Advertisement

Pathophysiology of Obesity and the Metabolic Syndrome: Rodent Models

  • David Sanchez-Infantes
  • Carrie M. Elks
  • Jacqueline M. StephensEmail author
Chapter
Part of the Nutrition and Health book series (NH)

Abstract

Metabolic syndrome (MetS) affects one in three Americans and is a strong predictor of cardiovascular disease risk; therefore, understanding the pathophysiological mechanisms that contribute to MetS is of great priority. While rodent models can only reproduce certain aspects of human diseases, they remain useful tools in our examination of the mechanisms contributing to the development of MetS. This chapter will provide a brief review of some of the more common mouse and rat MetS models. In addition to brief descriptions of the models, the advantages and disadvantages of using each model will be addressed.

Keywords

Metabolic syndrome Adipocyte Adipose tissue Obesity 

References

  1. 1.
    Ford ES, Li C, Zhao G. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US*. J Diabetes. 2010;2(3):180–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Hered. 1950;41(12):317–8.PubMedGoogle Scholar
  4. 4.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Hummel KP, Coleman DL, Lane PW. The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains. Biochem Genet. 1972;7(1):1–13.CrossRefPubMedGoogle Scholar
  6. 6.
    Bray GA, York DA. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev. 1979;59(3):719–809.PubMedGoogle Scholar
  7. 7.
    Genuth SM, Przybylski RJ, Rosenberg DM. Insulin resistance in genetically obese, hyperglycemic mice. Endocrinology. 1971;88(5):1230–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Coleman DL, Hummel KP. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia. 1973;9(4):287–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Kennedy AJ, Ellacott KLJ, King VL, Hasty AH. Mouse models of the metabolic syndrome. Dis Model Mech. 2010;3(3–4):156–66.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Miltenberger RJ, Mynatt RL, Wilkinson JE, Woychik RP. The role of the agouti gene in the yellow obese syndrome. J Nutr. 1997;127(9):1902S–7.PubMedGoogle Scholar
  11. 11.
    Dickie MM. Mutations at the agouti locus in the mouse. J Hered. 1969;60(1):20–5.PubMedGoogle Scholar
  12. 12.
    Jackson E, Stolz D, Martin R. Effect of adrenalectomy on weight gain and body composition of yellow obese mice (Ay/a). Horm Metab Res. 1976;8(06):452–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Tschöp M, Heiman ML. Rodent obesity models: an overview. Exp Clin Endocrinol Diabetes. 2001;109(06):307–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Overton JD, Leibel RL. Mahoganoid and mahogany mutations rectify the obesity of the yellow mouse by effects on endosomal traffic of MC4R protein. J Biol Chem. 2011;286(21):18914–29.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Lu D, Willard D, Patel IR, et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature. 1994;371(6500):799–802.CrossRefPubMedGoogle Scholar
  16. 16.
    Coleman DL, Eicher EM. Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered. 1990;81(6):424–7.PubMedGoogle Scholar
  17. 17.
    Naggert JK, Fricker LD, Varlamov O, et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet. 1995;10(2):135–42.CrossRefPubMedGoogle Scholar
  18. 18.
    Noben-Trauth K, Naggert JK, North MA, Nishina PM. A candidate gene for the mouse mutation tubby. Nature. 1996;380(6574):534–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Kleyn PW, Fan W, Kovats SG, et al. Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell. 1996;85(2):281–90.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang Y, Seburn K, Bechtel L, et al. Defective carbohydrate metabolism in mice homozygous for the tubby mutation. Physiol Genomics. 2006;27(2):131–40.CrossRefPubMedGoogle Scholar
  21. 21.
    Nishina PM, Lowe S, Wang J, Paigen B. Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism. 1994;43(5):549–53.CrossRefPubMedGoogle Scholar
  22. 22.
    North MA, Naggert JK, Yan Y, Noben-Trauth K, Nishina PM. Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc Natl Acad Sci U S A. 1997;94(7):3128–33.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Zucker LM, Zucker TF. Fatty, a new mutation in the rat. J Hered. 1961;52:275–8.Google Scholar
  24. 24.
    Chua Jr SC, Chung WK, Wu-Peng XS, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 1996;271(5251):994–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Johnson PR, Stern JS, Horwitz BA, Harris RE, Greene SF. Longevity in obese and lean male and female rats of the Zucker strain: prevention of hyperphagia. Am J Clin Nutr. 1997;66(4):890–903.PubMedGoogle Scholar
  26. 26.
    Phillips MS, Liu Q, Hammond HA, et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet. 1996;13(1):18–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Johnson PR, Zucker LM, Cruce JAF, Hirsch J. Cellularity of adipose depots in the genetically obese Zucker rat. J Lipid Res. 1971;12(6):706–14.PubMedGoogle Scholar
  28. 28.
    Maggio C, Greenwood M. Adipose tissue lipoprotein lipase (LPL) and triglyceride uptake in Zucker rats. Physiol Behav. 1982;29(6):1147–52.CrossRefPubMedGoogle Scholar
  29. 29.
    Boulangé A, Planche E, de Gasquet P. Onset of genetic obesity in the absence of hyperphagia during the first week of life in the Zucker rat (fa/fa). J Lipid Res. 1979;20(7):857–64.PubMedGoogle Scholar
  30. 30.
    Bray G. The Zucker-fatty rat: a review. Fed Proc. 1977;36(2):148–53.PubMedGoogle Scholar
  31. 31.
    Zucker TF, Zucker LM. Hereditary obesity in the rat associated with high serum fat and cholesterol. Exp Biol Med. 1962;110(1):165–71.CrossRefGoogle Scholar
  32. 32.
    Ionescu E, Sauter JF, Jeanrenaud B. Abnormal oral glucose tolerance in genetically obese (fa/fa) rats. Am J Physiol. 1985;248(5):E500–6.PubMedGoogle Scholar
  33. 33.
    Muller S, Cleary MP. Glucose metabolism in isolated adipocytes from ad libitum- and restricted-fed lean and obese Zucker rats at two different ages. Exp Biol Med. 1988;187(4):398–407.CrossRefGoogle Scholar
  34. 34.
    Barry WS, Bray GA. Plasma triglycerides in genetically obese rats. Metabolism. 1969;18(10):833–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Schonfeld G, Pfleger B. Utilization of exogenous free fatty acids for the production of very low density lipoprotein triglyceride by livers of carbohydrate-fed rats. J Lipid Res. 1971;12(5):614–21.PubMedGoogle Scholar
  36. 36.
    Zucker LM. Hereditary obesity in the rat associated with hyperlipemia. Ann N Y Acad Sci. 1965;131(1):447–58.CrossRefPubMedGoogle Scholar
  37. 37.
    Vasselli JR, Cleary MP, Jen K-LC, Greenwood MRC. Development of food motivated behavior in free feeding and food restricted zucker fatty (fa/fa) rats. Physiol Behav. 1980;25(4):565–73.CrossRefPubMedGoogle Scholar
  38. 38.
    Cleary MP, Vasselli JR, Greenwood MR. Development of obesity in Zucker obese (fafa) rat in absence of hyperphagia. Am J Physiol. 1980;238(3):E284–92.PubMedGoogle Scholar
  39. 39.
    Young RA, Frink R, Longcope C. Serum testosterone and gonadotropins in the genetically obese male Zucker Rat. Endocrinology. 1982;111(3):977–81.CrossRefPubMedGoogle Scholar
  40. 40.
    Whitaker EM, Robinson AC. Circulating reproductive hormones and hypothalamic oestradiol and progestin receptors in infertile Zucker rats. J Endocrinol. 1989;120(2):331–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Alonso-Galicia M, Brands MW, Zappe DH, Hall JE. Hypertension in obese Zucker rats: role of angiotensin II and adrenergic activity. Hypertension. 1996;28(6):1047–54.CrossRefPubMedGoogle Scholar
  42. 42.
    Kurtz TW, Morris RC, Pershadsingh HA. The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension. 1989;13(6 Pt 2):896–901.CrossRefPubMedGoogle Scholar
  43. 43.
    Hiraoka-Yamamoto J, Nara Y, Yasui N, Onobayashi Y, Tsuchikura S, Ikeda K. Establishment of a new animal model of metabolic syndrome: SHRSP fatty (fa/fa) rats. Clin Exp Pharmacol Physiol. 2004;31(1–2):107–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Koletsky RJ, Velliquette RA, Ernsberger P. The SHROB (Koletsky) Rat as a model for metabolic syndrome. In: Shafrir E, editor. Animal models of diabetes: frontiers in research. 2nd ed. Boca Raton, FL: CRC Press; 2007.Google Scholar
  45. 45.
    Takaya K, Ogawa Y, Hiraoka J, et al. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet. 1996;14(2):130–1.CrossRefPubMedGoogle Scholar
  46. 46.
    Yamashita T, Murakami T, Iida M, Kuwajima M, Shima K. Leptin receptor of Zucker fatty Rat performs reduced signal transduction. Diabetes. 1997;46(6):1077–80.CrossRefPubMedGoogle Scholar
  47. 47.
    Ernsberger P, Koletsky RJ, Baskin JS, Foley M. Refeeding hypertension in obese spontaneously hypertensive rats. Hypertension. 1994;24(6):699–705.CrossRefPubMedGoogle Scholar
  48. 48.
    Velliquette RA, Koletsky RJ, Ernsberger P. Plasma glucagon and free fatty acid responses to a glucose load in the obese spontaneous hypertensive rat (SHROB) model of metabolic syndrome X. Exp Biol Med. 2002;227(3):164–70.Google Scholar
  49. 49.
    Chen B, Moore A, Escobedo LVS, et al. Sitagliptin lowers glucagon and improves glucose tolerance in prediabetic obese SHROB rats. Exp Biol Med. 2011;236(3):309–14.CrossRefGoogle Scholar
  50. 50.
    Friedman JE, Ishizuka T, Liu S, et al. Anti-hyperglycemic activity of moxonidine: metabolic and molecular effects in obese spontaneously hypertensive rats. Blood Press. 1998;7(S3):32–9.Google Scholar
  51. 51.
    Koletsky S. Pathologic findings and laboratory data in a new strain of obese hypertensive rats. Am J Pathol. 1975;80(1):129–42.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Ernsberger P, Koletsky RJ, Collins LA, Douglas JG. Renal angiotensin receptor mapping in obese spontaneously hypertensive rats. Hypertension. 1993;21:1039–45.CrossRefPubMedGoogle Scholar
  53. 53.
    Aleixandre de Artiñano A, Miguel Castro M. Experimental rat models to study the metabolic syndrome. Br J Nutr. 2009;102(09):1246–53.CrossRefPubMedGoogle Scholar
  54. 54.
    Koletsky S. Animal model: obese hypertensive rat. Am J Pathol. 1975;81(2):463–6.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Michaelis OE, Ellwood KC, Judge JM, Schoene NW, Hansen CT. Effect of dietary sucrose on the SHR/N-corpulent rat: a new model for insulin-independent diabetes. Am J Clin Nutr. 1984;39(4):612–8.PubMedGoogle Scholar
  56. 56.
    Koch LG, Britton SL. Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol Genomics. 2001;5(1):45–52.PubMedGoogle Scholar
  57. 57.
    Wisløff U, Najjar SM, Ellingsen Ø, et al. Cardiovascular risk factors emerge after artificial selection for Low aerobic capacity. Science. 2005;307(5708):418–20.CrossRefPubMedGoogle Scholar
  58. 58.
    Noland RC, Thyfault JP, Henes ST, et al. Artificial selection for high-capacity endurance running is protective against high-fat diet-induced insulin resistance. Am J Physiol. 2007;293(1):E31–41.Google Scholar
  59. 59.
    van den Brandt J, Kovács P, Klöting I. Features of the metabolic syndrome in the spontaneously hypertriglyceridemic Wistar Ottawa Karlsburg W (RT1u haplotype) rat. Metabolism. 2000;49(9):1140–4.CrossRefPubMedGoogle Scholar
  60. 60.
    van den Brandt J, Kovacs P, Klöting I. Metabolic syndrome and aging in Wistar Ottawa Karlsburg W rats. Int J Obes Relat Metab Disord. 2002;26(4):573–6.CrossRefPubMedGoogle Scholar
  61. 61.
    Klöting N, Blüher M, Klöting I. The polygenetically inherited metabolic syndrome of WOKW rats is associated with insulin resistance and altered gene expression in adipose tissue. Diabetes Metab Res Rev. 2006;22(2):146–54.CrossRefPubMedGoogle Scholar
  62. 62.
    Kovács P, van den Brandt J, Klöting I. Genetic dissection of the syndrome X in the Rat. Biochem Biophys Res Commun. 2000;269(3):660–5.CrossRefPubMedGoogle Scholar
  63. 63.
    Kawano K. OLETF rats: model for the metabolic syndrome and diabetic nephropathy in humans. In: Shafrir E, editor. Animal models of diabetes: frontiers in research. 2nd ed. Boca Raton, FL: CRC Press; 2007.Google Scholar
  64. 64.
    Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992;41(11):1422–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Kawano K, Hirashima T, Mori S, Natori T. OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes Res Clin Pract. 1994;24:S317–20.CrossRefPubMedGoogle Scholar
  66. 66.
    Funakoshi A, Miyasaka K, Jimi A, Kawanai T, Takata Y, Kono A. Little or no expression of the cholecystokinin-a receptor gene in the pancreas of diabetic rats (Otsuka Long-Evans Tokushima Fatty=OLETF rats). Biochem Biophys Res Commun. 1994;199(2):482–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Otsuki M, Akiyama T, Shirohara H, Nakano S, Furumi K, Tachibana I. Loss of sensitivity to cholecystokinin stimulation of isolated pancreatic acini from genetically diabetic rats. Am J Physiol. 1995;268(3):E531–6.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • David Sanchez-Infantes
    • 1
  • Carrie M. Elks
    • 1
  • Jacqueline M. Stephens
    • 1
    Email author
  1. 1.Department of Adipocyte Biology, Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeUSA

Personalised recommendations