Genetics of obesity explained

Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors.[1] [2] Studies have identified variants in several genes that may contribute to weight gain and body fat distribution; although, only in a few cases are genes the primary cause of obesity.[3] [4]

Polymorphisms in various genes controlling appetite and metabolism predispose to obesity under certain dietary conditions. The percentage of obesity that can be attributed to genetics varies widely, depending on the population examined, from 6% to 85%,[5] with the typical estimate at 50%. It is likely that in each person a number of genes contribute to the likelihood of developing obesity in small part, with each gene increasing or decreasing the odds marginally, and together determining how an individual responds to the environmental factors.[6] As of 2006, more than 41 sites on the human genome have been linked to the development of obesity when a favorable environment is present.[7] Some of these obesogenic (weight gain) or leptogenic (weight loss) genes may influence the obese individual's response to weight loss or weight management.[8]

Genes

Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity.[9] [10] [11] Many candidate genes are highly expressed in the central nervous system.[12]

Several additional loci have been identified.[13] Also, several quantitative trait loci for BMI have been identified.

Confirmed and hypothesized associations include:

ConditionOMIMLocusNotes
leptin deficiency7q31.3
leptin receptor deficiency1p31
Ghrelin6053533p25.3
Ghrelin receptor6018983q26.31
prohormone convertase-1 deficiency5q15-q21
proopiomelanocortin deficiency 2p23.3
melanocortin-4 receptor polymorphism (MC4R[14])18q22
7q32.3near D7S1804[15]
13q14near D13S257
6q23-q25near D6S1009, GATA184A08, D6S2436, and D6S305[16]
11q24near D11S1998, D11S4464, and D11S912
16p13near ATA41E04[17]
20pter-p11.2near D20S482
2q14.1
16q12.2Adults who were homozygous for a particular FTO allele weighed about 3 kilograms more and had a 1.6-fold greater rate of obesity than those who had not inherited this trait.[18] This association disappeared, though, when those with FTO polymorphisms participated in moderately intensive physical activity equivalent to three to four hours of brisk walking.[19]
2p25.3
4p13
1p31.1
11p13
19q13.12KCTD15 plays a role in transcriptional repression of AP-2α, which in turn, inhibits the activity of C/EBPα, an early inducer of adipogenesis.[20]
[21] ?Although it does not play a role in the formation of fat itself, it does determine the location on the body where this fat is stored.
SH2B1[22] 16p11.2
MTCH211p11.2
PCSK15q15-q21
NPC1[23] 18q11-q12
LYPLAL1[24] 6165481q41Disputed metabolic function of being either a lipase[25] or a short-chain carboxylesterase.[26]
CB1[27] 1146106q15
NPY5R[28] 6020014q32.2

Some studies have focused upon inheritance patterns without focusing upon specific genes. One study found that 80% of the offspring of two obese parents were obese, in contrast to less than 10% of the offspring of two parents who were of normal weight.[29]

The thrifty gene hypothesis postulates that due to dietary scarcity during human evolution people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would more likely survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies.[30] This is the presumed reason that Pima Native Americans, who evolved in a desert ecosystem, developed some of the highest rates of obesity when exposed to a Western lifestyle.[31]

Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.[32] [33]

The risk of obesity is determined by not only specific genotypes but also gene-gene interactions. However, there are still challenges associated with detecting gene-gene interactions for obesity.[34]

Genes protective against obesity

There are also genes that can be protective against obesity. For instance, in GPR75 variants were identified as such alleles in ~640,000 sequenced exomes which may be relevant to e.g. therapeutic strategies against obesity.[35] [36] Other candidate anti-obesity-related genes include ALK,[37] TBC1D1,[38] and SRA1.[39]

Genetic syndromes

The term "non-syndromic obesity" is sometimes used to exclude these conditions.[40] In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single locus mutation.[41]

See also

Related:

Notes and References

  1. Albuquerque D, Stice E, etal . Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective . Mol. Genet. Genomics . Mar 2015 . 25749980 . 10.1007/s00438-015-1015-9 . 290 . 4 . 1191–221. 10316/45814 . 3238210 . free .
  2. Albuquerque . David . Nóbrega . Clévio . Manco . Licínio . Padez . Cristina . 7 July 2017 . The contribution of genetics and environment to obesity . . Advance articles . 1. 159–173 . 10.1093/bmb/ldx022. 28910990 . free .
  3. Book: Kushner, Robert . Treatment of the Obese Patient (Contemporary Endocrinology) . Humana Press . Totowa, NJ . 2007 . 158 . 978-1-59745-400-1 . April 5, 2009.
  4. Adams JP, Murphy PG . Obesity in anaesthesia and intensive care . Br J Anaesth . 85 . 1 . 91–108 . July 2000 . 10927998 . 10.1093/bja/85.1.91 . free .
  5. Yang W, Kelly T, He J . Genetic epidemiology of obesity . Epidemiol Rev . 29 . 49–61 . 2007 . 17566051 . 10.1093/epirev/mxm004. free .
  6. Lyon . Helen N . Hirschhorn . Joel N . 2005-07-01 . Genetics of common forms of obesity: a brief overview . The American Journal of Clinical Nutrition . en . 82 . 1 . 215S–217S . 10.1093/ajcn/82.1.215S . 0002-9165. free .
  7. Poirier P, Giles TD, Bray GA, etal . Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss . Arterioscler. Thromb. Vasc. Biol. . 26 . 5 . 968–76 . May 2006 . 16627822 . 10.1161/01.ATV.0000216787.85457.f3 . 10.1.1.508.7066 . 6052584 .
  8. Hainer. Vojtĕch. Hermann Toplak . Asimina Mitrakou . Treatment Modalities of Obesity: What fits whom?. Diabetes Care. February 2008. 31. 269–277. 10.2337/dc08-s265. 18227496. free.
  9. Lee YS . The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature . Ann. Acad. Med. Singap. . 38 . 1 . 34–44. January 2009 . 10.47102/annals-acadmedsg.V38N1p34 . 19221669 . 21049001 . 2009-06-08 . dead . https://web.archive.org/web/20110721001459/http://www.annals.edu.sg/pdf/38VolNo1Jan2009/V38N1p34.pdf . 2011-07-21 .
  10. Web site: Researchers discover DNA variants significantly influence body fat distribution. medicalxpress.com. en-us. 2019-03-12.
  11. Lindgren. Cecilia M.. North. Kari E.. Loos. Ruth J. F.. Cupples. L. Adrienne. Hirschhorn. Joel N.. Kutalik. Zoltán. Rotter. Jerome I.. Mohlke. Karen L.. Lettre. Guillaume. 18 February 2019. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics. en. 51. 3. 452–469. 10.1038/s41588-018-0334-2. 30778226. 6560635. 1546-1718.
  12. Willer CJ, Speliotes EK, Loos RJ, etal . Six new loci associated with body mass index highlight a neuronal influence on body weight regulation . Nat. Genet. . 41 . 1 . 25–34 . January 2009 . 19079261 . 2695662 . 10.1038/ng.287.
  13. Web site: OMIM - OBESITY . 2009-06-08.
  14. Zhao J, Bradfield JP, Li M, etal . The role of obesity-associated loci identified in genome wide association studies in the determination of pediatric BMI . Obesity (Silver Spring) . 17. 12. 2254–7. May 2009 . 19478790 . 2860782 . 10.1038/oby.2009.159.
  15. Feitosa MF, Borecki IB, Rich SS, etal . Quantitative-Trait Loci Influencing Body-Mass Index Reside on Chromosomes 7 and 13: The National Heart, Lung, and Blood Institute Family Heart Study . Am. J. Hum. Genet. . 70 . 1 . 72–82 . January 2002 . 11713718 . 384905 . 10.1086/338144 .
  16. Atwood LD, Heard-Costa NL, Cupples LA, Jaquish CE, Wilson PW, D'Agostino RB . Genomewide Linkage Analysis of Body Mass Index across 28 Years of the Framingham Heart Study . Am. J. Hum. Genet. . 71 . 5 . 1044–50 . November 2002 . 12355400 . 385083 . 10.1086/343822 .
  17. Gorlova OY, Amos CI, Wang NW, Shete S, Turner ST, Boerwinkle E . Genetic linkage and imprinting effects on body mass index in children and young adults . Eur. J. Hum. Genet. . 11 . 6 . 425–32 . June 2003 . 12774034 . 10.1038/sj.ejhg.5200979. free .
  18. Frayling TM, Timpson NJ, Weedon MN, etal . A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity . Science . 316 . 5826 . 889–94 . 2007 . 17434869 . 2646098 . 10.1126/science.1141634. 2007Sci...316..889F .
  19. Rampersaud E, Mitchell BD, Pollin TI, etal . Physical activity and the association of common FTO gene variants with body mass index and obesity . Arch Intern Med . 2008 . 168 . 16 . 1791–97 . 10.1001/archinte.168.16.1791 . 18779467. 3635949 .
  20. Skoblov. Mikhail. Andrey Marakhonov . Ekaterina Marakasova . Anna Guskova . Vikas Chandhoke . Aybike Birerdinc . Ancha Baranova . Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development. BioEssays. 2013. 35. 7. 586–596. 10.1002/bies.201300002. 23592240.
  21. 3192952 . 21572415 . 10.1038/ng.833 . 43 . 6 . Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes . June 2011 . Small KS, Hedman AK, Grundberg E. etal . Nat. Genet. . 561–4.
  22. Renström F, Payne F, Nordström A, etal . Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden . Hum. Mol. Genet. . 18 . 8 . 1489–96 . April 2009 . 19164386 . 2664142 . 10.1093/hmg/ddp041 .
  23. Meyre. David. Delplanque . 18 January 2009. Jérôme. 157–9. Chèvre. Jean-Claude. Lecoeur. CéCile. Lobbens. StéPhane. Gallina. Sophie. Durand. Emmanuelle. Vatin. Vincent. Degraeve. Franck. Proença. Christine. Gaget. Stefan. Körner. Antje. Kovacs. Peter. Kiess. Wieland. Tichet. Jean. Marre. Michel. Hartikainen. Anna-Liisa. Horber. Fritz. Potoczna. Natascha. Hercberg. Serge. Levy-Marchal. Claire. Pattou. François. Heude. Barbara. Tauber. Maithé. McCarthy. Mark I. Blakemore. Alexandra I F. Montpetit. Alexandre. Polychronakos. Constantin. Weill. Jacques. Coin. Lachlan J M. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. 41. Nature Genetics . 10.1038/ng.301 . 19151714 . 2. 11218794. 8.
  24. Heid. Iris M.. Jackson. Anne U.. Randall. Joshua C.. Winkler. Thomas W.. Qi. Lu. Steinthorsdottir. Valgerdur. Thorleifsson. Gudmar. Zillikens. M. Carola. Speliotes. Elizabeth K.. November 2010. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nature Genetics. 42. 11. 949–960. 10.1038/ng.685. 1546-1718. 3000924. 20935629.
  25. Steinberg. Gregory R.. Kemp. Bruce E.. Watt. Matthew J.. October 2007. Adipocyte triglyceride lipase expression in human obesity. American Journal of Physiology. Endocrinology and Metabolism. 293. 4. E958–964. 10.1152/ajpendo.00235.2007. 0193-1849. 17609260.
  26. Bürger. Marco. Zimmermann. Tobias J.. Kondoh. Yasumitsu. Stege. Patricia. Watanabe. Nobumoto. Osada. Hiroyuki. Waldmann. Herbert. Vetter. Ingrid R.. January 2012. Crystal structure of the predicted phospholipase LYPLAL1 reveals unexpected functional plasticity despite close relationship to acyl protein thioesterases. Journal of Lipid Research. 53. 1. 43–50. 10.1194/jlr.M019851 . free . 1539-7262. 3243480. 22052940.
  27. Pertwee . R G . June 2006 . The pharmacology of cannabinoid receptors and their ligands: an overview . International Journal of Obesity . en . 30 . S1 . S13–S18 . 10.1038/sj.ijo.0803272 . 0307-0565. free . 16570099 .
  28. MacNeil . Douglas J. . NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity Drugs . Current Topics in Medicinal Chemistry . 2007 . en . 7 . 17 . 1721–1733 . 10.2174/156802607782341028. 17979781 .
  29. Book: Kolata, Gina . Rethinking thin: The new science of weight loss - and the myths and realities of dieting . Picador . 2007 . 122 . 978-0-312-42785-6.
  30. Chakravarthy MV, Booth FW . Eating, exercise, and "thrifty" genotypes: Connecting the dots toward an evolutionary understanding of modern chronic diseases . J. Appl. Physiol. . 96 . 1 . 3–10 . 2004 . 14660491 . 10.1152/japplphysiol.00757.2003.
  31. Wells JC . Ethnic variability in adiposity and cardiovascular risk: the variable disease selection hypothesis . Int J Epidemiol . 38 . 1 . 63–71 . February 2009 . 18820320 . 10.1093/ije/dyn183 . free .
  32. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives . J. Exp. Biol. . 214 . 206–29 . 2011 . 21177942 . 10.1242/jeb.048397 . 2 . 3008631. Theodore . Garland Jr . Heidi . Schutz . Mark A. . Chappell . Brooke K. . Keeney . Thomas H. . Meek . Lynn E. . Copes . Wendy . Acosta . Clemens . Drenowatz . Robert C. . Maciel . Gertjan . van Dijk . Catherine M. . Kotz . Joey C. . Eisenmann . Theodore Garland .
  33. 23312289 . 10.1016/j.cmet.2012.12.007 . 3545283 . 17 . 1 . Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice . 2013 . Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, Pan C, Civelek M, Rau CD, Bennett BJ, Mehrabian M, Ursell LK, He A, Castellani LW, Zinker B, Kirby M, Drake TA, Drevon CA, Knight R, Gargalovic P, Kirchgessner T, Eskin E, Lusis AJ. Cell Metab . 141–52.
  34. Yang. Wenjie. Tanika Kelly . Jiang He . Genetic Epidemiology of Obesity. Epidemiologic Reviews. June 12, 2007. 29. 49–61. 10.1093/epirev/mxm004. 17566051. free.
  35. News: Gene variants related to controlling body weight isolated . 14 August 2021 . medicalxpress.com . en.
  36. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity . Science . 2 July 2021 . 373 . 6550 . 10.1126/science.abf8683 . en . 0036-8075. Akbari . Parsa . Gilani . Ankit . Sosina . Olukayode . Kosmicki . Jack A. . Khrimian . Lori . Fang . Yi-Ya . Persaud . Trikaldarshi . Garcia . Victor . Sun . Dylan . Li . Alexander . Mbatchou . Joelle . Locke . Adam E. . Benner . Christian . Verweij . Niek . Lin . Nan . Hossain . Sakib . Agostinucci . Kevin . Pascale . Jonathan V. . Dirice . Ercument . Dunn . Michael . Kraus . William E. . Shah . Svati H. . Chen . Yii-Der I. . Rotter . Jerome I. . Rader . Daniel J. . Melander . Olle . Still . Christopher D. . Mirshahi . Tooraj . Carey . David J. . Berumen-Campos . Jaime . eabf8683 . 34210852 . 235699731 . 1 . 10275396 .
  37. Orthofer . Michael . Valsesia . Armand . Mägi . Reedik . Wang . Qiao-Ping . Kaczanowska . Joanna . Kozieradzki . Ivona . Leopoldi . Alexandra . Cikes . Domagoj . Zopf . Lydia M. . Tretiakov . Evgenii O. . Demetz . Egon . Hilbe . Richard . Boehm . Anna . Ticevic . Melita . Nõukas . Margit . Jais . Alexander . Spirk . Katrin . Clark . Teleri . Amann . Sabine . Lepamets . Maarja . Neumayr . Christoph . Arnold . Cosmas . Dou . Zhengchao . Kuhn . Volker . Novatchkova . Maria . Cronin . Shane J. F. . Tietge . Uwe J. F. . Müller . Simone . Pospisilik . J. Andrew . Nagy . Vanja . Hui . Chi-Chung . Lazovic . Jelena . Esterbauer . Harald . Hagelkruys . Astrid . Tancevski . Ivan . Kiefer . Florian W. . Harkany . Tibor . Haubensak . Wulf . Neely . G. Gregory . Metspalu . Andres . Hager . Jorg . Gheldof . Nele . Penninger . Josef M. . Identification of ALK in Thinness . Cell . 11 June 2020 . 181 . 6 . 1246–1262.e22 . 10.1016/j.cell.2020.04.034 . 32442405 . English . 0092-8674. free .
  38. Chadt . Alexandra . Leicht . Katja . Deshmukh . Atul . Jiang . Lake Q. . Scherneck . Stephan . Bernhardt . Ulrike . Dreja . Tanja . Vogel . Heike . Schmolz . Katja . Kluge . Reinhart . Zierath . Juleen R. . Hultschig . Claus . Hoeben . Rob C. . Schürmann . Annette . Joost . Hans-Georg . Al-Hasani . Hadi . Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity . Nature Genetics . November 2008 . 40 . 11 . 1354–1359 . 10.1038/ng.244 . 18931681 . 4069428 . en . 1546-1718.
  39. Liu . Shannon . Sheng . Liang . Miao . Hongzhi . Saunders . Thomas L. . MacDougald . Ormond A. . Koenig . Ronald J. . Xu . Bin . SRA Gene Knockout Protects against Diet-induced Obesity and Improves Glucose Tolerance . Journal of Biological Chemistry . May 2014 . 289 . 19 . 13000–13009 . 10.1074/jbc.M114.564658. 24675075 . 4036315 . free .
  40. Walley AJ, Asher JE, Froguel P . The genetic contribution to non-syndromic human obesity . Nat. Rev. Genet. . 10. 7. 431–42. June 2009 . 19506576 . 10.1038/nrg2594. 10870369 .
  41. Farooqi. I. Sadaf. Sadaf Farooqi. O’Rahilly. Stephen. Stephen O'Rahilly. Genetics of Obesity in Humans. Endocrine Reviews. 27. 7. 2006. 710–718. 17122358 . 10.1210/er.2006-0040. free.

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