Obésité

, Volume 7, Issue 1, pp 18–25 | Cite as

Modèle animaux d’obésité

Article / Article
  • 94 Downloads

Résumé

Les modèles animaux ont permis des avancées majeures dans la compréhension des bases physiologiques, environnementales, génétiques et épigénétiques de l’obésité. La plupart des modèles rongeurs d’obésité sont étudiés depuis les années 50, mais ce n’est que beaucoup plus récemment que les mécanismes responsables de leur phénotype ont pu être identifiés grâce aux progrès de la biologie moléculaire. Cet article est une revue non exhaustive de différents modèles d’obésité chez les rongeurs, naturels ou générés par les chercheurs: obésités nutritionnelle induite par des régimes riches en graisse, provoquée par lésion de régions hypothalamiques contrôlant la prise alimentaire ou d’origine génétique causée par des mutations spontanées dans des gènes cruciaux pour l’équilibre énergétique, tels que les gènes de la leptine et de son récepteur. Chaque modèle fournit des informations relatives à différents aspects de l’obésité humaine, en particulier dans le domaine des obésités monogéniques rares mais souvent gravissimes, comme chez les patients déficients en leptine. Les modèles de rongeurs obèses représentent des outils précieux et nécessaires pour explorer la complexité de la régulation du bilan énergétique, ainsi que pour l’innovation thérapeutique dans le domaine de l’obésité, dont un exemple frappant est le succès du traitement par la leptine des patients déficients.

Mots clés

Rongeurs Régime gras Leptine Hypothalamus 

Animal models of obesity

Abstract

Animal models provide major contribution to our understanding of the physiological, environmental, genetic and epigenetic bases of obesity. Most rodent models of obesity have been investigated since the early fifties, but it’s only more recently that the mechanisms underlying their phenotype were identified, thanks to the development of molecular biology. This article reviews various models of rodent obesity, naturally occurring or created by researchers: nutritional obesity induced by a high fat diet, hypothalamic obesity resulting from lesions in areas controlling food intake and genetic obesity due to spontaneous mutations in crucial genes for energy balance, such as leptin and leptin receptor genes. Each model provides information related to specific aspects of human obesity, particularly in the field of monogenic obesities that are rare but often severe as in leptin-deficient patients. Models of obese rodents represent precious and necessary tools to explore the complexity of energy balance regulation and for innovative therapeutic intervention in obesity, of which the success of leptin treatment for leptin-deficient patients is a striking example.

Keywords

Rodents High fat diet Leptin Hypothalamus 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Références

  1. 1.
    Burcelin R, Crivelli V, Dacosta A, et al (2002) Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet. Am J Physiol Endocrinol Metab 282: E834–E842PubMedGoogle Scholar
  2. 2.
    Hariri N, Gougeon R, Thibault L (2010) A highly saturated fat-rich diet is more obesogenic than diets with lower saturated fat content. Nutr Res 30: 632–643PubMedCrossRefGoogle Scholar
  3. 3.
    Surwit RS, Feinglos MN, Rodin J, et al (1995) Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44: 645–651PubMedCrossRefGoogle Scholar
  4. 4.
    Levin BE, Dunn-Meynell AA, Banks WA (2004) Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am J Physiol Regul Integr Comp Physiol 286: R143–R150PubMedCrossRefGoogle Scholar
  5. 5.
    Fearnside JF, Dumas ME, Rothwell AR, et al (2008) Phylometabonomic patterns of adaptation to high fat diet feeding in inbred mice. PLoS One 3: e1668PubMedCrossRefGoogle Scholar
  6. 6.
    Madsen AN, Hansen G, Paulsen SJ, et al (2010) Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol 206: 287–296PubMedCrossRefGoogle Scholar
  7. 7.
    Scarpace PJ Zhang Y (2009) Leptin resistance: a prediposing factor for diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 296: R493–R500PubMedCrossRefGoogle Scholar
  8. 8.
    Levin BE, Dunn-Meynell AA (2000) Defense of body weight against chronic caloric restriction in obesity-prone and -resistant rats. Am J Physiol Regul Integr Comp Physiol 278: R231–R237PubMedGoogle Scholar
  9. 9.
    Kosteli A, Sugaru E, Haemmerle G, et al (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120: 3466–3479PubMedCrossRefGoogle Scholar
  10. 10.
    Troy S, Soty M, Ribeiro L, et al (2008) Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice. Cell Metab 8: 201–211PubMedCrossRefGoogle Scholar
  11. 11.
    Ainge H, Thompson C, Ozanne SE, et al (2011) A systematic review on animal models of maternal high fat feeding and offspring glycaemic control. Int J Obes (Lond) 35: 325–335CrossRefGoogle Scholar
  12. 12.
    Guo F, Jen KL (1995) High-fat feeding during pregnancy and lactation affects offspring metabolism in rats. Physiol Behav 57: 681–686PubMedCrossRefGoogle Scholar
  13. 13.
    Leibowitz KL, Chang GQ, Pamy PS, et al (2007) Weight gain model in prepubertal rats: prediction and phenotyping of obesity-prone animals at normal body weight. Int J Obes (Lond) 31: 1210–1221CrossRefGoogle Scholar
  14. 14.
    Boullu-Ciocca S, Achard V, Tassistro V, et al (2008) Postnatal programming of glucocorticoid metabolism in rats modulates high-fat diet-induced regulation of visceral adipose tissue glucocorticoid exposure and sensitivity and adiponectin and proinflammatory adipokines gene expression in adulthood. Diabetes 57: 669–677PubMedCrossRefGoogle Scholar
  15. 15.
    Patterson CM, Bouret SG, Park S, et al (2010) Large litter rearing enhances leptin sensitivity and protects selectively bred dietinduced obese rats from becoming obese. Endocrinology 151: 4270–4279PubMedCrossRefGoogle Scholar
  16. 16.
    Cani PD, Delzenne NM, Amar J, et al (2008) Role of gut microflora in the development of obesity and insulin resistance following high-fat diet feeding. Pathol Biol (Paris) 56: 305–309CrossRefGoogle Scholar
  17. 17.
    Ding S, Chi MM, Scull BP, et al (2010) High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One 5: e12191PubMedCrossRefGoogle Scholar
  18. 18.
    King BM (2006) The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol Behav 87: 221–244PubMedCrossRefGoogle Scholar
  19. 19.
    Marshall NB, Barrnett RJ, Mayer J (1955) Hypothalamic lesions in goldthioglucose injected mice. Proc Soc Exp Biol Med 90: 240–244PubMedGoogle Scholar
  20. 20.
    Pinkney J, Wilding J, Williams G, et al (2002) Hypothalamic obesity in humans: what do we know and what can be done? Obes Rev 3: 27–34PubMedCrossRefGoogle Scholar
  21. 21.
    Brockmann GA, Bevova MR (2002) Using mouse models to dissect the genetics of obesity. Trends Genet 18: 367–376PubMedCrossRefGoogle Scholar
  22. 22.
    Rankinen T, Zuberi A, Chagnon YC, et al (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14: 529–644CrossRefGoogle Scholar
  23. 23.
    Churchill GA, Airey DC, Allayee H, et al (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36: 1133–1137PubMedCrossRefGoogle Scholar
  24. 24.
    Valdar W, Solberg LC, Gauguier D, et al (2006) Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat Genet 38: 879–887PubMedCrossRefGoogle Scholar
  25. 25.
    Liu P, Vikis H, Lu Y, et al (2007) Large-scale in silico mapping of complex quantitative traits in inbred mice. PLoS One 2: e651PubMedCrossRefGoogle Scholar
  26. 26.
    Schadt EE, Lamb J, Yang X, et al (2005) An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 37: 710–717PubMedCrossRefGoogle Scholar
  27. 27.
    Pomp D, Nehrenberg D, Estrada-Smith D (2008) Complex genetics of obesity in mouse models. Annu Rev Nutr 28: 331–345PubMedCrossRefGoogle Scholar
  28. 28.
    Clement K (2006) Genetics of human obesity. C R Biol 329: 608–622PubMedCrossRefGoogle Scholar
  29. 29.
    Farooqi IS, Jebb SA, Langmack G, et al (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341: 879–884PubMedCrossRefGoogle Scholar
  30. 30.
    Bultman SJ, Michaud EJ, Woychik RP (1992) Molecular characterization of the mouse agouti locus. Cell 71: 1195–1204PubMedCrossRefGoogle Scholar
  31. 31.
    Miller MW, Duhl DM, Vrieling H, et al (1993) Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev 7: 454–467PubMedCrossRefGoogle Scholar
  32. 32.
    Michaud EJ, Bultman SJ, Klebig ML, et al (1994) A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc Natl Acad Sci USA 91: 2562–2566PubMedCrossRefGoogle Scholar
  33. 33.
    Barsh GS, Ollmann MM, Wilson BD, et al (1999) Molecular pharmacology of Agouti protein in vitro and in vivo. Ann N Y Acad Sci 885: 143–152PubMedCrossRefGoogle Scholar
  34. 34.
    Moussa NM, Claycombe KJ (1999) The yellow mouse obesity syndrome and mechanisms of agouti-induced obesity. Obes Res 7: 506–514PubMedGoogle Scholar
  35. 35.
    Naggert JK, Fricker LD, Varlamov O, et al (1995) Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet 10: 135–142PubMedCrossRefGoogle Scholar
  36. 36.
    Cawley NX, Yanik T, Woronowicz A, et al (2010) Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. Am J Physiol Endocrinol Metab 299: E189–E197PubMedGoogle Scholar
  37. 37.
    Plum L, Lin HV, Dutia R, et al (2009) The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 15: 1195–1201PubMedCrossRefGoogle Scholar
  38. 38.
    Kleyn PW, Fan W, Kovats SG, et al (1996) Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85: 281–290PubMedCrossRefGoogle Scholar
  39. 39.
    Noben-Trauth K, Naggert JK, North MA, et al (1996) A candidate gene for the mouse mutation tubby. Nature 380: 534–538PubMedCrossRefGoogle Scholar
  40. 40.
    Carroll K, Gomez C, Shapiro L (2004) Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol 5: 55–63PubMedCrossRefGoogle Scholar
  41. 41.
    Zhang Y, Proenca R, Maffei M, et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425–432PubMedCrossRefGoogle Scholar
  42. 42.
    Moon BC, Friedman JM (1997) The molecular basis of the obese mutation in ob2J mice. Genomics 42: 152–156PubMedCrossRefGoogle Scholar
  43. 43.
    Pelleymounter MA, Cullen MJ, Baker MB, et al (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269: 540–543PubMedCrossRefGoogle Scholar
  44. 44.
    Campfield LA, Smith FJ, Guisez Y, et al (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269: 546–549PubMedCrossRefGoogle Scholar
  45. 45.
    Halaas JL, Gajiwala KS, Maffei M, et al (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269: 543–546PubMedCrossRefGoogle Scholar
  46. 46.
    Coleman DL (2010) A historical perspective on leptin. Nat Med 16: 1097–1099PubMedCrossRefGoogle Scholar
  47. 47.
    Tartaglia LA, Dembski M, Weng X, et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83: 1263–1271PubMedCrossRefGoogle Scholar
  48. 48.
    Lee GH, Proenca R, Montez JM, et al (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379: 632–635PubMedCrossRefGoogle Scholar
  49. 49.
    Chen H, Charlat O, Tartaglia LA, et al (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84: 491–495PubMedCrossRefGoogle Scholar
  50. 50.
    Lee G, Li C, Montez J, et al (1997) Leptin receptor mutations in 129 db3J/db3J mice and NIH facp/facp rats. Mamm Genome 8: 445–447PubMedCrossRefGoogle Scholar
  51. 51.
    Li C, Ioffe E, Fidahusein N, et al (1998) Absence of soluble leptin receptor in plasma from dbPas/dbPas and other db/db mice. J Biol Chem 273: 10078–10082PubMedCrossRefGoogle Scholar
  52. 52.
    Phillips MS, Liu Q, Hammond HA, et al (1996) Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 13: 18–19PubMedCrossRefGoogle Scholar
  53. 53.
    Takaya K, Ogawa Y, Hiraoka J, et al (1996) Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet 14: 130–131PubMedCrossRefGoogle Scholar
  54. 54.
    Gilbert M, Magnan C, Turban S, et al (2003) Leptin receptordeficient obese Zucker rats reduce their food intake in response to a systemic supply of calories from glucose. Diabetes 52: 277–282PubMedCrossRefGoogle Scholar
  55. 55.
    Simler N, Grosfeld A, Peinnequin A, et al (2006) Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia. Am J Physiol Endocrinol Metab 290: E591–E597PubMedCrossRefGoogle Scholar
  56. 56.
    Justice MJ (2000) Capitalizing on large-scale mouse mutagenesis screens. Nat Rev Genet 1: 109–115PubMedCrossRefGoogle Scholar
  57. 57.
    Stubdal H, Lynch CA, Moriarty A, et al (2000) Targeted deletion of the tub mouse obesity gene reveals that tubby is a lossof-function mutation. Mol Cell Biol 20: 878–882PubMedCrossRefGoogle Scholar
  58. 58.
    Klebig ML, Wilkinson JE, Geisler JG, et al (1995) Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc Natl Acad Sci U S A 92: 4728–4732PubMedCrossRefGoogle Scholar
  59. 59.
    Perry WL, Hustad CM, Swing DA, et al (1995) A transgenic mouse assay for agouti protein activity. Genetics 140: 267–274PubMedGoogle Scholar
  60. 60.
    Huszar D, Lynch CA, Fairchild-Huntress V, et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141PubMedCrossRefGoogle Scholar
  61. 61.
    Ozcan L, Ergin AS, Lu A, et al (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9: 35–51PubMedCrossRefGoogle Scholar
  62. 62.
    Czupryn A, Zhou YD, Chen X, et al (2011) Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice. Science 334: 1133–1137PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France 2012

Authors and Affiliations

  1. 1.INSERM U872 Eq7Centre de Recherche des CordeliersParisFrance

Personalised recommendations