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Current Diabetes Reports

, Volume 3, Issue 2, pp 151–158 | Cite as

The genetics of adiponectin

  • Francis Vasseur
  • Frédéric Leprêtre
  • Corinne Lacquemant
  • Philippe Froguel
Article

Abstract

Adiponectin encoded by the APM1 gene is one of the adipocyte-expressed proteins that function in the homeostatic control of glucose, lipid, and energy metabolism. Its dysregulation has been suggested to be involved in disorders covering the metabolic X syndrome, such as insulin resistance, obesity, type 2 diabetes, and coronary artery disease. Recent data present evidence of a genetic modulation of the adiponectin level, and linkage of the 3q27 locus, where the APM 1 gene lies, with diabetes and features of the metabolic X syndrome playing a putative role of the APM 1 gene in this syndrome. In this article, we present an overview of the results available to date and discuss positive evidence for a role of genetic variants of the APM 1 gene and questions that genetic data raise.

Keywords

Insulin Resistance Genetic Modulation Adiponectin Level Insulin Resistance Syndrome Serum Adiponectin Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References and Recommended Reading

  1. 1.
    Scherer PE, Williams S, Fogliano M, et al.: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995, 270:26746–26749.CrossRefPubMedGoogle Scholar
  2. 2.
    Maeda K, Okubo K, Shimomura I, et al.: cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996, 221:286–289.CrossRefPubMedGoogle Scholar
  3. 3.
    Saito K, Tobe T, Minoshima S, et al.: Organization of the gene for gelatin-binding protein (GBP28). Gene 1999, 229:67–73.CrossRefPubMedGoogle Scholar
  4. 4.
    Mori Y, Otabe S, Dina C, et al.: Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p. Diabetes 2002, 51:1247–1255.CrossRefPubMedGoogle Scholar
  5. 5.
    Kissebah AH, Sonnenberg GE, Myklebust J, et al.: Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 2000, 97:14478–14483.CrossRefPubMedGoogle Scholar
  6. 6.
    Vionnet N, Hani ElH, Dupont S, et al.: Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 2000, 67:1470–1480.CrossRefPubMedGoogle Scholar
  7. 7.
    Hotta K, Funahashi T, Arita Y, et al.: Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000, 20:1595–1599.PubMedGoogle Scholar
  8. 8.
    Lindsay RS, Funahashi T, Hanson RL, et al.: Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 2002, 360:57–58.CrossRefPubMedGoogle Scholar
  9. 9.
    Arita Y, Kihara S, Ouchi N, et al.: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999, 257:79–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Weyer C, Funahashi T, Tanaka S, et al.: Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001, 86:1930–1935.CrossRefPubMedGoogle Scholar
  11. 11.
    Matsubara M, Maruoka S, Katayose S: Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 2002, 87:2764–2769. Presents strong biological evidence that in humans the circulated adiponectin levels are strongly correlated with clinical features of the insulin resistance X syndrome, giving an argument for an involvement of the adiponectin protein in the syndrome.CrossRefPubMedGoogle Scholar
  12. 12.
    Statnick MA, Beavers LS, Conner LJ, et al.: Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes. Int J Exp Diabetes Res 2000, 1:81–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Haque WA, Shimomura I, Matsuzawa Y, et al.: Serum adiponectin and leptin levels in patients with lipodystrophies. J Clin Endocrinol Metab 2002,87:2395.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamauchi T, Kamon J, Waki H, et al.: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001, 7:941–946.CrossRefPubMedGoogle Scholar
  15. 15.
    Fruebis J, Tsao TS, Javorschi S, et al.: Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001, 98:2005–2010. Presents experiments mostly in mouse models that explain the mechanism by which the adiponectin protein may modulate insulin sensitivity by enhancing fatty acid oxidation in muscle. They give direct evidence by correcting insulin resistance under adiponectin administration.CrossRefPubMedGoogle Scholar
  16. 16.
    Maeda N, Shimomura I, Kishida K, et al.: Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002, 8:731–737.CrossRefPubMedGoogle Scholar
  17. 17.
    Berliner JA, Navab M, Fogelman AM, et al.: Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 1995, 91:2488–2496.PubMedGoogle Scholar
  18. 18.
    Francke S, Manraj M, Lacquemant C, et al.: A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. Hum Mol Genet 2001, 10:2751–2765. Presents strong evidences of a genetic linkage of features of the insulin resistance metabolic X syndrome with the 3q27 locus where the APM1 (@#@ adiponectin) gene lies. Thus, the results that replicate in different populations and on several phenotypes give tracks to focus further genetic investigations at this locus.CrossRefPubMedGoogle Scholar
  19. 19.
    Yokota T, Oritani K, Takahashi I, et al.: Adiponectin, da new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000, 96:1723–1732.PubMedGoogle Scholar
  20. 20.
    Ouchi N, Kihara S, Arita Y, et al.: Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999, 100:2473–2476.PubMedGoogle Scholar
  21. 21.
    Ouchi N, Kihara S, Arita Y, et al.: Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte- derived macrophages. Circulation 2001, 103:1057–1063.PubMedGoogle Scholar
  22. 22.
    Arita Y, Kihara S, Ouchi N, et al.: Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor- BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 2002, 105:2893–2898.CrossRefPubMedGoogle Scholar
  23. 23.
    Matsuda M, Shimomura I, Sata M, et al.: Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vas- cular axis. J Biol Chem 2002,277:37487–37491.CrossRefPubMedGoogle Scholar
  24. 24.
    Comuzzie AG, Funahashi T, Sonnenberg G, et al.: The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. J Clin Endocrinol Metab 2001, 86:4321–4325. Supports a genetic modulation of adiponectin level through a strong heritability.CrossRefPubMedGoogle Scholar
  25. 25.
    Vasseur F, Helbecque N, Dina C, et al.: Single nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genet 2002, 11:2607–2614. Extensive screening of the APM1 gene gives evidence of a risk haplotype in the 5′ sequences, and the role of rare mutations in exon 3. Raises the question of what are, among the frequent polymorphisms, the true functional variants involved in the genetic risk of the metabolic X syndrome.CrossRefPubMedGoogle Scholar
  26. 26.
    Takahashi M, Arita Y, Yamagata K, et al.: Genomic structure and mutations in adipose-specific gene, adiponectin. Int J Obes Relat Metab Disord 2000, 24:861–868.CrossRefPubMedGoogle Scholar
  27. 27.
    Hara K, Boutin P, Mori Y, et al.: Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002, 51:536–540. Presents strong evidence of a modulation of adiponectin level by genetic variants of the gene.CrossRefPubMedGoogle Scholar
  28. 28.
    Menzaghi C, Ercolino T, Di Paola R, et al.: A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes 2002, 51:2306–2312.CrossRefPubMedGoogle Scholar
  29. 29.
    Stumvoll M, Tschritter O, Fritsche A, et al.: Association of the T- G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes 2002, 51:37–41.CrossRefPubMedGoogle Scholar
  30. 30.
    Populaire C, Mori Y, Dina C, et al.: Does the -11377 promoter variant of APM1 gene contribute to the genetic risk forT2DM in Japanese families? Diabetologia 2003, in press. Replicates in various populations the associations initially described by Vasseur et al. [25] and Hara et al. [27], thus strengthening the initially reported genetic results.Google Scholar
  31. 31.
    Cartegni L, Chew SL, Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 2002, 3:285–298.CrossRefPubMedGoogle Scholar
  32. 32.
    Uitterlinden AG, Burger H, Huang Q, et al.: Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 1998, 338:1016–1021.CrossRefPubMedGoogle Scholar
  33. 33.
    Horikawa Y, Oda N, Cox NJ, et al.: Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000, 26:163–175.CrossRefPubMedGoogle Scholar
  34. 34.
    Schaffler A, Langmann T, Palitzsch KD, et al.: Identification and characterization of the human adipocyte apM-1 promoter. Biochim Biophys Acta 1998, 1399:187–197.PubMedGoogle Scholar
  35. 35.
    Maekawa T, Imamoto F, Merlino GT, et al.: Cooperative function of two separate enhancers of the human epidermal growth factor receptor proto-oncogene. J Biol Chem 1989, 264:5488–5494.PubMedGoogle Scholar
  36. 36.
    Kondo H, Shimomura I, Matsukawa Y, et al.: Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes 2002, 51:2325–2328.CrossRefPubMedGoogle Scholar
  37. 37.
    Shapiro L, Scherer PE: The crystal structure of a complement- 1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 1998, 8:335–338.CrossRefPubMedGoogle Scholar
  38. 38.
    Sato C, Yasukawa Z, Honda N, et al.: Identification and adipocyte differentiation-dependent expression of the unique disialic acid residue in an adipose tissue-specific glycoprotein, adipo Q. J Biol Chem 2001, 276:28849–28856.CrossRefPubMedGoogle Scholar
  39. 39.
    Wang Y, Xu A, Knight C, etal.: Hydroxylation and glyco sylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J Biol Chem 2002, 277:19521–19529.CrossRefPubMedGoogle Scholar
  40. 40.
    Kubota N, Terauchi Y, Yamauchi T, et al.: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002, 277:25863–25866.CrossRefPubMedGoogle Scholar
  41. 41.
    Yang WS, Jeng CY, Wu TJ, et al.: Synthetic peroxisome prolifer- ator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002, 25:376–380.CrossRefPubMedGoogle Scholar
  42. 42.
    Stumvoll M, Haring H: The peroxisome proliferator-activated receptor-gamma2 Pro 12Ala polymorphism. Diabetes 2002, 51:2341–2347.CrossRefPubMedGoogle Scholar
  43. 43.
    Hotta K, Funahashi T, Bodkin NL, et al.: Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001, 50:1126–1133.CrossRefPubMedGoogle Scholar
  44. 44.
    Stefan N, Vozarova B, Funahashi T, et al.: Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 2002, 51:1884–1888. Presents data in agreement with a direct involvement of adiponectin in the progression of insulin resistance toward a patent disease.CrossRefPubMedGoogle Scholar
  45. 45.
    Berg AH, Combs TP, Du X, et al.: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001, 7:947–953.CrossRefPubMedGoogle Scholar
  46. 46.
    Combs TP, Berg AH, Obici S, et al.: Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 2001, 108:1875–1881.CrossRefPubMedGoogle Scholar
  47. 47.
    Lehto M, Tuomi T, Mahtani MM, et al.: Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. J Clin Invest 1997, 99:582–591.PubMedCrossRefGoogle Scholar
  48. 48.
    Rizzu P, Baldini A: Three members of the human cystatin gene superfamily, AHSG, HRG, and KNG, map within one megabase of genomic DNA at 3q27. Cytogenet Cell Genet 1995, 70:26–28.PubMedGoogle Scholar
  49. 49.
    Mather KJ, Paradisi G, Leaming R, et al.: Role of amylin in insulin secretion and action in humans: antagonist studies across the spectrum of insulin sensitivity. Diabetes Metab Res Rev 2002, 18:118–126.CrossRefPubMedGoogle Scholar
  50. 50.
    Strowski MZ, Parmar RM, Blake AD, et al.: Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 2000, 141:111–117.CrossRefPubMedGoogle Scholar
  51. 51.
    Vijayaraghavan S, Hitman GA, Kopelman PG: Apolipoprotein- D polymorphism: a genetic marker for obesity and hyperinsulinemia. J Clin Endocrinol Metab 1994, 79:568–570.CrossRefPubMedGoogle Scholar
  52. 52.
    Xu G, Marshall CA, Lin TA, et al.: Insulin mediates glucose-stimulated phosphorylation of PHAS-I by pancreatic beta cells. An insulin-receptor mechanism for autoregulation of protein synthesis by translation. J Biol Chem 1998, 273:4485–4491.CrossRefPubMedGoogle Scholar
  53. 53.
    Yoshizawa F, Kimball SR, Jefferson LS: Modulation of translation initiation in rat skeletal muscle and liver in response to food intake. Biochem Biophys Res Commun 1997, 240:825–831.CrossRefPubMedGoogle Scholar
  54. 54.
    Delepine M, Nicolino M, Barrett T, et al.: EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000, 25:406–409.CrossRefPubMedGoogle Scholar
  55. 55.
    Tsukiyama-Kohara K, Poulin F, Kohara M, et al.: Adipose tissue reduction in mice lacking the translational inhibitor 4E- BP1. Nat Med 2001, 7:1128–1132.CrossRefPubMedGoogle Scholar
  56. 56.
    Wesche H, Korherr C, Kracht M, et al.: The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J Biol Chem 1997, 272:7727–7731.CrossRefPubMedGoogle Scholar
  57. 57.
    Heitmeier MR, Arnush M, Scarim AL, et al: Pancreatic beta-cell damage mediated by beta-cell production of interleukin-1. A novel mechanism for virus-induced diabetes. J Biol Chem 2001, 276:11151–11158.CrossRefPubMedGoogle Scholar
  58. 58.
    Reich DE, Lander ES: On the allelic spectrum of human disease. Trends Genet 2001, 17:502–510.CrossRefPubMedGoogle Scholar
  59. 59.
    Pritchard JK: Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet 2001,69:124–137.CrossRefPubMedGoogle Scholar

Copyright information

© Current Science Inc. 2003

Authors and Affiliations

  • Francis Vasseur
    • 1
  • Frédéric Leprêtre
    • 1
  • Corinne Lacquemant
  • Philippe Froguel
    • 1
  1. 1.CNRS UMR 8090Institut de Biologie de Lille, Institut Pasteur de LilleLille cedexFrance

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