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Genetics of obesity

Topic: Biology

 From HandWiki - Reading time: 10 min

Short description: Relation between obesity and genetic factors
A painting of a dark haired pink cheeked obese nude young female leaning against a table. She is holding grapes and grape leaves in her left hand which cover her genitalia.
A 1680 painting by Juan Carreño de Miranda of a girl presumed to have Prader-Willi syndrome[1]

Template:Human body weight

Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors.[2][3] 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.[4][5] Recent research indicates that environmental influences can lead to epigenetic modifications affecting gene expression related to obesity. These changes can alter metabolic processes and appetite regulation, contributing to obesity development.[6]

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%,[7] with the typical estimate at 50%. Twin studies have consistently shown that genetics account for 40% to 70% of the variation in body mass index (BMI) across individuals (Loos & Yeo, 2022).[8] 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.[9] 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.[10] Some of these obesogenic (weight gain) or leptogenic (weight loss) genes may influence the obese individual's response to weight loss or weight management.[11]

Epigenetic influences and environmental interactions

Epigenetics plays a critical role in obesity susceptibility.[12] Environmental exposures, such as poor maternal nutrition and exposure to endocrine-disrupting chemicals, can induce epigenetic modifications that alter gene expression without changing the DNA sequence.[13] Research on epigenetic transgenerational inheritance suggests that environmental insults can reprogram the epigenome of germline cells (sperm and eggs), leading to obesity susceptibility in future generations.

Gene-environment interactions further complicate obesity risk. Certain genetic variants modify an individual's response to dietary intake, physical activity, and other lifestyle factors.[13] For example, some individuals with specific FTO variants may have an increased appetite and lower satiety, predisposing them to higher caloric intake and weight gain. Conversely, adherence to a healthy diet can significantly reduce the genetic effects on body mass index (BMI), emphasizing the importance of lifestyle modifications even in genetically predisposed individuals.

Specific genetic mechanisms

Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity.[14][15][16] Many candidate genes are highly expressed in the central nervous system.[17] The development of genetic tests, such as MyPhenome, enables the classification of obesity into specific subtypes based on genetic and phenotypic data. This stratification allows for personalized treatment approaches, improving the effectiveness of obesity interventions.[18] Research has identified genes associated with obesity in both humans and animals. For example, the DENND1B gene has been linked to obesity in Labrador retrievers and humans, highlighting shared genetic factors influencing weight gain across species.[19]

Several additional loci have been identified.[20] Also, several quantitative trait loci for BMI have been identified.

Confirmed and hypothesized associations include:

Condition OMIM Locus Notes
leptin deficiency Online Mendelian Inheritance in Man (OMIM) 164160 7q31.3
leptin receptor deficiency Online Mendelian Inheritance in Man (OMIM) 601007 1p31
Ghrelin 605353 3p25.3
Ghrelin receptor 601898 3q26.31
prohormone convertase-1 deficiency Online Mendelian Inheritance in Man (OMIM) 600955 5q15-q21
proopiomelanocortin deficiency Online Mendelian Inheritance in Man (OMIM) 609734 2p23.3
melanocortin-4 receptor polymorphism (MC4R[21]) Online Mendelian Inheritance in Man (OMIM) 155541 18q22
BMIQ1 7q32.3 near D7S1804[22]
BMIQ2 13q14 near D13S257[22]
BMIQ3 6q23-q25 near D6S1009, GATA184A08, D6S2436, and D6S305[23]
BMIQ4 11q24 near D11S1998, D11S4464, and D11S912[23]
BMIQ5 16p13
BMIQ6 20pter-p11.2 near D20S482[24]
INSIG2[21] 2q14.1
FTO[21] 16q12.2 Adults 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.[25] This association disappeared, though, when those with FTO polymorphisms participated in moderately intensive physical activity equivalent to three to four hours of brisk walking.[26]
TMEM18[21] 2p25.3
GNPDA2[21] 4p13
NEGR1[21] 1p31.1
BDNF[21] 11p13
KCTD15[21] 19q13.12 KCTD15 plays a role in transcriptional repression of AP-2α, which in turn, inhibits the activity of C/EBPα, an early inducer of adipogenesis.[27]
KLF14[28] ? 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[29] 16p11.2
MTCH2[29] 11p11.2
PCSK1[29] 5q15-q21
NPC1[30] 18q11-q12
LYPLAL1[31] 616548 1q41 Disputed metabolic function of being either a lipase[32] or a short-chain carboxylesterase.[33]
CB1[34] 114610 6q15
NPY5R[35] 602001 4q32.2

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, less than 10% of offspring of two parents who were of normal weight were obese.[36]

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.[37] 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.[38] Emerging research suggests that genetic factors may contribute to the common phenomenon of weight regain after weight loss, known as yo-yo dieting. These genetic influences can affect metabolic rate and appetite regulation, making sustained weight loss challenging for some individuals.[39]

Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.[40][41]

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.[42]

Monogenic and syndromic obesity

Monogenic obesity results from single-gene mutations that disrupt the body's ability to regulate weight. These cases are rare but often lead to severe early-onset obesity. Studies have identified mutations in genes such as LEP (leptin), LEPR(leptin receptor), MC4R (melanocortin 4 receptor), and POMC (pro-opiomelanocortin), which play crucial roles in appetite regulation and energy balance.[43] Syndromic obesity, a subset of monogenic obesity, is associated with additional developmental and endocrine abnormalities, as seen in conditions like Prader-Willi and Bardet-Biedl syndromes. Research suggests that these rare forms of genetic obesity may be more prevalent in severely obese children than previously estimated due to limited genetic screening availability.

Polygenic obesity

Polygenic obesity results from the combined effect of multiple genes that individually exert a small influence on body weight. Genome-wide association studies (GWAS) have identified numerous loci associated with obesity susceptibility, including the FTO(fat mass and obesity-associated) and MC4R genes.[43] These genes are involved in processes such as appetite regulation, lipid metabolism, and energy homeostasis. Genetic variants in these loci interact with lifestyle factors, influencing an individual's likelihood of developing obesity.

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.[44][45] Other candidate anti-obesity-related genes include ALK,[46] TBC1D1,[47] and SRA1.[48]

Genetic syndromes

The term "non-syndromic obesity" is sometimes used to exclude these conditions.[49] 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.[50]

Current and emerging treatments for genetic obesity

The primary management approach for genetic obesity remains lifestyle interventions, including dietary modifications and physical activity. However, emerging therapies are being developed to target specific genetic pathways. For example, leptin replacement therapy has shown efficacy in treating individuals with leptin deficiency, while melanocortin receptor agonists are being investigated for their potential in addressing MC4R-related obesity.[51] Ongoing clinical trials continue to explore novel pharmacological and gene-based therapies that may offer more effective treatment options for individuals with genetic obesity.

See also

Related:

References

  1. ↑ Mary Jones. "Case Study: Cataplexy and SOREMPs Without Excessive Daytime Sleepiness in Prader Willi Syndrome. Is This the Beginning of Narcolepsy in a Five Year Old?". European Society of Sleep Technologists. http://www.esst.org/newsletter2000.htm. 
  2. ↑ "Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective". Mol. Genet. Genomics 290 (4): 1191–221. Mar 2015. doi:10.1007/s00438-015-1015-9. PMID 25749980. 
  3. ↑ Albuquerque, David; Nóbrega, Clévio; Manco, Licínio; Padez, Cristina (7 July 2017). "The contribution of genetics and environment to obesity". British Medical Bulletin Advance articles (1): 159–173. doi:10.1093/bmb/ldx022. PMID 28910990. 
  4. ↑ Kushner, Robert (2007). Treatment of the Obese Patient (Contemporary Endocrinology). Totowa, NJ: Humana Press. p. 158. ISBN 978-1-59745-400-1. https://books.google.com/books?id=vWjK5etS7PMC. Retrieved April 5, 2009. 
  5. ↑ "Obesity in anaesthesia and intensive care". Br J Anaesth 85 (1): 91–108. July 2000. doi:10.1093/bja/85.1.91. PMID 10927998. 
  6. ↑ Bheda, Poonam (2021), "Aging-associated changes in metabolic regulation of epigenetic modifications and gene expression", Epigenetics and Metabolomics (Elsevier): pp. 75–95, doi:10.1016/b978-0-323-85652-2.00006-3, ISBN 978-0-323-85652-2 
  7. ↑ "Genetic epidemiology of obesity". Epidemiol Rev 29: 49–61. 2007. doi:10.1093/epirev/mxm004. PMID 17566051. 
  8. ↑ Loos, Ruth J. F.; Yeo, Giles S. H. (February 2022). "The genetics of obesity: from discovery to biology" (in en). Nature Reviews Genetics 23 (2): 120–133. doi:10.1038/s41576-021-00414-z. ISSN 1471-0064. PMID 34556834. 
  9. ↑ Lyon, Helen N; Hirschhorn, Joel N (2005-07-01). "Genetics of common forms of obesity: a brief overview" (in en). The American Journal of Clinical Nutrition 82 (1): 215S–217S. doi:10.1093/ajcn/82.1.215S. ISSN 0002-9165. PMID 16002823. https://academic.oup.com/ajcn/article/82/1/215S/4863389. 
  10. ↑ "Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss". Arterioscler. Thromb. Vasc. Biol. 26 (5): 968–76. May 2006. doi:10.1161/01.ATV.0000216787.85457.f3. PMID 16627822. 
  11. ↑ Hainer, Vojtĕch; Hermann Toplak; Asimina Mitrakou (February 2008). "Treatment Modalities of Obesity: What fits whom?". Diabetes Care 31: 269–277. doi:10.2337/dc08-s265. PMID 18227496. 
  12. ↑ King, S. E.; Skinner, M. K. (2025-02-03). "Epigenetic Transgenerational Inheritance of Obesity Susceptibility - PMC". Trends in Endocrinology and Metabolism: Tem 31 (7): 478–494. doi:10.1016/j.tem.2020.02.009. PMID 32521235. 
  13. ↑ 13.0 13.1 Heianza, Yoriko; Qi, Lu (2017-04-07). "Gene-Diet Interaction and Precision Nutrition in Obesity". International Journal of Molecular Sciences 18 (4): 787. doi:10.3390/ijms18040787. ISSN 1422-0067. PMID 28387720. 
  14. ↑ Lee YS (January 2009). "The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature". Ann. Acad. Med. Singap. 38 (1): 34–44. doi:10.47102/annals-acadmedsg.V38N1p34. PMID 19221669. http://www.annals.edu.sg/pdf/38VolNo1Jan2009/V38N1p34.pdf. Retrieved 2009-06-08. 
  15. ↑ "Researchers discover DNA variants significantly influence body fat distribution" (in en-us). https://medicalxpress.com/news/2019-02-dna-variants-significantly-body-fat.html. 
  16. ↑ Lindgren, Cecilia M.; North, Kari E.; Loos, Ruth J. F.; Cupples, L. Adrienne; Hirschhorn, Joel N.; Kutalik, Zoltán; Rotter, Jerome I.; Mohlke, Karen L. et al. (18 February 2019). "Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution" (in en). Nature Genetics 51 (3): 452–469. doi:10.1038/s41588-018-0334-2. ISSN 1546-1718. PMID 30778226. 
  17. ↑ "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation". Nat. Genet. 41 (1): 25–34. January 2009. doi:10.1038/ng.287. PMID 19079261. 
  18. ↑ Park, Alice (2024-10-30). "Phenomix Sciences MyPhenome: the 200 Best Inventions of 2024" (in en). TIME. https://time.com/7094906/phenomix-sciences-myphenome/. Retrieved 2025-03-24. 
  19. ↑ Correspondent, Rhys Blakely, Science (2025-03-06). "The 'hungry genes' that make labradors — and humans — fat" (in en). https://www.thetimes.com/uk/science/article/hungry-genes-fat-obesity-labradors-dennd1b-qv3w9g2dr. 
  20. ↑ "OMIM - OBESITY". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601665. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 "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. doi:10.1038/oby.2009.159. PMID 19478790. 
  22. ↑ 22.0 22.1 "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. doi:10.1086/338144. PMID 11713718. 
  23. ↑ 23.0 23.1 "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. doi:10.1086/343822. PMID 12355400. 
  24. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named pmid12774034
  25. ↑ "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. doi:10.1126/science.1141634. PMID 17434869. Bibcode: 2007Sci...316..889F. 
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  27. ↑ Skoblov, Mikhail; Andrey Marakhonov; Ekaterina Marakasova; Anna Guskova; Vikas Chandhoke; Aybike Birerdinc; Ancha Baranova (2013). "Protein partners of KCTD proteins provide insights about their functional roles in cell differentiation and vertebrate development". BioEssays 35 (7): 586–596. doi:10.1002/bies.201300002. PMID 23592240. 
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  29. ↑ 29.0 29.1 29.2 "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. doi:10.1093/hmg/ddp041. PMID 19164386. 
  30. ↑ Meyre, David; Delplanque, Jérôme; Chèvre, Jean-Claude; Lecoeur, CéCile; Lobbens, StéPhane; Gallina, Sophie; Durand, Emmanuelle; Vatin, Vincent et al. (18 January 2009). "Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations". Nature Genetics 41 (2): 157–9. doi:10.1038/ng.301. PMID 19151714. 
  31. ↑ Heid, Iris M.; Jackson, Anne U.; Randall, Joshua C.; Winkler, Thomas W.; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M. Carola et al. (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. doi:10.1038/ng.685. ISSN 1546-1718. PMID 20935629. 
  32. ↑ 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. doi:10.1152/ajpendo.00235.2007. ISSN 0193-1849. PMID 17609260. 
  33. ↑ 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. doi:10.1194/jlr.M019851. ISSN 1539-7262. PMID 22052940. 
  34. ↑ Pertwee, R G (June 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview" (in en). International Journal of Obesity 30 (S1): S13–S18. doi:10.1038/sj.ijo.0803272. ISSN 0307-0565. PMID 16570099. 
  35. ↑ MacNeil, Douglas J. (2007). "NPY Y1 and Y5 Receptor Selective Antagonists as Anti-Obesity Drugs" (in en). Current Topics in Medicinal Chemistry 7 (17): 1721–1733. doi:10.2174/156802607782341028. PMID 17979781. https://www.eurekaselect.com/article/23898. 
  36. ↑ Kolata, Gina (2007). Rethinking thin: The new science of weight loss - and the myths and realities of dieting. Picador. p. 122. ISBN 978-0-312-42785-6. 
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  38. ↑ Wells JC (February 2009). "Ethnic variability in adiposity and cardiovascular risk: the variable disease selection hypothesis". Int J Epidemiol 38 (1): 63–71. doi:10.1093/ije/dyn183. PMID 18820320. 
  39. ↑ Bee, Peta (2024-12-06). "Weight loss: The real reasons the pounds creep back on" (in en). https://www.thetimes.com/life-style/health-fitness/article/why-am-i-not-losing-weight-8b9pwrsp9. 
  40. ↑ Garland Jr, Theodore; Schutz, Heidi; Chappell, Mark A.; Keeney, Brooke K.; Meek, Thomas H.; Copes, Lynn E.; Acosta, Wendy; Drenowatz, Clemens et al. (2011). "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 (2): 206–29. doi:10.1242/jeb.048397. PMID 21177942. Bibcode: 2011JExpB.214..206G. 
  41. ↑ "Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice". Cell Metab 17 (1): 141–52. 2013. doi:10.1016/j.cmet.2012.12.007. PMID 23312289. 
  42. ↑ Yang, Wenjie; Tanika Kelly; Jiang He (June 12, 2007). "Genetic Epidemiology of Obesity". Epidemiologic Reviews 29: 49–61. doi:10.1093/epirev/mxm004. PMID 17566051. 
  43. ↑ 43.0 43.1 "Genomics and Obesity: We Need Both Population and Individualized Approaches in the Prevention and Management of Obesity | Blogs | CDC" (in en-us). 2018-01-29. https://blogs.cdc.gov/genomics/2018/01/29/genomics-and-obesity/. 
  44. ↑ "Gene variants related to controlling body weight isolated" (in en). medicalxpress.com. https://medicalxpress.com/news/2021-07-gene-variants-body-weight-isolated.html. 
  45. ↑ Akbari, Parsa et al. (2 July 2021). "Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity" (in en). Science 373 (6550). doi:10.1126/science.abf8683. ISSN 0036-8075. PMID 34210852. 
  46. ↑ Orthofer, Michael; Valsesia, Armand; Mägi, Reedik; Wang, Qiao-Ping; Kaczanowska, Joanna; Kozieradzki, Ivona; Leopoldi, Alexandra; Cikes, Domagoj et al. (11 June 2020). "Identification of ALK in Thinness" (in English). Cell 181 (6): 1246–1262.e22. doi:10.1016/j.cell.2020.04.034. ISSN 0092-8674. PMID 32442405. 
  47. ↑ Chadt, Alexandra; Leicht, Katja; Deshmukh, Atul; Jiang, Lake Q.; Scherneck, Stephan; Bernhardt, Ulrike; Dreja, Tanja; Vogel, Heike et al. (November 2008). "Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity" (in en). Nature Genetics 40 (11): 1354–1359. doi:10.1038/ng.244. ISSN 1546-1718. PMID 18931681. 
  48. ↑ Liu, Shannon; Sheng, Liang; Miao, Hongzhi; Saunders, Thomas L.; MacDougald, Ormond A.; Koenig, Ronald J.; Xu, Bin (May 2014). "SRA Gene Knockout Protects against Diet-induced Obesity and Improves Glucose Tolerance". Journal of Biological Chemistry 289 (19): 13000–13009. doi:10.1074/jbc.M114.564658. PMID 24675075. 
  49. ↑ "The genetic contribution to non-syndromic human obesity". Nat. Rev. Genet. 10 (7): 431–42. June 2009. doi:10.1038/nrg2594. PMID 19506576. 
  50. ↑ Farooqi, I. Sadaf; O'Rahilly, Stephen (2006). "Genetics of Obesity in Humans". Endocrine Reviews 27 (7): 710–718. doi:10.1210/er.2006-0040. PMID 17122358. 
  51. ↑ Faccioli, N.; Poitou, C.; Clément, K.; Dubern, B. (2025-02-03). "Current Treatments for Patients with Genetic Obesity - PMC". Journal of Clinical Research in Pediatric Endocrinology 15 (2): 108–119. doi:10.4274/jcrpe.galenos.2023.2023-3-2. PMID 37191347. 

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