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PMID: 17196040 Published · ppublish English Journal Article Review

Unraveling the genetics of human obesity.

PLoS genetics ·Vol. 2 ·No. 12 ·2006-12-29 ·Pages e188

Mutch DM, Clément K

Abstract

The use of modern molecular biology tools in deciphering the perturbed biochemistry and physiology underlying the obese state has proven invaluable. Identifying the hypothalamic leptin/melanocortin pathway as critical in many cases of monogenic obesity has permitted targeted, hypothesis-driven experiments to be performed, and has implicated new candidates as causative for previously uncharacterized clinical cases of obesity. Meanwhile, the effects of mutations in the melanocortin-4 receptor gene, for which the obese phenotype varies in the degree of severity among individuals, are now thought to be influenced by one's environmental surroundings. Molecular approaches have revealed that syndromes (Prader-Willi and Bardet-Biedl) previously assumed to be controlled by a single gene are, conversely, regulated by multiple elements. Finally, the application of comprehensive profiling technologies coupled with creative statistical analyses has revealed that interactions between genetic and environmental factors are responsible for the common obesity currently challenging many Westernized societies. As such, an improved understanding of the different "types" of obesity not only permits the development of potential therapies, but also proposes novel and often unexpected directions in deciphering the dysfunctional state of obesity.

MeSH Terms
Animals Chromosome Mapping Environment Gene Expression Profiling Humans Hypothalamus/physiopathology Mutation Obesity/genetics,physiopathology Phenotype Syndrome
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Mutch David M
French National Institute of Health and Medical Research (INSERM) U755 Nutriomique, Paris, France.
Clément Karine
Conflict of Interest

Competing interests. The authors have declared that no competing interests exist.

References (72)
72 references, click to expand
  1. MT-II induces penile erection via brain and spinal mechanisms.
    Ann N Y Acad Sci. 2003 Jun;994:90-5 PMID: 12851302
  2. Strategies for dissecting epigenetic mechanisms in the mouse.
    Nat Genet. 2005 Nov;37(11):1194-200 PMID: 16254566
  3. Finding genes that underlie complex traits.
    Science. 2002 Dec 20;298(5602):2345-9 PMID: 12493905
  4. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome.
    Nat Genet. 2004 Sep;36(9):989-93 PMID: 15314642
  5. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic.
    Diabetes. 2005 Jul;54(7):1899-906 PMID: 15983188
  6. The nature and identification of quantitative trait loci: a community's view.
    Nat Rev Genet. 2003 Nov;4(11):911-6 PMID: 14634638
  7. GAD2 on chromosome 10p12 is a candidate gene for human obesity.
    PLoS Biol. 2003 Dec;1(3):E68 PMID: 14691540
  8. Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist.
    J Med Chem. 2002 Oct 10;45(21):4589-93 PMID: 12361385
  9. A frameshift mutation in human MC4R is associated with a dominant form of obesity.
    Nat Genet. 1998 Oct;20(2):113-4 PMID: 9771699
  10. Gene-environment interactions in human diseases.
    Nat Rev Genet. 2005 Apr;6(4):287-98 PMID: 15803198
  11. Triallelic inheritance: a bridge between Mendelian and multifactorial traits.
    Ann Med. 2004;36(4):262-72 PMID: 15224652
  12. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating.
    J Clin Endocrinol Metab. 2006 May;91(5):1811-8 PMID: 16507637
  13. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency.
    J Clin Invest. 2000 Jul;106(2):271-9 PMID: 10903343
  14. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene.
    Am J Hum Genet. 2005 Dec;77(6):1021-33 PMID: 16380913
  15. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.
    Nat Neurosci. 2003 Jul;6(7):736-42 PMID: 12796784
  16. The 103I variant of the melanocortin 4 receptor is associated with low serum triglyceride levels.
    J Clin Endocrinol Metab. 2006 Feb;91(2):535-8 PMID: 16278267
  17. BDNF regulates eating behavior and locomotor activity in mice.
    EMBO J. 2000 Mar 15;19(6):1290-300 PMID: 10716929
  18. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.
    J Clin Invest. 2002 Oct;110(8):1093-103 PMID: 12393845
  19. Is GAD2 on chromosome 10p12 a potential candidate gene for morbid obesity?
    Nutr Rev. 2005 Sep;63(9):315-9 PMID: 16220643
  20. A frameshift mutation in MC4R associated with dominantly inherited human obesity.
    Nat Genet. 1998 Oct;20(2):111-2 PMID: 9771698
  21. Growth hormone therapy in children with Prader-Willi syndrome.
    J Pediatr. 2006 Jun;148(6):846; author reply 846-7 PMID: 16769405
  22. The metabolic syndrome: the crossroads of diet and genetics.
    Proc Nutr Soc. 2005 Aug;64(3):371-7 PMID: 16048671
  23. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.
    Cell Metab. 2006 Feb;3(2):135-40 PMID: 16459314
  24. Functional characterization of mutations in melanocortin-4 receptor associated with human obesity.
    J Biol Chem. 1999 Dec 10;274(50):35816-22 PMID: 10585465
  25. The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models.
    Philos Trans R Soc Lond B Biol Sci. 2006 Jul 29;361(1471):1265-74 PMID: 16815803
  26. Proopiomelanocortin and energy balance: insights from human and murine genetics.
    J Clin Endocrinol Metab. 2004 Jun;89(6):2557-62 PMID: 15181023
  27. Targeting melanocortin receptors as potential novel therapeutics.
    Pharmacol Ther. 2006 Jul;111(1):1-15 PMID: 16488018
  28. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity.
    Am J Hum Genet. 2004 Mar;74(3):572-81 PMID: 14973783
  29. Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.
    Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8664-9 PMID: 15173597
  30. Cilia: tuning in to the cell's antenna.
    Curr Biol. 2006 Aug 8;16(15):R604-14 PMID: 16890522
  31. Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients.
    Hum Genet. 2002 Jun;110(6):561-7 PMID: 12107442
  32. Elevated plasma ghrelin levels in Prader Willi syndrome.
    Nat Med. 2002 Jul;8(7):643-4 PMID: 12091883
  33. The case for strategic international alliances to harness nutritional genomics for public and personal health.
    Br J Nutr. 2005 Nov;94(5):623-32 PMID: 16277761
  34. Statistical false positive or true disease pathway?
    Nat Genet. 2006 Jul;38(7):731-3 PMID: 16804532
  35. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.
    Nat Genet. 1998 Jun;19(2):155-7 PMID: 9620771
  36. Personalized medicine: decades away?
    Pharmacogenomics. 2006 Mar;7(2):237-41 PMID: 16515403
  37. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).
    Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6287-92 PMID: 16606853
  38. Family-based designs in the age of large-scale gene-association studies.
    Nat Rev Genet. 2006 May;7(5):385-94 PMID: 16619052
  39. Lack of support for the association between GAD2 polymorphisms and severe human obesity.
    PLoS Biol. 2005 Sep;3(9):e315 PMID: 16122350
  40. Does my diet fit my genes? The new science of nutrigenomics has some answers. It explains why fat and caffeine are worse for some than others.
    Time. 2006 Jun 12;167(24):69-70 PMID: 16792216
  41. The human obesity gene map: the 2005 update.
    Obesity (Silver Spring). 2006 Apr;14(4):529-644 PMID: 16741264
  42. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes.
    J Clin Invest. 2005 Dec;115(12):3484-93 PMID: 16284652
  43. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.
    Nat Neurosci. 2004 Nov;7(11):1187-9 PMID: 15494731
  44. Nutrigenomics and nutrigenetics: the emerging faces of nutrition.
    FASEB J. 2005 Oct;19(12):1602-16 PMID: 16195369
  45. Genetics of human obesity.
    Proc Nutr Soc. 2005 May;64(2):133-42 PMID: 15960858
  46. DiOGenes: a multidisciplinary offensive focused on the obesity epidemic.
    Obes Rev. 2005 May;6(2):175-6 PMID: 15836468
  47. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany.
    J Clin Endocrinol Metab. 2006 May;91(5):1761-9 PMID: 16492696
  48. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.
    Nat Genet. 2006 May;38(5):521-4 PMID: 16582908
  49. Genetics of body-weight regulation.
    Nature. 2000 Apr 6;404(6778):644-51 PMID: 10766251
  50. The genetics of human obesity.
    Nat Rev Genet. 2005 Mar;6(3):221-34 PMID: 15703762
  51. Monogenic obesity in humans.
    Annu Rev Med. 2005;56:443-58 PMID: 15660521
  52. Molecular physiology of syndromic obesities in humans.
    Trends Endocrinol Metab. 2005 Aug;16(6):267-72 PMID: 16005242
  53. A common genetic variant is associated with adult and childhood obesity.
    Science. 2006 Apr 14;312(5771):279-83 PMID: 16614226
  54. Population structure, differential bias and genomic control in a large-scale, case-control association study.
    Nat Genet. 2005 Nov;37(11):1243-6 PMID: 16228001
  55. The effect of the melanocortin agonist, MT-II, on the defended level of body adiposity.
    Endocrinology. 2005 Sep;146(9):3732-8 PMID: 15932932
  56. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.
    J Clin Invest. 2000 Jul;106(2):253-62 PMID: 10903341
  57. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment.
    Trends Endocrinol Metab. 2004 Jan-Feb;15(1):12-20 PMID: 14693421
  58. Patterns of linkage disequilibrium in the human genome.
    Nat Rev Genet. 2002 Apr;3(4):299-309 PMID: 11967554
  59. Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats.
    Diabetologia. 2005 Nov;48(11):2376-85 PMID: 16205885
  60. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome.
    J Pediatr. 2004 Dec;145(6):744-9 PMID: 15580194
  61. Exploring the molecular basis of Bardet-Biedl syndrome.
    Hum Mol Genet. 2001 Oct 1;10(20):2293-9 PMID: 11673413
  62. Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons.
    Mol Endocrinol. 2006 Oct;20(10):2483-92 PMID: 16728530
  63. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.
    Hum Mol Genet. 2000 Jan 1;9(1):101-8 PMID: 10587584
  64. Emerging trends in the search for genetic variants predisposing to human obesity.
    Curr Opin Clin Nutr Metab Care. 2003 Jul;6(4):369-75 PMID: 12806208
  65. Melanocortin-4 receptors, beta-MSH and leptin: key elements in the satiety pathway.
    Peptides. 2006 Feb;27(2):365-71 PMID: 16290320
  66. Genetic polymorphisms and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets.
    PLoS Clin Trials. 2006 Jun;1(2):e12 PMID: 16871334
  67. Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity.
    Int J Obes (Lond). 2007 Feb;31(2):359-64 PMID: 16702999
  68. Perspectives: molecular genetic research in human obesity.
    Obes Rev. 2003 Aug;4(3):139-46 PMID: 12916815
  69. Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys.
    J Med Genet. 2005 Apr;42(4):e21 PMID: 15805150
  70. Polygenic control of Caenorhabditis elegans fat storage.
    Nat Genet. 2006 Mar;38(3):363-8 PMID: 16462744
  71. PT-141: a melanocortin agonist for the treatment of sexual dysfunction.
    Ann N Y Acad Sci. 2003 Jun;994:96-102 PMID: 12851303
  72. Molecular genetics of human obesity-associated MC4R mutations.
    Ann N Y Acad Sci. 2003 Jun;994:49-57 PMID: 12851297
Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.0020188
Published
2006-12-29
Pages
e188
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC1756898
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pgen.0020188 PMC Full Text View journal details
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