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Candidate genes for obesity revealed from a C57BL/6J × 129S1/SvImJ intercross

International Journal of Obesity volume 32, pages 1180–1189 (2008)Cite this article

Abstract

Objective:

To identify the genes controlling body fat, we carried out a quantitative trait locus (QTL) analysis using C57BL/6J (B6) and 129S1/SvImJ (129) mice, which differ in obesity susceptibility after consuming an atherogenic diet.

Methods:

Mice were fed chow until 8 weeks and an atherogenic diet from 8 to 16 weeks; body fatness was measured by X-ray absorptiometry in 528 (B6 × 129) F2 at 8 and 16 weeks. A high-density genome scan was performed using 508 polymorphic markers. After identifying the genetic loci, we narrowed the QTL using comparative genomics and bioinformatics.

Results:

The percentage of body fat was significantly linked to loci on chromosomes (Chr) 1 (22, 68 and 173 Mb), 4 (74 Mb), 5 (73 Mb), 7 (88 Mb), 8 (43 and 80 Mb), 9 (55 Mb), 11 (115 Mb) and 12 (32 Mb); three suggestive loci on Chrs 6 (76 Mb), 9 (30 Mb) and 16 (26 Mb) and two pairs of interacting loci (Chr 2 at 99.8 Mb with Chr 7; Chr 1 at 68 Mb with Chr 11). Comparative genomics narrowed the QTL intervals by 20–57% depending on the chromosome; in most cases, haplotype analysis further narrowed them by about 90%.

Conclusions:

Our analysis identified 15 QTL for percentage of body fat. We narrowed the QTL using comparative genomics and haplotype analysis and suggest several candidate genes: Apcs on Chr 1, Ppargc1a on Chr 5, Ucp1 on Chr 8, Angptl6 on Chr 9 and Lpin1 on Chr 12.

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References

  1. Bell CG, Walley AJ, Froguel P . The genetics of human obesity. Nat Genet Rev 2005; 6: 221–234.

    Article  CAS  Google Scholar 

  2. Brockmann GA, Bevova MR . Using mouse models to dissect the genetics of obesity. Trends Genet 2002; 18: 367–376.

    Article  CAS  PubMed  Google Scholar 

  3. Lusis AJ, Yu J, Wang SS . The problem of passenger genes in transgenic mice. Arterioscler Thromb Vasc Biol 2007; 27: 2100–2103.

    Article  CAS  PubMed  Google Scholar 

  4. Reed DR, McDaniel AH, Li X, Tordoff MG, Bachmanov AA . Quantitative trait loci for individual adipose depot weights in C57BL/6ByJ x 129P3/J F2 mice. Mamm Genome 2006; 17: 1065–1077.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ishimori N, Li R, Kelmenson PM, Korstanje R, Walsh KA, Churchill GA et al. Quantitative trait loci that determine plasma lipids and obesity in C57BL/6J and 129S1/SvImJ inbred mice. J Lipid Res 2004; 45: 1624–1632.

    Article  CAS  PubMed  Google Scholar 

  6. Flint J, Valdar W, Shifman S, Mott R . Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 2005; 6: 271–286.

    Article  CAS  PubMed  Google Scholar 

  7. DiPetrillo K, Wang X, Stylianou IM, Paigen B . Bioinformatics toolbox for narrowing rodent quantitative trait loci. Trends Genet 2005; 21: 683–692.

    Article  CAS  PubMed  Google Scholar 

  8. Nishina PM, Verstuyft J, Paigen B . Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J Lipid Res 1990; 31: 859–869.

    CAS  PubMed  Google Scholar 

  9. Nagy TR, Clair AL . Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. Obes Res 2000; 8: 392–398.

    Article  CAS  PubMed  Google Scholar 

  10. Broman KW, Wu H, Sen S, Churchill GA . R/qtl: QTL mapping in experimental crosses. Bioinformatics 2003; 19: 889–890.

    Article  CAS  PubMed  Google Scholar 

  11. Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW et al. Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm Genome 2004; 15: 648–662.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sen S, Churchill GA . A statistical framework for quantitative trait mapping. Genetics 2001; 159: 371–387.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B et al. The human obesity gene map: the 2005 update. Obesity (Silver Spring) 2006; 14: 529–644.

    Article  Google Scholar 

  14. Dai F, Keighley ED, Sun G, Indugula SR, Roberts ST, Aberg K et al. Genome-wide scan for adiposity-related phenotypes in adults from American Samoa. Int J Obes (Lond) 2007; 31: 1832–1842.

    Article  CAS  Google Scholar 

  15. Wuschke S, Dahm S, Schmidt C, Joost HG, Al-Hasani H . A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice. Int J Obes (Lond) 2007; 31: 829–841.

    Article  CAS  Google Scholar 

  16. Abiola O, Angel JM, Avner P, Bachmanov AA, Belknap JK, Bennett B et al. The nature and identification of quantitative trait loci: a community's view. Nat Rev Genet 2003; 4: 911–916.

    PubMed  Google Scholar 

  17. Wang S, Yehya N, Schadt EE, Wang H, Drake TA, Lusis AJ . Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet 2006; 2: e15.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Reed DR, Li X, McDaniel AH, Lu K, Li S, Tordoff MG et al. Loci on chromosomes 2, 4, 9, and 16 for body weight, body length, and adiposity identified in a genome scan of an F2 intercross between the 129P3/J and C57BL/6ByJ mouse strains. Mamm Genome 2003; 14: 302–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mouzeyan A, Choi J, Allayee H, Wang X, Sinsheimer J, Phan J et al. A locus conferring resistance to diet-induced hypercholesterolemia and atherosclerosis on mouse chromosome 2. J Lipid Res 2000; 41: 573–582.

    CAS  PubMed  Google Scholar 

  20. Simpson EM, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp JJ . Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Genet 1997; 16: 19–27.

    Article  CAS  PubMed  Google Scholar 

  21. Almind K, Kahn CR . Genetic determinants of energy expenditure and insulin resistance in diet-induced obesity in mice. Diabetes 2004; 53: 3274–3285.

    Article  CAS  PubMed  Google Scholar 

  22. 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: 425–432.

    Article  CAS  PubMed  Google Scholar 

  23. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903–908.

    Article  CAS  PubMed  Google Scholar 

  24. Su Z, Li Y, James JC, Matsumoto AH, Helm GA, Lusis AJ et al. Genetic linkage of hyperglycemia, body weight and serum amyloid-P in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice. Hum Mol Genet 2006; 15: 1650–1658.

    Article  CAS  PubMed  Google Scholar 

  25. Jenny NS, Arnold AM, Kuller LH, Tracy RP, Psaty BM . Serum amyloid P and cardiovascular disease in older men and women: results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2007; 27: 352–358.

    Article  CAS  PubMed  Google Scholar 

  26. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 2005; 3: e101.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Stone S, Abkevich V, Hunt SC, Gutin A, Russell DL, Neff CD et al. A major predisposition locus for severe obesity, at 4p15-p14. Am J Hum Genet 2002; 70: 1459–1468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Esterbauer H, Oberkofler H, Linnemayr V, Iglseder B, Hedegger M, Wolfsgruber P et al. Peroxisome proliferator-activated receptor-gamma coactivator-1 gene locus: associations with obesity indices in middle-aged women. Diabetes 2002; 51: 1281–1286.

    Article  CAS  PubMed  Google Scholar 

  29. Vimaleswaran KS, Radha V, Anjana M, Deepa R, Ghosh S, Majumder PP et al. Effect of polymorphisms in the PPARGC1A gene on body fat in Asian Indians. Int J Obes (Lond) 2006; 30: 884–891.

    Article  CAS  Google Scholar 

  30. Pihlajamaki J, Kinnunen M, Ruotsalainen E, Salmenniemi U, Vauhkonen I, Kuulasmaa T et al. Haplotypes of PPARGC1A are associated with glucose tolerance, body mass index and insulin sensitivity in offspring of patients with type 2 diabetes. Diabetologia 2005; 48: 1331–1334.

    Article  CAS  PubMed  Google Scholar 

  31. Ridderstrale M, Johansson LE, Rastam L, Lindblad U . Increased risk of obesity associated with the variant allele of the PPARGC1A Gly482Ser polymorphism in physically inactive elderly men. Diabetologia 2006; 49: 496–500.

    Article  CAS  PubMed  Google Scholar 

  32. Lowell BB, V SS, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993; 366: 740–742.

    Article  CAS  PubMed  Google Scholar 

  33. Oppert JM, Vohl MC, Chagnon M, Dionne FT, Cassard-Doulcier AM, Ricquier D et al. DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. Int J Obes Relat Metab Disord 1994; 18: 526–531.

    CAS  PubMed  Google Scholar 

  34. Heilbronn LK, Kind KL, Pancewicz E, Morris AM, Noakes M, Clifton PM . Association of -3826 G variant in uncoupling protein-1 with increased BMI in overweight Australian women. Diabetologia 2000; 43: 242–244.

    Article  CAS  PubMed  Google Scholar 

  35. Fumeron F, Durack-Bown I, Betoulle D, Cassard-Doulcier AM, Tuzet S, Bouillaud F et al. Polymorphisms of uncoupling protein (UCP) and beta 3 adrenoreceptor genes in obese people submitted to a low calorie diet. Int J Obes Relat Metab Disord 1996; 20: 1051–1054.

    CAS  PubMed  Google Scholar 

  36. Kim KS, Cho DY, Kim YJ, Choi SM, Kim JY, Shin SU et al. The finding of new genetic polymorphism of UCP-1 A-1766G and its effects on body fat accumulation. Biochim Biophys Acta 2005; 1741: 149–155.

    Article  CAS  PubMed  Google Scholar 

  37. Oike Y, Akao M, Yasunaga K, Yamauchi T, Morisada T, Ito Y et al. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat Med 2005; 11: 400–408.

    Article  CAS  PubMed  Google Scholar 

  38. Phan J, Peterfy M, Reue K . Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro. J Biol Chem 2004; 279: 29558–29564.

    Article  CAS  PubMed  Google Scholar 

  39. Phan J, Reue K . Lipin, a lipodystrophy and obesity gene. Cell Metab 2005; 1: 73–83.

    Article  CAS  PubMed  Google Scholar 

  40. Banerjee SS, Feinberg MW, Watanabe M, Gray S, Haspel RL, Denkinger DJ et al. The Kruppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis. J Biol Chem 2003; 278: 2581–2584.

    Article  PubMed  Google Scholar 

  41. Oishi Y, Manabe I, Tobe K, Tsushima K, Shindo T, Fujiu K et al. Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab 2005; 1: 27–39.

    Article  CAS  PubMed  Google Scholar 

  42. Mori T, Sakaue H, Iguchi H, Gomi H, Okada Y, Takashima Y et al. Role of Kruppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis. J Biol Chem 2005; 280: 12867–12875.

    Article  CAS  PubMed  Google Scholar 

  43. de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H et al. Premature aging in mice deficient in DNA repair and transcription. Science 2002; 296: 1276–1279.

    Article  CAS  PubMed  Google Scholar 

  44. Xie L, Boyle D, Sanford D, Scherer PE, Pessin JE, Mora S . Intracellular trafficking and secretion of adiponectin is dependent on GGA-coated vesicles. J Biol Chem 2006; 281: 7253–7259.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by US National Institutes of Health grants CA034196, GM076468, HL 81162, HL74086 and HL77796, and the American Heart Association grant 0725905T (to SZ). We thank Harry Whitmore and Fred Rumill for their invaluable help in mouse husbandry, Jesse Hammer for graphical assistance and Dr Ed Leiter for helpful comments with regard to the paper.

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Authors and Affiliations

  1. The Jackson Laboratory, Bar Harbor, ME, USA

    Z Su, R Korstanje, S-W Tsaih & B Paigen

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  1. Z Su
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Correspondence to B Paigen.

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Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo)

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Su, Z., Korstanje, R., Tsaih, SW. et al. Candidate genes for obesity revealed from a C57BL/6J × 129S1/SvImJ intercross. Int J Obes 32, 1180–1189 (2008). https://doi.org/10.1038/ijo.2008.56

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