Advertisement
Canadian Journal of Cardiology
Advanced searchSave search
Research Article| Volume 23, SUPPLEMENT A, 23A-27A, August 2007

Genetic contributors to obesity

DOI:https://doi.org/10.1016/S0828-282X(07)71002-4
Genetic contributors to obesity
Previous ArticleElectrical heart disease: Genetic and molecular basis of cardiac arrhythmias in normal structural hearts
Next ArticlePredict, prevent and personalize: Genomic and proteomic approaches to cardiovascular medicine
      This paper is only available as a PDF. To read, Please Download here.
      Genetic and environmental factors interact to regulate body weight. Overall, the heritability of obesity is estimated at 40% to 70%. More than 244 genes have been found to strongly affect adiposity when overexpressed or deleted in mice. These genes can be considered in four broad categories: regulation of food intake by molecular signalling in the hypothalamus and hindbrain by signals originating in adipose tissue, gut and other organs; regulation of adipocyte differentiation and fat storage; regulation of spontaneous exercise activity; and effect on basal and postprandial thermogenesis. Rare variants in the coding sequences of major candidate genes account for an obese phenotype in 5% to 10% of individuals.
      Les facteurs génétiques et environnementaux interagissent pour réguler le poids corporel. Dans l’ensemble, on estime l’héritabilité de l’obésité à entre 40% et 70%. On a découvert que plus de 244 gènes ont un effet important sur l’adiposité lorsqu’ils sont surexprimés et ou supprimés chez les souris. Ces gènes peuvent être divisés entre quatre grandes catégories : la régulation de l’apport alimentaire par la signalisation moléculaire dans l’hypothalamus et le rhombencéphale au moyen de signaux en provenance des tissus adipeux, de l’estomac et d’autres organes, la régulation de la différenciation adipeuse et du stockage de gras, la régulation de l’activité physique spontanée et l’effet de la thermogenèse basale et postprandiale. De rares variantes des séquences de codage des principaux gènes candidats représentent un phénotype d’obésité chez 5% à 10% des individus.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Register: Create an account
      Institutional Access: Sign in to ScienceDirect

      References

        • Bodurtha J.N.
        • Mosteller M.
        • Hewitt J.K.
        • et al.
        Genetic analysis of anthropometric measures in 11-year-old twins: The Medical College of Virginia Twin Study.
        Pediatr Res. 1990; 28: 1-4
        • MacDonald A.
        • Stunkard A.
        Body-mass indexes of British separated twins.
        N Engl J Med. 1990; 322: 1530
        • Stunkard A.J.
        • Sorensen T.I.
        • Hanis C.
        • et al.
        An adoption study of human obesity.
        N Engl J Med. 1986; 314: 193-198
        • Stunkard A.J.
        • Harris J.R.
        • Pedersen N.L.
        • McClearn G.E.
        The body-mass index of twins who have been reared apart.
        N Engl J Med. 1990; 322: 1483-1487
        • Rankinen T.
        • Zuberi A.
        • Chagnon Y.C.
        • et al.
        The human obesity gene map: The 2005 update.
        Obesity (Silver Spring). 2006; 14: 529-644
        • Flier J.S.
        Obesity wars: Molecular progress confronts an expanding epidemic.
        Cell. 2004; 116: 337-350
        • Schwartz M.W.
        • Woods S.C.
        • Porte Jr., D.
        • Seeley R.J.
        • Baskin D.G.
        Central nervous system control of food intake.
        Nature. 2000; 404: 661-671
        • Shimada M.
        • Tritos N.A.
        • Lowell B.B.
        • Flier J.S.
        • Maratos-Flier E.
        Mice lacking melanin-concentrating hormone are hypophagic and lean.
        Nature. 1998; 396: 670-674
        • Montague C.T.
        • Farooqi I.S.
        • Whitehead J.P.
        • et al.
        Congenital leptin deficiency is associated with severe early-onset obesity in humans.
        Nature. 1997; 387: 903-908
        • Lowell B.B.
        • Spiegelman B.M.
        Towards a molecular understanding of adaptive thermogenesis.
        Nature. 2000; 404: 652-660
        • Broberger C.
        Brain regulation of food intake and appetite: Molecules and networks.
        J Intern Med. 2005; 258: 301-327
        • Flier J.S.
        AgRP in energy balance: Will the real AgRP please stand up?.
        Cell Metab. 2006; 3: 83-85
        • Shinyama H.
        • Masuzaki H.
        • Fang H.
        • Flier J.S.
        Regulation of melanocortin-4 receptor signaling: Agonist-mediated desensitization and internalization.
        Endocrinology. 2003; 144: 1301-1314
        • Farooqi I.S.
        • Keogh J.M.
        • Yeo G.S.
        • Lank E.J.
        • Cheetham T.
        • O’Rahilly S.
        Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.
        N Engl J Med. 2003; 348: 1085-1095
        • Farooqi I.S.
        • Yeo G.S.
        • Keogh J.M.
        • et al.
        Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency.
        J Clin Invest. 2000; 106: 271-279
        • Vaisse C.
        • Clement K.
        • Durand E.
        • Hercberg S.
        • Guy-Grand B.
        • Froguel P.
        Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.
        J Clin Invest. 2000; 106: 253-262
        • Enriori P.J.
        • Evans A.E.
        • Sinnayah P.
        • Cowley M.A.
        Leptin resistance and obesity.
        Obesity (Silver Spring). 2006; 14: 254S-258S
        • Howard J.K.
        • Flier J.S.
        Attenuation of leptin and insulin signaling by SOCS proteins.
        Trends Endocrinol Metab. 2006; 17: 365-371
        • Bell C.G.
        • Walley A.J.
        • Froguel P.
        The genetics of human obesity.
        Nat Rev Genet. 2005; 6: 221-234
        • Michaud J.L.
        • Boucher F.
        • Melnyk A.
        • et al.
        Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus.
        Hum Mol Genet. 2001; 10: 1465-1473
        • Holder Jr., J.L.
        • Butte N.F.
        • Zinn A.R.
        Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.
        Hum Mol Genet. 2000; 9: 101-108
        • Xu B.
        • Goulding E.H.
        • Zang K.
        • et al.
        Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.
        Nat Neurosci. 2003; 6: 736-742
        • Gray J.
        • Yeo G.S.
        • Cox J.J.
        • et al.
        Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene.
        Diabetes. 2006; 55: 3366-3371
        • Badman M.K.
        • Flier J.S.
        The gut and energy balance: Visceral allies in the obesity wars.
        Science. 2005; 307: 1909-1914
        • Flier J.S.
        • Maratos-Flier E.
        The stomach speaks – ghrelin and weight regulation.
        N Engl J Med. 2002; 346: 1662-1663
        • Batterham R.L.
        • Cohen M.A.
        • Ellis S.M.
        • et al.
        Inhibition of food intake in obese subjects by peptide YY3-36.
        N Engl J Med. 2003; 349: 941-948
        • Ahituv N.
        • Kavaslar N.
        • Schackwitz W.
        • et al.
        A PYY Q62P variant linked to human obesity.
        Hum Mol Genet. 2006; 15: 387-391
        • Altshuler D.
        • Hirschhorn J.N.
        • Klannemark M.
        • et al.
        The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.
        Nat Genet. 2000; 26: 76-80
        • Deeb S.S.
        • Fajas L.
        • Nemoto M.
        • et al.
        A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.
        Nat Genet. 1998; 20: 284-287
        • Ristow M.
        • Muller-Wieland D.
        • Pfeiffer A.
        • Krone W.
        • Kahn C.R.
        Obesity associated with a mutation in a genetic regulator of adipocyte differentiation.
        N Engl J Med. 1998; 339: 953-959
        • Anand A.
        • Chada K.
        In vivo modulation of Hmgic reduces obesity.
        Nat Genet. 2000; 24: 377-380
        • Chen H.C.
        • Farese Jr., R.V.
        DGAT and triglyceride synthesis: A new target for obesity treatment?.
        Trends Cardiovasc Med. 2000; 10: 188-192
        • Chen H.C.
        • Ladha Z.
        • Farese Jr., R.V.
        Deficiency of acyl coenzyme a:diacylglycerol acyltransferase 1 increases leptin sensitivity in murine obesity models.
        Endocrinology. 2002; 143: 2893-2898
        • Chen H.C.
        • Smith S.J.
        • Ladha Z.
        • et al.
        Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1.
        J Clin Invest. 2002; 109: 1049-1055
        • Kershaw E.E.
        • Flier J.S.
        Adipose tissue as an endocrine organ.
        J Clin Endocrinol Metab. 2004; 89: 2548-2556
        • Meirhaeghe A.
        • Helbecque N.
        • Cottel D.
        • Amouyel P.
        Beta2-adrenoceptor gene polymorphism, body weight, and physical activity.
        Lancet. 1999; 353: 896
        • Meirhaeghe A.
        • Helbecque N.
        • Cottel D.
        • Amouyel P.
        Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population.
        Int J Obes Relat Metab Disord. 2000; 24: 382-387
        • Oberkofler H.
        • Esterbauer H.
        • Hell E.
        • Krempler F.
        • Patsch W.
        The Gln27Glu polymorphism in the beta2-adrenergic receptor gene is not associated with morbid obesity in Austrian women.
        Int J Obes Relat Metab Disord. 2000; 24: 388-390
        • Ukkola O.
        • Rankinen T.
        • Weisnagel S.J.
        • et al.
        Interactions among the alpha2-, beta2-, and beta3-adrenergic receptor genes and obesityrelated phenotypes in the Quebec Family Study.
        Metabolism. 2000; 49: 1063-1070
        • Osuga J.
        • Ishibashi S.
        • Oka T.
        • et al.
        Targeted disruption of hormonesensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
        Proc Natl Acad Sci USA. 2000; 97: 787-792
        • Haemmerle G.
        • Lass A.
        • Zimmermann R.
        • et al.
        Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase.
        Science. 2006; 312: 734-737
        • Martinez-Botas J.
        • Anderson J.B.
        • Tessier D.
        • et al.
        Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice.
        Nat Genet. 2000; 26: 474-479
        • Tansey J.T.
        • Sztalryd C.
        • Gruia-Gray J.
        • et al.
        Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity.
        Proc Natl Acad Sci USA. 2001; 98: 6494-6499
        • Lowell B.B.
        Adaptive thermogenesis: Turning on the heat.
        Curr Biol. 1998; 8: R517-R520
        • Finck B.N.
        • Kelly D.P.
        PGC-1 coactivators: Inducible regulators of energy metabolism in health and disease.
        J Clin Invest. 2006; 116: 615-622
        • McKnight G.S.
        • Cummings D.E.
        • Amieux P.S.
        • Cyclic A.M.P.
        • et al.
        PKA, and the physiological regulation of adiposity.
        Recent Prog Horm Res. 1998; 53: 139-159
        • Cummings D.E.
        • Brandon E.P.
        • Planas J.V.
        • Motamed K.
        • Idzerda R.L.
        • McKnight G.S.
        Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A.
        Nature. 1996; 382: 622-626
        • Cederberg A.
        • Gronning L.M.
        • Ahren B.
        • Tasken K.
        • Carlsson P.
        • Enerback S.
        FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance.
        Cell. 2001; 106: 563-573
        • Vaisse C.
        • Clement K.
        • Durand E.
        • Hercberg S.
        • Guy-Grand B.
        • Froguel P.
        Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.
        J Clin Invest. 2000; 106: 253-262
        • Hirschhorn J.N.
        • Daly M.J.
        Genome-wide association studies for common diseases and complex traits.
        Nat Rev Genet. 2005; 6: 95-108
        • Jorgenson E.
        • Witte J.S.
        A gene-centric approach to genome-wide association studies.
        Nat Rev Genet. 2006; 7: 885-891
        • Wang W.Y.
        • Barratt B.J.
        • Clayton D.G.
        • Todd J.A.
        Genome-wide association studies: Theoretical and practical concerns.
        Nat Rev Genet. 2005; 6: 109-118
        • Swarbrick M.M.
        • Waldenmaier B.
        • Pennacchio L.A.
        • et al.
        Lack of support for the association between GAD2 polymorphisms and severe human obesity.
        PLoS Biol. 2005; 3: e315
        • Ahituv N.
        • Kavaslar N.
        • Schackwitz W.
        • et al.
        Medical sequencing at the extremes of human body mass.
        Am J Hum Genet. 2007; 80: 779-791
        • Herbert A.
        • Gerry N.P.
        • McQueen M.B.
        • et al.
        A common genetic variant is associated with adult and childhood obesity.
        Science. 2006; 312: 279-283
        • Osler W.
        Textbook of Medicine.
        4th edition. D Appleton and Company, New York1901

      Article info

      Publication history

      Accepted: March 19, 2007
      Received: March 8, 2007

      Identification

      DOI: https://doi.org/10.1016/S0828-282X(07)71002-4

      Copyright

      © 2007 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

      ScienceDirect

      Access this article on ScienceDirect
      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties. The content on this site is intended for healthcare professionals.


      RELX