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Serum leptin concentration is linked to Chromosomes 2 and 6 in the OLETF rat, an animal model of type 2 diabetes with mild obesity

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Abstract

Leptin is produced by adipose tissue and acts as a feedback signal to the hypothalamus controlling energy homeostasis, by reducing food consumption and increasing energy expenditure. Because serum leptin levels are highly correlated with body fat mass, they can be used as an index to predict obesity-related diseases. However, the identity of genetic factors that influence the obesity and the obesity-related metabolic disorders remains largely unknown. In this study, we performed a whole-genome scan search, using 382 F2 intercross progeny between the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for obese type 2 diabetes in human, and F344 rat, in order to identify loci responsible for the regulation of leptin and other obesity-related plasma substances. We have identified two quantitative trait loci (QTLs) contributing to serum leptin levels. These two loci, designated Olep1 [Chromosome (Chr) 2] and Olep2 (Chr 6), were homologous to those of human genome regions containing several potential candidate genes for obesity. These are fatty acid-binding protein 2 (FABP2), FABP4, and FABP5 for Olep1, and proopiomelanocortin (POMC) and glucose regulatory protein (GCKR) for Olep2.

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References

  1. LL Bernardis JR Border (1975) ArticleTitleFood intake of weanling rats with lesions in the ventromedial and dorsomedial hypothalamic nuclei in response to intragastric loading and caloric density manipulation. J Neurosci Res 1 377–391 Occurrence Handle1:STN:280:CSmC1Mzos1A%3D Occurrence Handle1225996

    CAS  PubMed  Google Scholar 

  2. MT Bihoreau D Gauguier N Kato G Hyne K Lindpaintner et al. (1997) ArticleTitleA linkage map of the rat genome derived from three F2 crosses. Genome Res 7 434–440

    Google Scholar 

  3. BA Boston KM Blaydon J Varnerin RD Cone (1997) ArticleTitleIndependent and additive effects of central POMC and leptin pathways on murine obesity. Science 28 1641–1644 Occurrence Handle10.1126/science.278.5343.1641

    Article  Google Scholar 

  4. GA Brockmann J Kratzsch CS Haley U Renne M Schwerin et al. (2000) ArticleTitleSingle QTL effects, epistasis, and pleiotropy account for two-thirds of the phenotypic F(2) variance of growth and obesity in DU6i × DBA/2 mice. Genome Res 10 1941–1957 Occurrence Handle11116089

    PubMed  Google Scholar 

  5. JF Caro MK Sinha JW Kolaczynski PL Zhang RV Considine (1996) ArticleTitleLeptin: the tale of an obesity. Diabetes 11 1455–1462

    Google Scholar 

  6. AG Comuzzie JE Hixson L Almasy BD Mitchell MC Mahaney et al. (1997) ArticleTitleA major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 15 273–276 Occurrence Handle1:CAS:528:DyaK2sXhsVGrs7c%3D Occurrence Handle9054940

    CAS  PubMed  Google Scholar 

  7. RV Considine MK Sinha ML Heiman A Kriauciunas TW Stephens et al. (1996) ArticleTitleSerum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334 292–295 Occurrence Handle1:STN:280:BymC3sznsVU%3D Occurrence Handle8532024

    CAS  PubMed  Google Scholar 

  8. W Fan BA Boston RA Kesterson VJ Hruby RD Cone (1997) ArticleTitleRole of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385 165–168 Occurrence Handle1:CAS:528:DyaK2sXks1Witw%3D%3D Occurrence Handle8990120

    CAS  PubMed  Google Scholar 

  9. KN Frayn SW Coppack (1992) ArticleTitleInsulin resistance, adipose tissue and coronary heart disease. Clin Sci (Lond) 82 1–8 Occurrence Handle1:STN:280:By2C2Mvos1Y%3D

    CAS  Google Scholar 

  10. J Hager C Dina S Francke S Dubois M Houari et al. (1998) ArticleTitleA genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet 20 304–308 Occurrence Handle1:CAS:528:DyaK1cXntFOgs7k%3D Occurrence Handle9806554

    CAS  PubMed  Google Scholar 

  11. JE Hixson L Almasy S Cole S Birnbaum BD Mitchell et al. (1999) ArticleTitleNormal variation in leptin levels is associated with polymorphisms in the proopiomelanocortin gene, POMC. J Clin Endocr Metab 84 3187–3191 Occurrence Handle1:CAS:528:DyaK1MXlvVGksbo%3D Occurrence Handle10487685

    CAS  PubMed  Google Scholar 

  12. HJ Jacob DM Brown RK Bunker MJ Daly VJ Dzau et al. (1995) ArticleTitleA genetic linkage map of the laboratory rat, Rattus norvegicus. Nat Genet 9 63–69 Occurrence Handle1:CAS:528:DyaK2MXjtFCrtrw%3D Occurrence Handle7704027

    CAS  PubMed  Google Scholar 

  13. K Kawano T Hirashima S Mori Y Saitoh M Kurosumi et al. (1992) ArticleTitleSpontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41 1422–1428

    Google Scholar 

  14. H Krude H Biebermann W Luck R Horn G Brabant et al. (1998) ArticleTitleSevere early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19 155–157 Occurrence Handle10.1038/509 Occurrence Handle1:CAS:528:DyaK1cXls1Crt7o%3D Occurrence Handle9620771

    Article  CAS  PubMed  Google Scholar 

  15. E Lander L Kruglyak (1995) ArticleTitleGenetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11 241–247 Occurrence Handle1:CAS:528:DyaK2MXptlSjs74%3D Occurrence Handle7581446

    CAS  PubMed  Google Scholar 

  16. ES Lander P Green J Abrahamson A Barlow MJ Daly et al. (1987) ArticleTitleMAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1 174–181 Occurrence Handle1:CAS:528:DyaL1cXhsVCksrk%3D Occurrence Handle3692487

    CAS  PubMed  Google Scholar 

  17. SE Lincoln ES Lander (1992) ArticleTitleSystematic detection of errors in genetic linkage data. Genomics 14 604–610 Occurrence Handle1:CAS:528:DyaK3sXhvVCntbs%3D Occurrence Handle1427888

    CAS  PubMed  Google Scholar 

  18. M Maffei J Halaas E Ravussin RE Pratley GH Lee et al. (1995) ArticleTitleLeptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1 1155–1161 Occurrence Handle1:CAS:528:DyaK2MXptFahs7s%3D

    CAS  Google Scholar 

  19. M Mehrabian PZ Wen J Fisler RC Davis AJ Lusis (1998) ArticleTitleGenetic loci controlling body fat, lipoprotein metabolism and insulin levels in a multifactorial mouse model. J Clin Invest 101 2485–2496 Occurrence Handle1:CAS:528:DyaK1cXjvVajsbs%3D Occurrence Handle9616220

    CAS  PubMed  Google Scholar 

  20. CT Montague IS Farooqi JP Whitehead MA Soos H Rau et al. (1997) ArticleTitleCongenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387 903–908 Occurrence Handle1:CAS:528:DyaK2sXkt1Grtbg%3D Occurrence Handle9202122

    CAS  PubMed  Google Scholar 

  21. DH Moralejo S Wei K Wei S Weksler-Zangen G Koike et al. (1998) ArticleTitleIdentification of quantitative trait loci for non-insulin-dependent diabetes mellitus that interact with body weight in the Otsuka Long-Evans Tokushima Fatty rat. Proc Assoc Am Physicians 110 545–558 Occurrence Handle1:STN:280:DyaK1M%2Fks12quw%3D%3D Occurrence Handle9824537

    CAS  PubMed  Google Scholar 

  22. M Niimi M Sato R Yokote S Tada J Takahara (1999) ArticleTitleEffects of central and peripheral injection of leptin on food intake and on brain Fos expression in the Otsuka Long-Evans Tokushima Fatty rat with hyperleptinaemia. J Neuroendocrinol 11 605–611 Occurrence Handle10.1046/j.1365-2826.1999.00368.x Occurrence Handle1:CAS:528:DyaK1MXltFCgtLo%3D Occurrence Handle10447798

    Article  CAS  PubMed  Google Scholar 

  23. T Ogino S Wei K Wei DH Moralejo H Kose et al. (2000) ArticleTitleGenetic evidence for obesity loci involved in the regulation of body fat distribution in obese type 2 diabetes rat, OLETF. Genomics 70 19–25 Occurrence Handle10.1006/geno.2000.6349 Occurrence Handle1:CAS:528:DC%2BD3cXotFyqs7w%3D Occurrence Handle11087657

    Article  CAS  PubMed  Google Scholar 

  24. AH Paterson ES Lander JD Hewitt S Peterson SE Lincoln et al. (1988) ArticleTitleResolution of quantitative traits into Mendelian factors by using a complete linkage map of restriction fragment length polymorphisms. Nature 335 721–726 Occurrence Handle1:STN:280:BiaD3MvnsVU%3D Occurrence Handle2902517

    CAS  PubMed  Google Scholar 

  25. L Pérusse YC Chagnon SJ Weisnagel T Rankinen E Snyder et al. (2001) ArticleTitleThe human obesity gene map: the 2000 update. Obes Res 9 135–169 Occurrence Handle11316348

    PubMed  Google Scholar 

  26. M Prochazka S Lillioja JF Tait WC Knowler DM Mott et al. (1993) ArticleTitleLinkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42 514–519 Occurrence Handle1:CAS:528:DyaK3sXitVGltLs%3D Occurrence Handle8454101

    CAS  PubMed  Google Scholar 

  27. T Rankinen L Pérusse SJ Weisnagel EE Snyder YC Chagnon et al. (2002) ArticleTitleThe human obesity gene map: the 2001 update. Obes Res 10 196–243 Occurrence Handle1:CAS:528:DC%2BD38XisFGlu78%3D Occurrence Handle11886943

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  29. CN Rotimi AG Comuzzie WL Lowe A Luke J Blangero et al. (1999) ArticleTitleThe quantitative trait locus on chromosome 2 for serum leptin levels is confirmed in African-Americans. Diabetes 48 643–644 Occurrence Handle1:CAS:528:DyaK1MXhsFymt7c%3D Occurrence Handle10078570

    CAS  PubMed  Google Scholar 

  30. MW Schwartz RJ Seeley SC Woods DS Weigle LA Campfield et al. (1997) ArticleTitleLeptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46 2119–2123 Occurrence Handle1:CAS:528:DyaK2sXnslGqtbY%3D Occurrence Handle9392508

    CAS  PubMed  Google Scholar 

  31. BM Spiegelman JS Flier (1996) ArticleTitleAdipogenesis and obesity: rounding out the big picture. Cell 87 377–389 Occurrence Handle1:CAS:528:DyaK28XmvVOktrg%3D Occurrence Handle8898192

    CAS  PubMed  Google Scholar 

  32. TK Watanabe MT Bihoreau LC McCarthy SL Kiguwa H Hishigaki et al. (1999) ArticleTitleA radiation hybrid map of the rat genome containing 5,255 markers. Nat Genet 22 27–36 Occurrence Handle1:CAS:528:DyaK1MXjtVags7w%3D Occurrence Handle10319858

    CAS  PubMed  Google Scholar 

  33. Y Zhang R Proenca M Maffei M Barone L Leopold et al. (1994) ArticleTitlePositional cloning of the mouse obese gene and its human homologue. Nature 372 425–432 Occurrence Handle1:CAS:528:DyaK2MXisVGqsbs%3D Occurrence Handle7984236

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by a grant from the Ministry of Education, Culture, Sports, Science & Technology of Japan. We thank Dr. Kazuya Kawano for kindly providing OLETF rats.

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Authors and Affiliations

  1. Institute for Animal Experimentation, University of Tokushima School of Medicine, Kuramoto 3, Tokushima 770-8503, Japan

    Tomoe Ogino, Daniel H. Moralejo, Hiroyuki Kose & Kozo Matsumoto

  2. Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi, Osaka 558-8585, Japan

    Tomoe Ogino

  3. Department of Medicine, University of Washington, Seattle, Washington 98195-7710, USA

    Daniel H. Moralejo

  4. Laboratory of Animal Breeding and Genetics, Graduate School of Agriculture, Kyoto University, Sakyoku, Kyoto 606-8502, Japan

    Takahisa Yamada

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  1. Tomoe Ogino
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Correspondence to Kozo Matsumoto.

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Ogino, T., Moralejo, D.H., Kose, H. et al. Serum leptin concentration is linked to Chromosomes 2 and 6 in the OLETF rat, an animal model of type 2 diabetes with mild obesity . Mamm Genome 14, 239–244 (2003). https://doi.org/10.1007/s00335-003-2295-7

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  • DOI: https://doi.org/10.1007/s00335-003-2295-7

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