  9. Chankiewitz E (2005) Beiträge zur Charak­terisierung eines diabetischen Tiermodells: die New Zealand obese-Maus (NZO). In: Medizinische Fakultät. Martin-Luther-Universität, Halle-Wittenberg, p 79

    Google Scholar 

  10. Radavelli-Bagatini S et al (2011) The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function. J Endocrinol 209(3):307–315

    Article  PubMed  CAS  Google Scholar 

  11. Crofford OB, Davis CK Jr (1965) Growth characteristics, glucose tolerance and insulin sensitivity of New Zealand obese mice. Metabolism 14:271–280

    Article  PubMed  CAS  Google Scholar 

  12. Ackert-Bicknell C et al (2011) Aging study: bone mineral density and body composition of 32 inbred strains of mice. Mouse Phenome Database web site, The Jackson Laboratory, Bar Harbor, ME. http://phenome.jax.org

    Google Scholar 

  13. Plum L et al (2002) Characterisation of the mouse diabetes susceptibility locus Nidd/SJL: islet cell destruction, interaction with the obesity QTL Nob1, and effect of dietary fat. Diabetologia 45:823–830

    Article  PubMed  CAS  Google Scholar 

  14. Mirhashemi F et al (2011) Diet dependence of diabetes in the New Zealand obese (NZO) mouse: total fat, but not fat quality or sucrose accelerates and aggravates diabetes. Exp Clin Endocrinol Diabetes 119:167–171

    Article  PubMed  CAS  Google Scholar 

  15. Jürgens HS et al (2006) Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. Physiol Genomics 25:234–241

    Article  PubMed  Google Scholar 

  16. Igel M et al (1997) Hyperleptinemia, leptin resistance, and polymorphic leptin receptor in the New Zealand obese mouse. Endocrinology 138:4234–4239

    Article  PubMed  CAS  Google Scholar 

  17. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770

    Article  PubMed  CAS  Google Scholar 

  18. Halaas JL et al (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 94:8878–8883

    Article  PubMed  CAS  Google Scholar 

  19. Ferreras L et al (1994) Early decrease in GLUT4 protein levels in brown adipose tissue of New Zealand obese mice. Int J Obes Relat Metab Disord 18:760–765

    PubMed  CAS  Google Scholar 

  20. Subrahmanyam K (1960) Metabolism in the New Zealand strain of obese mice. Biochem J 76:548–556

    PubMed  CAS  Google Scholar 

  21. Larkins RG (1971) Plasma growth hormone in the New Zealand obese mouse. Diabetologia 7:302–307

    Article  PubMed  CAS  Google Scholar 

  22. Huchzermeyer H, Rudorff KH, Staib W (1973) (Experimental studies on the problem of insulin resistance in adipositas and diabetes mellitus, with the aid of New Zealand obese mice. Pathogenesis of the obese-hyperglycaemic syndrome (author’s transl)). Z Klin Chem Klin Biochem 11:249–256

    PubMed  CAS  Google Scholar 

  23. Jürgens HS et al (2007) Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction. Diabetologia 50:1481–1489

    Article  PubMed  CAS  Google Scholar 

  24. Veroni MC, Proietto J, Larkins RG (1991) Evolution of insulin resistance in New Zealand obese mice. Diabetes 40:1480–1487

    Article  PubMed  CAS  Google Scholar 

  25. Rudorff KH et al (1970) The influence of insulin on the alanine gluconeogenesis in isolated perfused livers of New Zealand obese mice. Eur J Biochem 16:481–486

    Article  PubMed  CAS  Google Scholar 

  26. Sneyd JG (1964) Pancreatic and serum insulin in the New Zealand strain of obese mice. J Endocrinol 28:163–172

    Article  PubMed  CAS  Google Scholar 

  27. Stauffacher W, Renold AE (1969) Effect of insulin in vivo on diaphragm and adipose tissue of obese mice. Am J Physiol 216:98–105

    PubMed  CAS  Google Scholar 

  28. Fesus G et al (2007) Adiponectin is a novel humoral vasodilator. Cardiovasc Res 75:719–727

    Article  PubMed  Google Scholar 

  29. Joost HG (2010) The genetic basis of obesity and type 2 diabetes: lessons from the New Zealand obese mouse, a polygenic model of the metabolic syndrome. Results Probl Cell Differ 52:1–11

    Article  PubMed  CAS  Google Scholar 

  30. Leiter EH et al (1998) NIDDM genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds. Diabetes 47:1287–1295

    Article  PubMed  CAS  Google Scholar 

  31. Plum L et al (2000) Type 2 diabetes-like hyperglycemia in a backcross model of NZO and SJL mice: characterization of a susceptibility locus on chromosome 4 and its relation with obesity. Diabetes 49:1590–1596

    Article  PubMed  CAS  Google Scholar 

  32. Bray GA, York DA (1971) Genetically transmitted obesity in rodents. Physiol Rev 51:598–646

    PubMed  CAS  Google Scholar 

  33. Stauffacher W et al (1967) Measurements of insulin activities in pancreas and serum of mice with spontaneous (“Obese” and “New Zealand Obese”) and induced (Goldthioglucose) obesity and hyperglycemia, with considerations on the pathogenesis of the spontaneous syndrome. Diabetologia 3:230–237

    Article  PubMed  CAS  Google Scholar 

  34. Haskell BD et al (2002) The diabetes-prone NZO/HlLt strain. I. Immunophenotypic comparison to the related NZB/BlNJ and NZW/LacJ strains. Lab Invest 82:833–842

    PubMed  Google Scholar 

  35. Kluth O et al (2011) Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia 54:605–616

    Article  PubMed  CAS  Google Scholar 

  36. Cameron DP, Opat F, Insch S (1974) Studies of immunoreactive insulin secretion in NZO mice in vivo. Diabetologia 10(suppl):649–654

    Article  PubMed  CAS  Google Scholar 

  37. Lange C et al (2006) The diabetes-prone NZO/Hl strain. Proliferation capacity of beta cells in hyperinsulinemia and hyperglycemia. Arch Physiol Biochem 112:49–58

    Article  PubMed  CAS  Google Scholar 

  38. Junger E et al (2002) The diabetes-prone NZO/Hl strain. II. Pancreatic immunopathology. Lab Invest 82:843–853

    PubMed  Google Scholar 

  39. Gates RJ et al (1972) Return to normal of blood-glucose, plasma-insulin, and weight gain in New Zealand obese mice after implantation of islets of Langerhans. Lancet 2:567–570

    Article  PubMed  CAS  Google Scholar 

  40. Gates RJ et al (1972) Studies on implanted islets of Langerhans: normalization of blood glucose concentration, blood insulin concentration and weight gain in New Zealand obese mice. Biochem J 130:26P–27P

    PubMed  CAS  Google Scholar 

  41. Gates RJ, Hunt MI, Lazarus NR (1974) Further studies on the amelioration of the characteristics of New Zealand obese (NZO) mice following implantation of islets of Langerhans. Diabetologia 10:401–406

    Article  PubMed  CAS  Google Scholar 

  42. Leiter EH, Chapman HD, Falany CN (1991) Synergism of obesity genes with hepatic steroid sulfotransferases to mediate diabetes in mice. Diabetes 40:1360–1363

    Article  PubMed  CAS  Google Scholar 

  43. Tsukahara C et al (2004) Blood pressure in 15 inbred mouse strains and its lack of relation with obesity and insulin resistance in the progeny of an NZO/HILtJ x C3H/HeJ intercross. Mamm Genome 15:943–950

    Article  PubMed  CAS  Google Scholar 

  44. Leiter EH, Reifsnyder PC (2004) Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes. Diabetes 53(suppl 1):S4–S11

    Article  PubMed  CAS  Google Scholar 

  45. Brosius FC III et al (2009) Mouse models of diabetic nephropathy. J Am Soc Nephrol 20:2503–2512

    Article  PubMed  Google Scholar 

  46. Brennick MJ et al (2009) Altered upper airway and soft tissue structures in the New Zealand obese mouse. Am J Respir Crit Care Med 179:158–169

    Article  PubMed  Google Scholar 

  47. Goodall CM et al (1973) Oncological and survival reference data for NZO-B1 inbred mice. Lab Anim 7:65–71

    Article  PubMed  CAS  Google Scholar 

  48. Clee SM et al (2006) Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38:688–693

    Article  PubMed  CAS  Google Scholar 

  49. Dokmanovic-Chouinard M et al (2008) Positional cloning of “Lisch-Like”, a candidate modifier of susceptibility to type 2 diabetes in mice. PLoS Genet 4:e1000137

    Article  PubMed  Google Scholar 

  50. Taylor BA et al (2001) Multiple obesity QTLs identified in an intercross between the NZO (New Zealand obese) and the SM (small) mouse strains. Mamm Genome 12:95–103

    Article  PubMed  CAS  Google Scholar 

  51. Giesen K et al (2003) Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5. Biochem Biophys Res Commun 304:812–817

    Article  PubMed  CAS  Google Scholar 

  52. Pan HJ et al (2006) A polymorphism in New Zealand inbred mouse strains that inactivates phosphatidylcholine transfer protein. FEBS Lett 580:5953–5958

    Article  PubMed  CAS  Google Scholar 

  53. Schmolz K et al (2007) Role of neuromedin-U in the central control of feeding behavior: a variant of the neuromedin-U receptor 2 contributes to hyperphagia in the New Zealand obese mouse. Obes Metab Milan 3:28–37

    Google Scholar 

  54. Buchmann J et al (2007) Ablation of the cholesterol transporter adenosine triphosphate-binding cassette transporter G1 reduces adipose cell size and protects against diet-induced obesity. Endocrinology 148:1561–1573

    Article  PubMed  CAS  Google Scholar 

  55. Schulz N et al (2011) Role of medium- and short-chain L-3-hydroxyacyl-CoA dehydrogenase in the regulation of body weight and thermogenesis. Endocrinology 152:4641–4651

    Article  PubMed  CAS  Google Scholar 

  56. Reifsnyder PC, Leiter EH (2002) Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice. Diabetes 51:825–832

    Article  PubMed  CAS  Google Scholar 

  57. Pan HJ et al (2005) Pharmacogenetic analysis of rosiglitazone-induced hepatosteatosis in new mouse models of type 2 diabetes. Diabetes 54:1854–1862

    Article  PubMed  CAS  Google Scholar 

  58. Leiter EH et al (2006) Differential endocrine responses to rosiglitazone therapy in new mouse models of type 2 diabetes. Endocrinology 147:919–926

    Article  PubMed  CAS  Google Scholar 

  59. Pan HJ et al (2006) Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: relation to dysregulated phosphatidylcholine metabolism. Vascul Pharmacol 45:65–71

    Article  PubMed  CAS  Google Scholar 

  60. Kluge R et al (2000) Quantitative trait loci for obesity and insulin resistance (Nob1, Nob2) and their interaction with the leptin receptor allele (LeprA720T/T1044I) in New Zealand obese mice. Diabetologia 43:1565–1572

    Article  PubMed  CAS  Google Scholar 

  61. Chadt A et al (2008) Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nat Genet 40:1354–1359

    Article  PubMed  CAS  Google Scholar 

  62. Meyre D et al (2008) R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. Hum Mol Genet 17:1798–1802

    Article  PubMed  CAS  Google Scholar 

  63. Stone S et al (2006) TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Hum Mol Genet 15:2709–2720

    Article  PubMed  CAS  Google Scholar 

  64. Stewart TP, Kim HY, Saxton AM et al (2010) Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J  ×  TALLYHO/JngJ) F2 mice. BMC Genomics 11:713

    Article  PubMed  CAS  Google Scholar 

  65. Scherneck S et al (2009) Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL. PLoS Genet 5:e1000541

    Article  PubMed  Google Scholar 

  66. Scherneck S et al (2010) Role of zinc finger transcription factor zfp69 in body fat storage and diabetes susceptibility of mice. Results Probl Cell Differ 52:57–68

    Article  PubMed  CAS  Google Scholar 

  67. Vogel H et al (2009) Characterization of Nob3, a major quantitative trait locus for obesity and hyperglycemia on mouse chromosome 1. Physiol Genomics 38:226–232

    Article  PubMed  CAS  Google Scholar 

  68. Scherneck S (2007) Identifizierung eines diabetogenen Allels im Suszeptibilitätslocus Nidd/SJL der Maus. Department of Pharmacology (German Institute of Human Nutrition), Universität Potsdam, Potsdam, p 85

    Google Scholar 

  69. Reifsnyder PC, Churchill G, Leiter EH (2000) Maternal environment and genotype interact to establish diabesity in mice. Genome Res 10:1568–1578

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Reinhart Kluge .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Kluge, R., Scherneck, S., Schürmann, A., Joost, HG. (2012). Pathophysiology and Genetics of Obesity and Diabetes in the New Zealand Obese Mouse: A Model of the Human Metabolic Syndrome. In: Joost, HG., Al-Hasani, H., Schürmann, A. (eds) Animal Models in Diabetes Research. Methods in Molecular Biology, vol 933. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-068-7_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-068-7_5

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-067-0

  • Online ISBN: 978-1-62703-068-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics