Molecular Biology of Human Obesity: Nonepigenetics in Comparison with Epigenetic Processes

  • David AlbuquerqueEmail author
  • Licínio Manco
  • Clévio Nóbrega
Reference work entry


The rapid increase in the prevalence of obesity worldwide is undoubtedly linked to a “social globalization”; however, a genetic component also accounts for individual differences in the predisposition to weight gain. The contribution of candidate gene studies identified several mutations related to obesity in the leptin/melanocortin pathway, which is involved in the regulation of food intake and energy expenditure. Other studies including genome-wide association study (GWAS) found genetic variants across the genome associated with the susceptibility risk to develop obesity. However, until now, all these genetic variations explain only a small fraction of the estimated heritability of obesity. Furthermore, our genome is not likely to change profoundly through mutations in few generations as to explain the rapid increase in the prevalence of obesity. More recently, epigenetic regulation of gene expression emerged as a potential factor that might explain differences in obesity risk. Several genes have been found whose expression is controlled by epigenetic factors. Diet and nutrition appear to be the most important factors influencing epigenetic mechanisms leading to an obese phenotype. Effectively, our diet suffered drastic changes in the last decades with the incorporation of new nutrients and bioactive molecules. Several studies performed both in humans and animal models found differences at different epigenetic mechanisms between obese and non-obese individuals. However, our knowledge on which and how nutrients affect epigenetic mechanisms remains limited. Currently, it is thought that the obesity condition might be a consequence of an interplay between genetic, epigenetic, and lifestyle factors. In the near future, studies based on alterations on gene expression due to environmental signals will help to draw a more complete picture of the obesity etiology.


Obesity Genetic of obesity Mutations Genome-wide association study (GWAS) Energy homeostasis Leptin/melanocortin pathway Single-nucleotide polymorphism (SNP) Heritability Copy number variation (CNV) DNA methylation Histone modification MicroRNA Fetal programming 

List of Abbreviations


Alpha-melanocyte-stimulating hormone


Aryl-hydrocarbon receptor repressor


Yellow agouti allele


Brain-derived neurotrophic factor


Body mass index


Cyclic adenosine monophosphate


Methyl group


Central nervous system


Copy number variations




Deoxyribonucleic acid


DNA methyltransferases


Developmental origins of health and disease


Genome-wide association study


Hypoxia-inducible factor 3 alpha subunit




Leptin receptor


Melanocortin 4 receptor


Nicotinamide N-methyltransferase


Neuropeptide Y


Neurotrophic receptor tyrosine kinase 2


Proprotein convertase subtilisin/kexin type 1




Prader-Willi syndrome


Ribonucleic acid


Single-minded homolog 1


Tropomyosin receptor kinase B


  1. Albuquerque D, Estévez MN, Víbora PB et al (2014) Novel variants in the MC4R and LEPR genes among severely obese children from the Iberian population. Ann Hum Genet 78:195–207CrossRefGoogle Scholar
  2. Albuquerque D, Manco L, Nóbrega C (2015a) Epigenetics of human obesity: a link between genetics and nutrition. In: Nóbrega C, Rodríguez-López R (eds) Molecular mechanisms underpinning the development of obesity. Springer, Basel, pp 101–127Google Scholar
  3. Albuquerque D, Stice E, Rodríguez-López R et al (2015b) Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective. Mol Gen Genomics 290:1191–1221CrossRefGoogle Scholar
  4. Arner P, Kulyté A (2015) MicroRNA regulatory networks in human adipose tissue and obesity. Nat Rev Endocrinol 11:276–288CrossRefGoogle Scholar
  5. Aslibekyan S, Demerath EW, Mendelson M et al (2015) Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference. Obesity 23:1493–1501CrossRefGoogle Scholar
  6. Burris HH, Baccarelli AA, Byun H-M et al (2015) Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight. Epigenetics 10:913CrossRefGoogle Scholar
  7. Chavatte-Palmer P, Tarrade A, Rousseau-Ralliard D (2016) Diet before and during pregnancy and offspring health: the importance of animal models and what can be learned from them. Int J Environ Res Public Health 13:E586CrossRefGoogle Scholar
  8. Choi S-W, Friso S (2010) Epigenetics: a new bridge between nutrition and health. Adv Nutr An Int Rev J 1:8–16CrossRefGoogle Scholar
  9. Clément K, Ferré P (2003) Genetics and the pathophysiology of obesity. Pediatr Res 53:721–725CrossRefGoogle Scholar
  10. Coll AP, Raffin-Sanson ML, de Keyzer Y et al (2007) Effects of pro-opiomelanocortin (POMC) on food intake and body weight: mechanisms and therapeutic potential? Clin Sci (Lond) 113:171–182CrossRefGoogle Scholar
  11. Crujeiras AB, Campion J, Díaz-Lagares A et al (2013) Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: a translational study. Regul Pept 186:1–6CrossRefGoogle Scholar
  12. Crujeiras AB, Diaz-Lagares A, Moreno-Navarrete JM et al (2016) Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Transl Res 178:13–24CrossRefGoogle Scholar
  13. Demerath EW, Guan W, Grove ML et al (2015) Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet 24:4464–4479CrossRefGoogle Scholar
  14. Dick KJ, Nelson CP, Tsaprouni L et al (2014) DNA methylation and body-mass index: a genome-wide analysis. Lancet 383:1990–1998CrossRefGoogle Scholar
  15. Dolinoy DC (2008) The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev 66(Suppl 1):S7–11CrossRefGoogle Scholar
  16. Dong S-S, Guo Y, Zhu D-L et al (2016) Epigenomic elements analyses for promoters identify ESRRG as a new susceptibility gene for obesity-related traits. Int J Obes 40:1170–1176CrossRefGoogle Scholar
  17. Drake AJ, Reynolds RM (2010) Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 140:387–398CrossRefGoogle Scholar
  18. Feinleib M, Garrison RJ, Fabsitz R et al (1977) The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol 106:284–285CrossRefGoogle Scholar
  19. Gamero-Villarroel C, Gordillo I, Carrillo JA et al (2014) BDNF genetic variability modulates psychopathological symptoms in patients with eating disorders. Eur Child Adolesc Psychiatry 23:669–679CrossRefGoogle Scholar
  20. Gillberg L, Perfilyev A, Brøns C et al (2016) Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding. Diabetologia 59:799–812CrossRefGoogle Scholar
  21. Goryakin Y, Lobstein T, James WPT et al (2015) The impact of economic, political and social globalization on overweight and obesity in the 56 low and middle income countries. Soc Sci Med 133:67–76CrossRefGoogle Scholar
  22. Gray J, Yeo G, Hung C et al (2007) Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity. Int J Obes 31:359–364CrossRefGoogle Scholar
  23. Haggarty P (2013) Epigenetic consequences of a changing human diet. Proc Nutr Soc 72:1–9CrossRefGoogle Scholar
  24. Hernández-Aguilera A, Fernández-Arroyo S, Cuyàs E et al (2016) Epigenetics and nutrition-related epidemics of metabolic diseases: current perspectives and challenges. Food Chem Toxicol 96:191–204CrossRefGoogle Scholar
  25. Hinney A, Volckmar A-L, Knoll N (2013) Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci 114:147–191CrossRefGoogle Scholar
  26. Jufvas Å, Strålfors P, Vener AV (2011) Histone variants and their post-translational modifications in primary human fat cells. PLoS One 6:e15960CrossRefGoogle Scholar
  27. Keller M, Kralisch S, Rohde K et al (2014) Global DNA methylation levels in human adipose tissue are related to fat distribution and glucose homeostasis. Diabetologia 57:2374–2383CrossRefGoogle Scholar
  28. Kornfeld J-W, Baitzel C, Könner AC et al (2013) Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494:111–115CrossRefGoogle Scholar
  29. Krude H, Biebermann H, Luck W et al (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157CrossRefGoogle Scholar
  30. Kühnen P, Handke D, Waterland RA et al (2016) Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity. Cell Metab 24:502–509CrossRefGoogle Scholar
  31. Lee YS (2009) The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature. Ann Acad Med Singap 38:34–44PubMedGoogle Scholar
  32. Li J, Zhou C, Li J et al (2015) Global correlation analysis for microRNA and gene expression profiles in human obesity. Pathol Res Pract 211:361–368CrossRefGoogle Scholar
  33. Liu M, Li L, Chu J et al (2016) Os 33-03 serum n1-methylnicotinamide is associated with obesity and diabetes in Chinese. J Hypertens 34:e393–e394CrossRefGoogle Scholar
  34. Lo KA, Bauchmann MK, Baumann AP et al (2011) Genome-wide profiling of H3K56 acetylation and transcription factor binding sites in human adipocytes. PLoS One 6:e19778CrossRefGoogle Scholar
  35. McKay JA, Mathers JC (2016) Maternal folate deficiency and metabolic dysfunction in offspring. Proc Nutr Soc 75:90–95CrossRefGoogle Scholar
  36. Meerson A, Traurig M, Ossowski V et al (2013) Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α. Diabetologia 56:1971–1979CrossRefGoogle Scholar
  37. Mehanna E, Ghattas MH, Mesbah NM et al (2015) Association of MicroRNA-146a rs2910164 gene polymorphism with metabolic syndrome. Folia Biol 61:43–48Google Scholar
  38. Mendiratta MS, Yang Y, Balazs AE et al (2011) Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation. Int J Pediatr Endocrinol 2011(1):5CrossRefGoogle Scholar
  39. Montague CT, Farooqi IS, Whitehead JP et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908CrossRefGoogle Scholar
  40. Navarro E, Funtikova AN, Fíto M et al (2016) Prenatal nutrition and the risk of adult obesity: long-term effects of nutrition on epigenetic mechanisms regulating gene expression. J Nutr Biochem 39:1–14CrossRefGoogle Scholar
  41. Ng M, Fleming T, Robinson M et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781CrossRefGoogle Scholar
  42. Oswal A, Yeo GSH (2007) The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes Rev 8:293–306CrossRefGoogle Scholar
  43. Pan H, Lin X, Wu Y et al (2015) HIF3A association with adiposity: the story begins before birth. Epigenomics 7:937CrossRefGoogle Scholar
  44. Perera F, Herbstman J (2011) Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol 31:363–373CrossRefGoogle Scholar
  45. Pritchard LE, Turnbull AV, White A (2002) Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. J Endocrinol 172:411–421CrossRefGoogle Scholar
  46. Rau H, Reaves BJ, O’Rahilly S et al (1999) Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport. Endocrinology 140:1718–1723CrossRefGoogle Scholar
  47. Rönn T, Volkov P, Davegårdh C et al (2013) A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet 9:e1003572CrossRefGoogle Scholar
  48. Russo VEA, Martienssen RA, Riggs AD (1996) Epigenetic mechanisms of gene regulation. Cold Spring Harbor Monograph Archive 32:i–xiiGoogle Scholar
  49. Silventoinen K, Rokholm B, Kaprio J et al (2010) The genetic and environmental influences on childhood obesity: a systematic review of twin and adoption studies. Int J Obes 34:29–40CrossRefGoogle Scholar
  50. Singh G, Danaei G, Farzadfar F et al (2016) Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387:1377–1396CrossRefGoogle Scholar
  51. Soubry A, Schildkraut JM, Murtha A et al (2013) Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 11:29CrossRefGoogle Scholar
  52. Soubry A, Murphy SK, Wang F et al (2015) Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes 39:650–657CrossRefGoogle Scholar
  53. Stunkard AJ, Foch TT, Hrubec Z (1986a) A twin study of human obesity. JAMA 256:51–54CrossRefGoogle Scholar
  54. Stunkard AJ, Sørensen TI, Hanis C et al (1986b) An adoption study of human obesity. N Engl J Med 314:193–198CrossRefGoogle Scholar
  55. Tateishi K, Okada Y, Kallin EM et al (2009) Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458:757–761CrossRefGoogle Scholar
  56. van Dijk SJ, Molloy PL, Varinli H et al (2015) Epigenetics and human obesity. Int J Obes 39:85–97CrossRefGoogle Scholar
  57. van den Dungen MW, Murk AJ, Kok DE et al (2016) Comprehensive DNA methylation and gene expression profiling in differentiating human adipocytes. J Cell Biochem 117:2707–2718CrossRefGoogle Scholar
  58. Vickers MH (2014) Early life nutrition, epigenetics and programming of later life disease. Forum Nutr 6:2165–2178Google Scholar
  59. Voisin S, Almén MS, Zheleznyakova GY et al (2015) Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers. Genome Med 7:103CrossRefGoogle Scholar
  60. Volkov P, Olsson AH, Gillberg L et al (2016) A genome-wide mQTL analysis in human adipose tissue identifies genetic variants associated with DNA methylation, gene expression and metabolic traits. PLoS One 11:e0157776CrossRefGoogle Scholar
  61. Waddington CH (2014) The strategy of the genes: a discussion of some aspects of theoretical biology, Routledge library edition: 20th century science. Routledge, AbingdonCrossRefGoogle Scholar
  62. Wang S, Song J, Yang Y et al (2015) HIF3A DNA methylation is associated with childhood obesity and ALT. PLoS One 10:e0145944CrossRefGoogle Scholar
  63. Wheatley KE, Nogueira LM, Perkins SN, Hursting SD (2011) Differential effects of calorie restriction and exercise on the adipose transcriptome in diet-induced obese mice. J Obes 2011:265417CrossRefGoogle Scholar
  64. Whitaker RC (2004) Predicting preschooler obesity at birth: the role of maternal obesity in early pregnancy. Pediatrics 114(1):e29–e36CrossRefGoogle Scholar
  65. Whitaker RC, Wright JA, Pepe MS, Seidel KD, Dietz WH (1997) Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med 337(13):869–873CrossRefGoogle Scholar
  66. Williams L, Seki Y, Delahaye F, Cheng A, Fuloria M, Hughes Einstein F, Charron MJ (2016) DNA hypermethylation of CD3(+) T cells from cord blood of infants exposed to intrauterinegrowth restriction. Diabetologia 59(8):1714–1723CrossRefGoogle Scholar
  67. Xu B, Xie X (2016) Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci 17(5):282–292CrossRefGoogle Scholar
  68. Yan J, Liu L, Zhu Y, Huang G, Wang PP (2014) The association between breastfeeding and childhood obesity: a meta-analysis. BMC Public Health 14:1267CrossRefGoogle Scholar
  69. Yang J, Loos RJ, Powell JE et al (2012) FTO genotype is associated with phenotypic variability of body mass index. Nature 490(7419):267–272CrossRefGoogle Scholar
  70. Youngson NA, Morris MJ (2013) What obesity research tell us about epigenetic mechanisms. Philos Trans R Soc Lond B Biol Sci 368(1609):20110337CrossRefGoogle Scholar
  71. Zegers D, Beckers S, Hendrickx R, Van Camp JK, de Craemer V, Verrijken A et al (2014) Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity. Int J Obes 38:1000–1004CrossRefGoogle Scholar
  72. Zhang Q, Ramlee MK, Brunmeir R et al (2012) Dynamic and distinct histone modifications modulate the expression of key adipogenesis regulatory genes. Cell Cycle 11:4310CrossRefGoogle Scholar
  73. Zhou JY, Li L (2014) MicroRNAs are key regulators of brown adipogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 1841:1590–1595CrossRefGoogle Scholar
  74. Zhu J-G, Xia L, Ji C-B et al (2012) Differential DNA methylation status between human preadipocytes and mature adipocytes. Cell Biochem Biophys 63:1–15CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • David Albuquerque
    • 1
    Email author
  • Licínio Manco
    • 1
  • Clévio Nóbrega
    • 2
    • 3
  1. 1.Department of Life Sciences, Research Centre for Anthropology and Health (CIAS)University of CoimbraCoimbraPortugal
  2. 2.Department of Biomedical Sciences and Medicine, Center for Biomedical Research (CBMR)University of AlgarveFaroPortugal
  3. 3.Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal

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