Skip to main content Accessibility help
×
Home

Obesity — a genetic disease of adipose tissue?

  • Peter Arner (a1)

Abstract

Although the rapid increase in the prevalence of obesity in many countries suggests that environmental factors (mainly overeating and physical inactivity) play the most important role in the development of overweight, it is very likely that genetic factors also contribute. It appears that one major gene in combination with one or several minor genes constitute the genetic components behind excess accumulation of body fat in most obese individuals. However, monogenic obesity has been described in a few families due to changes in leptin, leptin receptor, prohormone convertase, pro-opiomelanocortin or melanocortin-4 receptor. None of the monogenic variants is of great importance for common human obesity; the latter genes are unknown so far. Results from genomic scans suggest that major obesity genes are located on chromosomes 2, 10, 11 and 20. Studies of candidate genes indicate that the minor obesity genes control important functions of adipose tissue, and that structural variance in these genes may alter adipose tissue function in a way that promotes obesity. Such genes are β2- and β3-adrenoceptors, hormone-sensitive lipase, tumour necrosis factor alpha, uncoupling protein-1, low-density lipoprotein receptor, and peroxisome proliferator activator receptor gamma-2. Some of these genes may promote obesity by gene–gene interactions (for example β3-adrenoceptors and uncoupling protein-1) or gene–environment interactions (for example β2-adrenoceptors and physical activity). Some are important for obesity only among women (for example β2- and β3-adrenoceptors, low-density lipoprotein receptor and tumour necrosis factor alpha). Few ‘non-adipose’ genes have so far shown a firm association to common human obesity, which could suggest that the important genes for the development of excess body fat also control adipose tissue function.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Obesity — a genetic disease of adipose tissue?
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Obesity — a genetic disease of adipose tissue?
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Obesity — a genetic disease of adipose tissue?
      Available formats
      ×

Copyright

Corresponding author

*Corresponding author: P. Arner, fax +46 8 58582407, email peter.arner@medhs.ki.se

References

Hide All
Allison, DB, Kaprio, J, Korkeila, M, Koskenvuo, M, Neale, MC & Kayakawa, K (1996) The heritability of body mass index among an international sample of monozygotic twins reared apart. International Journal of Obesity 20, 501506.
Allison, DB, Heo, M, Faith, MS & Pietrobelli, A (1998) Meta-analysis of the associaton of the Trp64Arg polymorphism in the β3-adrenergic receptor with body mass index. International Journal of Obesity 22, 559566.
Arner, P & Hoffstedt, F (1999) Adrenoceptor genes in human obesity. Journal of Internal Medicine 6, 667672.
Bouchard, C (1993) Genes and body fat. American Journal of Human Biology 5, 425432.
Bouchard, C, Pérusse, L (1996) Current status of the human obesity gene map. Obesity Research 4, 8190.
Buscher, R, Herrmann, V & Insel, PA (1999) Human adrenoceptor polymorphisms: evolving recognition of clinical importance. Trends in Pharmacological Sciences 20, 9499.
Cagnon, J, Lago, F, Chagnon, YC, Pérusse, L, Näslund, I, Lissner, L, Sjöström, L & Bouchard, C (1998) DNA polymorphism in the uncoupling protein 1 (UCP1) gene has no effect on obesity related phenotypes in the Swedish obese subjects cohorts. International Journal of Obesity 22, 500505.
Cannon, B, Houstek, J & Nedergaard, J (1998) Brown adipose tissue. More than an effector of thermogenesis?. Annals of New York Academy of Science 856, 171187.
Carpene, C, Bousquet-Melou, A, Galitzky, J, Berlan, M & Lafontan, M (1998) Lipolytic effects of beta1-, beta2- and beta3-adrenergic agonists in white adipose tissue of mammals. Annals of New York Academy of Science 839, 186189.
Cassard-Doulcier, AM, Bouillaud, F, Chagnon, M, Gelly, C, Dionne, FT, Oppert, JM, Bouchard, C, Chagnon, Y & Ricquier, D (1996) The BclI polymorphism of the human uncoupling protein (UCP) gene is due to a point mutation in the 5′ flanking region. International Journal of Obesity 3, 278279.
Chagnon, YC, Pérusse, L & Bouchard, C (1998) The human obesity gene map: the 1997 update. Obesity Research 6, 7692.
Chua, S & Leibel, RL (1997) Obesity genes. Molecular and metabolic mechanisms. Diabetes Reviews 5, 27.
Clément, K, Ruiz, J, Cassard-Doulcier, AM, Bouillaud, R, Ricquier, D, Basdevant, A, Guy-Grand, B & Froguel, P (1996) Additive effect of A G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta3-adrenergic gene on weight gain in morbid obesity. International Journal of Obesity 12, 10621066.
Clément, K, Vaiesse, C, Lahlou, N, Cabrol, S, Pelbux, V, Cassuto, D, Gourmelen, M, Dina, C, Chambay, J, Lacorte, JM, Basdevant, A, Bougneres, P, Lebouc, Y, Frougel, P, Guy-Grand, B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 6674, 398401.
Clément, K, Dina, C, Basdevant, A, Chastang, N, Pelloux, V, Lahlou, N, Berlan, M, Langin, D, Guy-Grand, B & Frougel, P (1999) A sib-pair analysis study of 15 candidate genes in French families with morbid obesity. Diabetes 48, 398402.
Comuzzie, AG & Allison, DB (1998) The search for human obesity genes. Science 280, 13741377.
Comuzzie, AG, Hixson, JE, Almasy, L, Mitchell, BD, Mahaney, MC, Dyer, TD, Stern, MP, MacCluer, JW & Blangero, J (1997) A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genetics 15, 273276.
Deeb, SS, Fajas, L, Nemoto, M, Pihlajamäki, J, Mykkänen, L, Kuusisto, J, Laakso, M, Fujimoto, W & Auwerx, J (1998) A Pro12Ala substitution in PPARγ-2 with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nature Genetics 20, 284287.
Descamps, O, Bilheimer, D & Herz, J (1993) Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes. Journal of Biological Chemistry 2, 974981.
Echwald, SM, Sörensen, TIA, Tybjaerg-Hansen, A, Andersen, T & Pedersen, O (1998) Gln 27Glu variant of the human β2-adrenoceptor gene is not associated with early-onset obesity in Danish men. Diabetes 47, 16571658.
Echwald, SM, Sörensen, TIA, Andersen, T, Tubjaerg-Hansen, A, Clausen, JO & Pedersen, O (1999) Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity. International Journal of Obesity 23, 293298.
Ek, J, Urhammer, SA, Sörensen, TIA, Andersen, T, Auwerz, J & Pedersen, O (1999) Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-γ-2 (PPARγ-2): divergent modulating effects on body mass index in obese and lean Caucasian men. Diabetologia 42, 892895.
Férnandez-Real, JM, Gutierrez, C, Ricart, W, Casamitjana, R, Fernández-Castaner, M, Vendrell, J, Richart, C & Soler, J (1997) The TNF–α gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat and increased serum leptin levels. Diabetes 46, 14681472.
Fogelholm, M, Valve, R, Kukkonne-Harjula, K, Nenonen, A, Hakkarainen, V, Laakso, M & Uusitupa, M (1998) Additive effects of the mutations in the β3-adrenergic receptor and uncoupling protein-1 genes on weight loss and weight maintenance in Finnish women. Journal of Clinical Endocrinology Metabolism 83, 42464250.
Fujisawa, T, Ikegami, H, Kwaguchi, Y & Ogihara, T (1998) Meta-analysis of the association of Trp64Arg polymorphism of β3-adrenergic receptor gene with body mass index. Journal of Clinical Endocrinology and Metabolism 83, 24412444.
Fumeron, F, Durack-Bown, I, Betoulle, D, Cassard-Doulcier, AM, Tuzet, S, Bouillaud, F, Melchior, JC, Ricquier, D & Apfelbaum, M (1996) Polymorphisms of uncoupling protein (UCP) and beta3-adrenoceptor genes in obese people submitted to a low calorie diet. International Journal of Obesity 12, 10511054.
Gasic, S, Tian, B & Green, A (1999) Tumor necrosis factor-alpha stimulates lipolysis in adipocytes by decreased Gi protein concentrations. Journal of Biological Chemistry 10, 67706775.
Ginsburg, E, Livshits, G, Yakovenko, K & Kobyliansky, E (1998) Major gene control of human body height, weight and BMI in five ethnically different populations. Annals of Human Genetics 62, 307322.
Gu, Z, Hillier, L, Kowk, P-Y (1998) Single nucleotide polymorphism hunting in cyberspace. Human Mutation 12, 221225.
Häger, J, Dina, C, Francke, S, Dubouis, S, Houari, M, Vatin, V, Vaillant, E, Lorentz, N, Basdevant, A, Clement, K, Guy-Grand, B & Frougel, P (1998) A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nature Genetics 20, 304308.
Hellström, L, Langin, D, Reynisdottir, S, Dauzats, M & Arner, P (1996) Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives. Diabetologia 8, 921928.
Hellström, L, Large, V, Reynisdottir, S, Wahrenberg, H & Arner, P (1999) The different effects of Gln27Glu beta2-adrenoceptor gene polymorphism on obesity in males and females. Journal of Internal Medicine 3, 253259.
Herrmann, SM, Ricard, S, Nicaud, V, Mallet, C, Arveilert, D, Evans, A, Ruidavets, JB, Luc, G, Bara, L, Parra, HJ, Poirier, O & Cambien, F (1998) Polymorphisms of the tumour necrosis factor-α gene, coronary heart disease and obesity. European Journal of Clinical Investigation 28, 5966.
Hill, JO & Peters, JC (1998) Environmental contributions to the obesity epidemic. Science 280, 13711374.
Hoffstedt, J, Eriksson, P, Hellström, L, Rössner, S, Rydén, M & Arner, P (2000) Excessive fat accumulation is associated with the TNF-α -308 G/A promoter polymorphism in women but not in men. Diabetologia 43, 117120.
Hoffstedt, J, Poirier, O, Thörne, A, Lönnqvist, F, Herrmann, SM, Cambien, F & Arner, P (1999) Polymorphism of the human β3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. Diabetes 48, 203205.
Hotamisligil, GS (1999) Mechanisms of TNF-alpha-induced insulin resistance. Experimental Clinical Endocrinology and Diabetes 107, 119125.
Hotamisligil, GS & Spiegelman, BM (1994) Tumor necrosis factor alpha: a key component of the obesity–diabetes link. Diabetes 43, 12711278.
Ishiyama-Shigemoto, S, Yamada, K, Yuan, X, Ichikawa, E & Nonaka, K (1999) Association of polymorphisms in the β2-adrenergic receptor gene with obesity, hypertriglyceridaemia, and diabetes mellitus. Diabetologia 42, 98101.
Jackson, RS, Creemers, JW, Ohagi, S, Raffin-Sanson, ML, Sanders, L, Montague, CT, Hutton, JC, O'Rahilly, S (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genetics 3, 303306.
Katzmarzyk, P, Pérusse, L & Bouchard, C (1999) Genetics of abdominal visceral fat levels. American Journal of Human Biology 11, 225235.
Klannemark, M, Orho, M, Langin, D, Laurell, H, Holm, C, Reynisdottir, S, Arner, P & Groop, L (1998) The putative role of the hormone-sensitive lipase gene in the pathogenesis in type II diabetes mellitus and abdominal obesity. Diabetologia 41, 15161522.
Krief, S, Lönnqvist, F, Raimbault, S, Baude, B, van Spronsen, A, Arner, P, Strosberg, AD, Ricquier, D & Emorine, LJ (1993) Tissue distribution of beta3-adrenergic receptor mRNA in man. Journal of Clinical Investigation 91, 344349.
Krude, H, Biebergmann, H, Luck, W, Horn, R, Brabant, C & Gruters, A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics 2, 155157.
Langin, D, Holm, C & Lafontan, M (1996) Adipocyte hormone sensitive lipase: a major regulator of lipid metabolism. Proceedings of the Nutrition Society 55, 93109.
Large, V & Arner, P (1998) Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes and hyperlipidaemia. Diabetes and Metabolism 5, 409418.
Large, V, Hellström, L, Reynisdottir, S, Lönnqvist, F, Eriksson, P, Lannfelt, L & Arner, P (1997) Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. Journal of Clinical Investigation 100, 30053013.
Large, V, Reynisdottir, S, Langin, D, Fredby, K, Klannemark, M, Holm, C & Arner, P (1999) Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. Journal of Lipid Research 40, 20592065.
Lee, JH, Reed, DR, Li, W-D, Xu, W, Joo, E-J, Kilker, RL, Nanthakumar, E, North, M, Sakul, H, Bell, C & Price, RA (1999) Genome scan for human obesity and linkage to markers in 20q13. American Journal of Human Genetics 64, 196209.
Lembertas, AV, Pérusse, L, Chagnon, YC, Fisler, JS, Warden, CH, Purcell-Huynh, DA, Dionne, FT, Gagnon, J, Nadeua, A, Lusis, AJ & Bouchard, C (1997) Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. Journal of Clinical Investigation 100, 12401247.
Lowell, BB & Fliers, JS (1997) Brown adipose tissue, beta3-adrenergic receptor and obesity. Annual Review of Medicine 48, 307316.
Magré, J, Laurell, H, Fizames, C, Antoine, PJ, Dib, C, Vigouroux, C, Bourut, C, Capeau, J, Weissenbach, J & Langin, D (1998) Genetic mapping, identification of a new dinucleotide repeat, and association with obesity and NIDDM. Diabetes 47, 284286.
Meirhaeghe, A, Helbecque, N, Cottel, D & Amouyel, P (1999) β2-adrenoceptor gene polymorphism, body weight and physical activity. Lancet 353, 896.
Montague, CT, Faroogi, IS, Whitehead, JP, Soos, MA, Rau, H, Wareham, NJ, Sewter, CP, Digby, JE, Mohammed, SN, Hurst, JA, Cheetham, CH, Earley, AR, Barnett, AH, Prins, JB & O'Rahilly, S (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903908.
Mori, Y, Kim-Motoyama, H, Katakura, T, Yasuda, K, Kadowaki, H, Beamer, BA, Shuldiner, AR, Akanuma, Y, Yazaki, Y & Kadowaki, T (1998) Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor γ-2 gene on adiposity, fat distribution and insulin sensitivity in Japanese men. Biochemical and Biophysical Research Communications 251, 195198.
Mori, Y, Kim-Motoyama, H, Ito, Y, Katakura, T, Yasuda, K, Ishiyama-Shigemoto, S, Yamada, K, Akanuma, Y, Ohashi, Y, Kimura, S, Yazaki, Y & Kadowaki, Y (1999) The Gln27Glu β2-adrenergic receptor variant is associated with obesity due to subcutaneous fat accumulation in Japanese men. Biochemical and Biophysical Research Communciations 258, 138140.
Norman, RA, Bogardus, C & Ravussin, E (1995) Linkage between obesity and a marker near the tum or necrosis factor-alpha locus in Pima Indians. Journal of Clinical Investigation 96, 158162.
Norman, RA, Tataranni, PA, Pratley, R, Thompson, DB, Hanson, RL, Prochazka, M, Baier, L, Ehm, MG, Sakul, H, Foroud, T, Garvey, WT, Burns, D, Knowler, WC, Bennett, PH, Bogardus, C & Ravussin, E (1998) Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. American Journal of Human Genetics 62, 659668.
Norman, RA, Permana, P, Tanizawa, Y & Ravussin, E (1999) Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima Indians. International Journal of Obesity 23, 163165.
Oberkofler, H, Dallinger, G, Liu, YM, Hell, E, Krempler, F & Patcsh, W (1997) Uncoupling protein gene: quantification of expression levels in adipose tissue of obese and non-obese humans. Journal of Lipid Research 10, 21252133.
Oppert, JM, Vohlm, C, Chagnon, M, Dionne, F, Cassard-Doulcier, AM, Ricquier, D, Perusse, L & Bouchard, C (1999) DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. International Journal of Obesity 8, 526531.
Otabe, S, Clement, K, Dubois, S, Lepretre, F, Pelloux, V, Leibel, R, Chung, W, Boutin, P, Guy-Grand, B, Frougel, P & Vasseur, F (1999) Mutation screening and association studies of the human uncoupling protein 3 gene in normoglycemic and diabetic morbidyly obese patients. Diabetes 48, 206208.
Pérusse, L, Chagnon, YC, Dionne, FT & Bouchard, C (1996) The human obesity gene map: the 1996 update. Obesity Research 5, 4951.
Pérusse, L, Chagnon, YC, Weisnagel, J & Bouchard, C (1999) The human obesity gene map: the 1998 update. Obesity Research 7, 111129.
Prins, JB, Nielser, CU, Winterford, CM, Bright, NA, Siddle, K, O'Rahilly, S, Walker, NI & Cameron, DP (1997) Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes 46, 19391944.
Ricquier, B (1999) Uncoupling protein-2 (UCP2): molecular and genetic studies. International Journal of Obesity 23, S38-S42.
Ristow, M, Muller-Wieland, D, Pfeiffer, A, Krone, W & Kahn, CR (1998) Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. New England Journal of Medicine 339, 953959.
Rosenbaum, MD, Leibel, RL & Hirsch, MD (1997) Obesity. New England Journal of Medicine 337, 396407.
Rotimi, CN, Comuzzie, AG, Lowe, WL, Luke, A, Blangero, J & Cooper, RS (1999) The quantitative trait locus on chormosome 2 for serum leptin levels is confirmed in African-Americans. Diabetes 48, 643–276.
Rutherford, S, Nyholt, DR, Curtain, RP, Quinan, SR, Gaffney, PT, Morris, BJ & Griffiths, LR (1997) Association of low density lipoprotein receptor microsatellite variant with obesity. International Journal Obesity 11, 10321037.
Schoonjans, K, Maring, G, Staels, B & Auwerx, J (1997) Peroxisome proliferator-activated receptors, orphans with lgiands and function. Current Opinion in Lipidology 8, 159166.
Schrauwen, P, Walder, K & Ravussin, E (1999) Human uncoupling proteins and obesity. Obesity Research 7, 97105.
Sipiläinen, R, Uusitupa, M, Heikkinen, S, Rissanen, A & Laakso, M (1997) Polymorphism of the β3-adrenergic receptor gene affects basal metabolic rate in obese Finns. Diabetes 46, 7780.
Strobel, A, Issad, T, Camoin, L, Ozata, M & Strosberg, AD (1998) Leptin missense mutation association with hypogonadism and morbid obesity. Nature Genetics 18, 213215.
Strosberg, D (1997) Association of beta3-adrenoceptor polymorphism with obesity and diabetes: current status. Trends in Pharmacological Sciences 12, 449454.
Strosberg, D (1997) Structure and function of the beta3-adrenergic receptor. Annual Review of Pharmacology and Toxicolocy 37, 421450.
Umekawa, T, Yoshida, T, Sakane, N, Kogure, A, Kondo, M & Honjyo, H (1999) Trp64Arg mutation of β3-adrenocpetor gene deteriorates lipolysis induced by β3-adrenoceptor agonist in human omental adipocytes. Diabetes 48, 117120.
Vaisse, C, Clement, K, Guy-Grand, B & Frougel, P (1998) A framshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genetics 20, 113114.
Valve, R, Heikkinen, S, Rissanen, A, Laakso, M & Uusitupa, M (1998) Synergistic effect of polymorphisms in uncoupling protein 1 and β3-adrenergic receptor genes on basal metabolic rate in obese Finns. Diabetologia 41, 357361.
Wacey, AL & Tuddenham, EGD (1998) Mutation databases on the web. Journal of Medical Genetics 35, 529533.
Warden, C (1999) Genetics of uncoupling proteins in humans. International Journal of Obesity 23, S46-S48.
Willnow, TE (1999) The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism. Journal of Molecular Medicine 77, 306315.
Wilson, AG, Symons, JA, McDowell, TL, McDevitt, HO & Duff, GW (1997) Effects of polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proceedings of the National Academy of Sciences, USA 7, 31943199.
Yeo, GSH, Faroogi, IS, Aminian, S, Halshall, DJ, Stanhope, RG & O'Rahilly, S (1999) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genetics 20, 111112.

Keywords

Obesity — a genetic disease of adipose tissue?

  • Peter Arner (a1)

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed