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Biochemical Genetics

, Volume 48, Issue 5–6, pp 538–547 | Cite as

Identification of a QTL for Adipocyte Volume and of Shared Genetic Effects with Aspartate Aminotransferase

  • Tanushree BoseEmail author
  • V. Saroja Voruganti
  • M. Elizabeth Tejero
  • J. Michael Proffit
  • Laura A. Cox
  • John L. VandeBerg
  • Michael C. Mahaney
  • Jeffrey Rogers
  • Jeanne H. Freeland-Graves
  • Shelley A. Cole
  • Anthony G. Comuzzie
Article

Abstract

Plasma levels of aspartate aminotransferase (AST), a liver enzyme, are elevated in patients with visceral obesity. This study examined whether adipocyte volume is under the influence of genetic factors and evaluated its genetic correlations with AST. Fasting plasma levels of 344 pedigreed baboons from the Southwest National Primate Research Center in San Antonio, TX, USA, were assayed for AST. Adipocyte volume was measured using biopsies of omental adipose tissue. Adipocyte volume, body weight, and plasma AST were heritable. Genetic correlations between the measured adiposity-related phenotypes and AST were significant. A quantitative trait locus (LOD score 3.2) for adipocyte volume was identified on the baboon homolog of human chromosome 6 near marker D6S1028. These results suggest that omental adipocyte volume is under genetic regulation and that shared genetic factors influence adiposity-associated traits and AST.

Keywords

Nonalcoholic fatty liver disease Obesity Adipocyte size Genome scan QTL Aspartate aminotransferase 

Notes

Acknowledgments

This investigation was conducted in part in facilities constructed with support from the Research Facilities Improvement Program under grants C06 RR014578, C06 RR013556, C06 RR015456, and C06 RR017515 and with support from NIH grants PO1 HL028972, P51 RR013986, and R01 MH59490, as well as research support from the Kronkosky Charitable Foundation.

References

  1. Adams LA, Angulo P (2005) Recent concepts in non-alcoholic fatty liver disease. Diabet Med 22:1129–1133CrossRefPubMedGoogle Scholar
  2. Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1121–1198CrossRefGoogle Scholar
  3. Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (1998) Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 47:187–199CrossRefPubMedGoogle Scholar
  4. Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Fiorello S, Cavallo MG, Zalunardo B, Lirussi F, Alessandri C, Violi F (2005) Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. J Clin Endocrinol Metab 90:1578–1582CrossRefPubMedGoogle Scholar
  5. Avram MM, Avram AS, James WD (2005) Subcutaneous fat in normal and diseased states: 1. Introduction. J Am Acad Dermatol 53:663–670CrossRefPubMedGoogle Scholar
  6. Bakker AH, Nijhuis J, Buurman WA, van Dielen FM, Greve JW (2006) Low number of omental preadipocytes with high leptin and low adiponectin secretion is associated with high fasting plasma glucose levels in obese subjects. Diabetes Obes Metab 8:585–588CrossRefPubMedGoogle Scholar
  7. Bathum L, Petersen HC, Rosholm JU, Hyltoft Petersen P, Vaupel J, Christensen K (2001) Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin Chem 47:81–87PubMedGoogle Scholar
  8. Bose T, Lopez-Alvarenga JC, Dick E, Tejero ME, Freeland-Graves JH, Cole SA, Comuzzie AG (2006) Presence of non-alcoholic fatty liver in baboons. Am J Primatol Suppl 68(1):41Google Scholar
  9. Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, Coussieu C, Basdevant A, Bar Hen A, Bedossa P, Guerre-Millo M, Clément K (2006) Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 55:1554–1561CrossRefPubMedGoogle Scholar
  10. Chen A, Mumick S, Zhang C, Lamb J, Dai H, Weingarth D, Mudgett J, Chen H, MacNeil DJ, Reitman ML, Qian S (2005) Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res 13:1311–1320CrossRefPubMedGoogle Scholar
  11. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355CrossRefPubMedGoogle Scholar
  12. Cole SA, Martin LJ, Peebles KW, Leland MM, Rice K, VandeBerg JL, Blangero J, Comuzzie AG (2003) Genetics of leptin expression in baboons. Int J Obes Relat Metab Disord 27:778–783CrossRefPubMedGoogle Scholar
  13. Comuzzie AG, Cole SA, Martin L, Carey KD, Mahaney MC, Blangero J, VandeBerg JL (2003) The baboon as a nonhuman primate model for the study of the genetics of obesity. Obes Res 11:75–80CrossRefPubMedGoogle Scholar
  14. Cox LA, Mahaney MC, VandeBerg JL, Rogers J (2006) A second-generation genetic linkage map of the baboon (Papio hamadryas) genome. Genomics 88:274–281CrossRefPubMedGoogle Scholar
  15. Danforth E Jr (2000) Failure of adipocyte differentiation causes type II diabetes mellitus? Nat Genet 26:13CrossRefPubMedGoogle Scholar
  16. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Investig 115:1343–1351PubMedGoogle Scholar
  17. Eguchi Y, Eguchi T, Mizuta T, Ide Y, Yasutake T, Iwakiri R, Hisatomi A, Ozaki I, Yamamoto K, Kitajima Y, Kawaguchi Y, Kuroki S, Ono N (2006) Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease. J Gastroenterol 41:462–469CrossRefPubMedGoogle Scholar
  18. Farnier C, Krief S, Blache M, Diot-Dupuy F, Mory G, Ferre P, Bazin R (2002) The signaling pathway for beta1-integrin/ERKs is involved in the adaptation of adipocyte functions to cell size. Ann N Y Acad Sci 973:594–597CrossRefPubMedGoogle Scholar
  19. Feingold E, Brown PO, Siegmund D (1993) Gaussian models for genetic linkage analysis using complete high-resolution maps of identity by descent. Am J Hum Genet 53:234–251PubMedGoogle Scholar
  20. Gholam PM, Flancbaum L, Machan JT, Charney DA, Kotler DP (2007) Non-alcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol 102:399–408CrossRefPubMedGoogle Scholar
  21. Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83:461S–465SPubMedGoogle Scholar
  22. Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ (2001) The biology of white adipocyte proliferation. Obes Rev 2:239–254CrossRefPubMedGoogle Scholar
  23. Heilbronn L, Smith SR, Ravussin E (2004) Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 28(4):S12–S21CrossRefPubMedGoogle Scholar
  24. Kawada T, Takahashi N, Fushiki T (2001) Biochemical and physiological characteristics of fat cell. J Nutr Sci Vitaminol 47:1–12PubMedGoogle Scholar
  25. Lewis DS (1986) Effects of dietary cholesterol on adipose tissue lipoprotein lipase in the baboon. Biochim Biophys Acta 879:44–50PubMedGoogle Scholar
  26. Lin J, Page KA, Della-Fera MA, Baile CA (2004) Evaluation of adipocyte apoptosis by laser scanning cytometry. Int J Obes Relat Metab Disord 28:1535–1540CrossRefPubMedGoogle Scholar
  27. Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, Cao Q, Atsumi G, Malone H, Krishnan B, Minokoshi Y, Kahn BB, Parker RA, Hotamisligil GS (2005) Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab 1:107–119CrossRefPubMedGoogle Scholar
  28. Marchesini G, Avagnina S, Barantani EG, Ciccarone AM, Corica F, Dall’Aglio E, Dalle Grave R, Morpurgo PS, Tomasi F, Vitacolonna E (2005) Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome. J Endocrinol Investig 28:333–339Google Scholar
  29. McGarry JD, Dobbins RL (1999) Fatty acids, lipotoxicity and insulin secretion. Diabetologia 42:128–138CrossRefPubMedGoogle Scholar
  30. Mendez-Sanchez N, Chavez-Tapia NC, Medina-Santillan R, Villa AR, Sanchez-Lara K, Ponciano-Rodriguez G, Ramos MH, Uribe M (2006) The efficacy of adipokines and indices of metabolic syndrome as predictors of severe obesity-related hepatic steatosis. Dig Dis Sci 51:1716–1722CrossRefPubMedGoogle Scholar
  31. Monteiro R, de Castro PM, Calhau C, Azevedo I (2006) Adipocyte size and liability to cell death. Obes Surg 16:804–806CrossRefPubMedGoogle Scholar
  32. Panteghini M (1990) Aspartate aminotransferase isoenzymes. Clin Biochem 23:311–319CrossRefPubMedGoogle Scholar
  33. Paolisso G, Tataranni PA, Foley JE, Bogardus C, Howard BV, Ravussin E (1995) A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 38:1213–1217CrossRefPubMedGoogle Scholar
  34. Permana PA, Menge C, Reaven PD (2006) Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun 341:507–514CrossRefPubMedGoogle Scholar
  35. Prins JB, O’Rahilly S (1997) Regulation of adipose cell number in man. Clin Sci 92:3–11PubMedGoogle Scholar
  36. Relling DP, Esberg LB, Fang CX, Johnson WT, Murphy EJ, Carlson EC, Saari JT, Ren J (2006) High-fat diet-induced juvenile obesity leads to cardiomyocyte dysfunction and upregulation of Foxo3a transcription factor independent of lipotoxicity and apoptosis. J Hypertens 24:549–561CrossRefPubMedGoogle Scholar
  37. Rogers J, Hixson JE (1997) Baboons as an animal model for genetic studies of common human disease. Am J Hum Genet 61:489–493CrossRefPubMedGoogle Scholar
  38. Schling P, Loffler G (2002) Cross talk between adipose tissue cells: impact on pathophysiology. News Physiol Sci 17:99–104PubMedGoogle Scholar
  39. Self S, Liang K (1987) Asymptotic properties of maximum likelihood-ratio tests under nonstandard conditions. J Am Stat Assoc 82:605–610CrossRefGoogle Scholar
  40. Shi H, Cave B, Inouye K, Bjorbaek C, Flier JS (2006) Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes 55:699–707CrossRefPubMedGoogle Scholar
  41. Shimizu F, Watanabe TK, Shinomiya H, Nakamura Y, Fujiwara T (1997) Isolation and expression of a cDNA for human brain fatty acid-binding protein (B-FABP). Biochim Biophys Acta 1354:24–28PubMedGoogle Scholar
  42. Skurk T, Alberti-Huber C, Herder C, Hauner H (2007) Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92:1023–1033CrossRefPubMedGoogle Scholar
  43. Smith J, Al-Amri M, Dorairaj P, Sniderman A (2006) The adipocyte life cycle hypothesis. Clin Sci 110:1–9CrossRefPubMedGoogle Scholar
  44. Spiegelman BM, Flier JS (1996) Adipogenesis and obesity: rounding out the big picture. Cell 87:377–389CrossRefPubMedGoogle Scholar
  45. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante A W Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112:1796–1808PubMedGoogle Scholar
  46. Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE (2000) Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43:1498–1506CrossRefPubMedGoogle Scholar
  47. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112:1821–1830PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Tanushree Bose
    • 1
    • 4
    Email author
  • V. Saroja Voruganti
    • 2
  • M. Elizabeth Tejero
    • 2
  • J. Michael Proffit
    • 2
  • Laura A. Cox
    • 2
    • 3
  • John L. VandeBerg
    • 2
    • 3
  • Michael C. Mahaney
    • 2
    • 3
  • Jeffrey Rogers
    • 2
    • 3
  • Jeanne H. Freeland-Graves
    • 1
  • Shelley A. Cole
    • 2
  • Anthony G. Comuzzie
    • 2
    • 3
  1. 1.Division of Nutritional Sciences, Department of Human EcologyUniversity of Texas at AustinAustinUSA
  2. 2.Department of GeneticsSouthwest Foundation for Biomedical ResearchSan AntonioUSA
  3. 3.Southwest National Primate Research CenterSan AntonioUSA
  4. 4.Department of Food Science and NutritionCalifornia Polytechnic State UniversitySan Luis ObispoUSA

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