Aggiornamento monografico
Genetica ed epigenetica dell'obesità
GENETICS AND EPIGENETICS OF OBESITY
Franco Panizon
Dipartimento di Scienze della Riproduzione e dello Sviluppo, Università di Trieste
Settembre 2009 - pagg. 431 -439
Abstract
Obesity is, first of all, a matter of genetics and it better develops in conditions of more food
availability and sedentary lives as it occurs in rich countries. The control of the energetic
balance (intake > accumulation > dispersion) is connected to a complex system of signal
molecules that correlate the hypothalamus, the adipocyte, muscular tissue and the adrenal
gland. Up to now 7 types of monogenic obesity have been identified in mice or rats but
there are few homologous correspondences in men; however it is possible to say that
“common” obesity is polygenic, namely due to a number of genes having a quantitative
effects (genes QTL - Quantitative Trait Loci). Moreover, the relationship between “common”
obesity and single nucleotide polymorhisms (SNP) has been described. Among these
genetic variations a special role is attributed to the polymorhisms of a gene recently identified,
the FTO (Fat Mass and Obesity Associated). Furthermore, it is well known that remarkable
food restrictions during pregnancy (especially in preterm infants) as well as an
excessive caloric intake with a rapid ponderal growth after birth cause a rearrangement
of the epigenoma that during early adulthood will lead to an obese phenotype mainly associated
with metabolic syndrome.
Parole chiave
Suggerite dall'AI
Classificazione MeSH
Bibliografia
Biologia molecolare e genetica umana
1. Wardie J, Carnell S, Haworth CM, Plomin R. Evidence for a strong genetic influence in childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 2008;87:398-404.
2. Musani SK, Erickson E. Allison DB. Obesity- still highly heritable after all these years. Amer J Clin Nutr 2008;87:275-6.
3. Donohoue P. Obesity. In: Behrman RE, Kliegman RM, Jenson HB (Eds.). Nelson Textbook of Pediatrics, 17th ed. Philadelphia: Saunders, 2004:173-7.
4. Shuldiner AR, Yang R, Gong DW. Resisting obesity and insulin resistance. The emerging role of the adipocyte as an endocrine organ. N Engl J Med 2001;345:1345-9.
5. Stepan CM, Bailey ST, Bhat S. The hormone resistine links obesity and diabetes. Nature 2001;409:307-12.
6. O’Railly S. Human obesity and insulin resistance: lessons from experiments of nature. Novartis Found Symp 2007;286:13-20.
7. van Hammerlen V, Eikson A, Astroem G, et al. Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis. Diabetes 2008;57:378-6.
8. O’Rally S, Farooqui IS. Recent advances in the genetics of severe childhood obesity. Arch Dis Child 2000;83:31-9. Obesità monogeniche
9. Dubern B, Clement K, Pelloux V. Mutation analysis of melanocortin-4 receptor, Agouti-related protein, and alpha-melanocyte stimulating hormone genes in severely obese children. J Pediatr 2001;139:204-11.
10. Graham KS, Leibel RI. Yellow mice, red hair, and childhood obesity: the melanocortine pathway of energy homeostasis. J Pediatr 2001;139:177-85.
11. Habener JF. Detective melanocortin 4 receptor in hyperfagia and morbid obesity. N Engl J Med 2003;348:1160-5.
12. Farooqui S, Keogh JM, Yeo GSH. Clinical spectrum of obesity and mutations in melanocortin 4 receptor gene. N Engl J Med 2003;348:1085-7.
13. Farooqui IS, Wangenstess T, Collins S. Clinical and molecular genetic spectrum of congenital deficiency of the leptine receptor. N Engl J Med 2007;356:237-47.
14. Musso G, Gambino R, De Michieli E, Dirazzo M, Pagano G, Casasder M. Adiponectine gene polimorphism modulate acute adiponectin response to dietary fat. Possibile pathogenetic role in NASH. Hepatology 2008; 47:1167-77. Polimorfismi genetici
15. Reue K. The role of lipin-1 in adipogenesis and lipid metabolism. Novartis Found Symp 2007;286:68-71.
16. Kinik ST, Ozbeck N, Yuce M. Yaziki AC, Verdi H, Atac PB. PAI-1 gene 4G/5G polymorphism, cytokine level and the relations with metabolic parameters in obese children. Thromb Haemost 2008;99:352-6.
17. Popko K, Gorska E, Wasik M, et al. Frequency and distribution of leptin receptor gene polymorphism in obstructive sleep apnea. J Physiol Pharmacol 2007;58:S51-S61.
18. Loos RJ, Bouchar C. FTO. The first gene contributing to common forms of human obesity. Obes Rev 2008;9:246-50.
19. Chu X, Erdman R, Susek M, et al. Association of morbid obesity with FTO and INSIGH2 allelic variants. Discussion Arch Surg 2008; 143:235-40.
20. Do R, Bailey SD, Desbiens K, et al. Genetic variants of FTO influence adiposity, insuline sensitivity, leptin levels and resting metabolic rate in the Quebec family study. Diabetes 2008;57:1147-50.
21. Jacobsson JA, Danilesson P, Svensson V, et al. Major gender differences in association of FTO gene variant among severely obese children with obesity and obesity-related phenotypes. Biochem Biophys Res Commun 2008;368:476-82.
22. Lin RCY, Wang YS, Morris BJ. High penetrance, overweight and glucocorticoid receptor variant: case-control study. BMJ 2000;319: 1337.
23. Wang GJ, Volkow ND, Logan J. Brain dopamine and obesity. Lancet 2001;357:354.
24. Xinli W, Xiaomei T, Meihua P, Song L. Association of a mutation in beta3-adrenergic receptor gene with obesity and response to dietary intervention in Chinese children. Acta Paediatr 2001;90:1233. Rapporto gene-ambiente
25. Soerensen TH, Sabroe S, Rothman KJ. Relation between weight and leght at birth and body mass index in young adulthood: cohort study. BJM 1997;315:1137-43.
26. Hanson MA, Gluckman PD. Developmental origins of health and disease: new insight. Basic Clin Pharmacol Toxicol 2008;102:90-3.
27. Vickers MH. Developmental programming and adult obesity. The role of leptine. Curr Opinion Endocrinol Diabetes Obes 2007;14: 17-22.
28. Whithaker RC, Dietz WH. Role of perinatal environment in the development of obesity. J Pediatr 1998;132:768-73.
29. Ravelli ACJ, van der Meulen JHP, Michels RPJ. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998;351:173-6.
30. Fioretto ML, Davis TA, Schocknecht P. Both maternal over-and-undernutrition during gestation increases the adiposity of young adults pregnancy in rats. Obes Res 1995;3: 131-8.
31. Kinra S, Baumer JH, Daver Smith G. Early growth and childhood obesity. A historical cohort study. Arch Dis Child 2005;90:1122-7.
32. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5-20.
33. Hesse V, Voigt M, Salzler A. Alteration in height, weight, and body mass index of newborn, children, and young adults in Eastern germany, after German reunification. J Pediatr 2003;142:259-65. Epigenetica
34. Waddington CH. The epigenotype. Endeavour 1942;1:18-20.
35. Jablonka E, Lamb MJ. The changing concept of epigenetics. Ann NY Acad Sci 2002; 981:82-96.
36. Bird A. Perceptions of epigenetics. Nature 2007;447:396-8.
37. Roloff TC, Nuber UA. Chromatin, epigenetics and stem cells. Eur J Cell Biol 2005;84: 123-35.
38. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet 2000;1:11-9.
39. von Kries R, Koletzko B, Sauerwald T, et al. Breast feeding and obesity: cross sectional study. BMJ 1999;319:147-50.
40. Gillman MW, Rifas-Shiman SL, Frazier AL, et al. Family dinner and diet quality among older children and adolescents. Arch Fam Med 2000;9:235-40.
41. Robinson TN. Reducing children’s television viewing to prevent obesity: a randomized controlled trial. JAMA 1999;282:1561-7.
42. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome. Diabetes 2005;54:1899-906.
43. Dabalea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risk for type 2 diabetes and obesity. A study of discordant sibships. Diabetes 2000;49: 2208-11.
44. Issa JP. Epigenetic variation and human diseases. J Nutr 2002;132:2388S-92S.
45. Frontiera M, Dickins B, Plagge A, Kelsey G. Imprinted genes, postnatal adaptation and enduring effects on energy homeostasis. Adv Exp Med Biol 2008;626:41-61. Fattori di rischio
46. Washington RL. Evidence-based medicine and the obesogen environment. J Pediatr 2006;149:5-7.
47. Davidson KK, Marshall SJ, Birch LL. Cross-sectional and longitudinal association between TV-viewing and girl’s body mass index. J Pediatr 2006;149-32-8.
48. Dencker M, Thomson O, Karlsson MK. Daily physical activity related to body fat in children aged 8-11 years. J Pediatr 2006;49:38- 41.
49. Tosche AM, Vignerova J, Lhostka L. Overweight and obesity in 6-14-year-old Czech children in 1991. Protective effect of breast feeding. J Pediatr 2002;141:764-9.
50. Gillman MW. Breast feeding and obesity. J Pediatr 2002;141:749-50.
51. Li L, Parson TJ, Power C. Breast feeding and obesity in childhood: cross sectional study. BMJ 2003;327:904-9.
52. Victora CG, Barros F, Lima RC, et al. Anthropometry and body composition of 18-yearold men according to the duration of breast feeding: birth cohort study from Brazil. BMJ 2003;327:879-83.
53. Reilly JJ, Armstrong J, Dorosty AR. Early life risk factors for obesity in childhood: cohort study. BMJ 2005;330:1357-63.
54. Davson KK, Francis LA, Birch LL. Links between parents’ and girls’ television viewing behaviors: a longotudinal study. J Pediatr 2005;147:436-70.
55. Viner RM, Cole IJ. Television viewing in early childhood predicts adult body mass index. J Pediatr 2005;147:429-35.
56. Kuepper-Nybelen J, lamerz A, Bruning N. Major differences in prevalence of overweight according to nationality in preschool children living in Germany: determinants and public health implications. Arch Dis Child 2005;90: 359-65.
57. Sherry B, Mei Z, Seanlon S. Trends in state-specific prevalence of overweight and underweight in 2-through 4-year-old children from low-income families, from 1989 through
2000. Arch Pediatr Adolesc Med 2004;158: 1116-20.
58. Ordovas JM. Why study gene-environment interactions? Curr Opin Lipidol 2008;19: 158-67.
59. Corl BA, Mathews Olivier SA, Lin X, et al. Conjugated linoleic acid reduces body fat accretion and lipogenic gene expression in neonatal pigs fed low or high-fat formula. J Nutr 2008;138:449-54.
1. Wardie J, Carnell S, Haworth CM, Plomin R. Evidence for a strong genetic influence in childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 2008;87:398-404.
2. Musani SK, Erickson E. Allison DB. Obesity- still highly heritable after all these years. Amer J Clin Nutr 2008;87:275-6.
3. Donohoue P. Obesity. In: Behrman RE, Kliegman RM, Jenson HB (Eds.). Nelson Textbook of Pediatrics, 17th ed. Philadelphia: Saunders, 2004:173-7.
4. Shuldiner AR, Yang R, Gong DW. Resisting obesity and insulin resistance. The emerging role of the adipocyte as an endocrine organ. N Engl J Med 2001;345:1345-9.
5. Stepan CM, Bailey ST, Bhat S. The hormone resistine links obesity and diabetes. Nature 2001;409:307-12.
6. O’Railly S. Human obesity and insulin resistance: lessons from experiments of nature. Novartis Found Symp 2007;286:13-20.
7. van Hammerlen V, Eikson A, Astroem G, et al. Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis. Diabetes 2008;57:378-6.
8. O’Rally S, Farooqui IS. Recent advances in the genetics of severe childhood obesity. Arch Dis Child 2000;83:31-9. Obesità monogeniche
9. Dubern B, Clement K, Pelloux V. Mutation analysis of melanocortin-4 receptor, Agouti-related protein, and alpha-melanocyte stimulating hormone genes in severely obese children. J Pediatr 2001;139:204-11.
10. Graham KS, Leibel RI. Yellow mice, red hair, and childhood obesity: the melanocortine pathway of energy homeostasis. J Pediatr 2001;139:177-85.
11. Habener JF. Detective melanocortin 4 receptor in hyperfagia and morbid obesity. N Engl J Med 2003;348:1160-5.
12. Farooqui S, Keogh JM, Yeo GSH. Clinical spectrum of obesity and mutations in melanocortin 4 receptor gene. N Engl J Med 2003;348:1085-7.
13. Farooqui IS, Wangenstess T, Collins S. Clinical and molecular genetic spectrum of congenital deficiency of the leptine receptor. N Engl J Med 2007;356:237-47.
14. Musso G, Gambino R, De Michieli E, Dirazzo M, Pagano G, Casasder M. Adiponectine gene polimorphism modulate acute adiponectin response to dietary fat. Possibile pathogenetic role in NASH. Hepatology 2008; 47:1167-77. Polimorfismi genetici
15. Reue K. The role of lipin-1 in adipogenesis and lipid metabolism. Novartis Found Symp 2007;286:68-71.
16. Kinik ST, Ozbeck N, Yuce M. Yaziki AC, Verdi H, Atac PB. PAI-1 gene 4G/5G polymorphism, cytokine level and the relations with metabolic parameters in obese children. Thromb Haemost 2008;99:352-6.
17. Popko K, Gorska E, Wasik M, et al. Frequency and distribution of leptin receptor gene polymorphism in obstructive sleep apnea. J Physiol Pharmacol 2007;58:S51-S61.
18. Loos RJ, Bouchar C. FTO. The first gene contributing to common forms of human obesity. Obes Rev 2008;9:246-50.
19. Chu X, Erdman R, Susek M, et al. Association of morbid obesity with FTO and INSIGH2 allelic variants. Discussion Arch Surg 2008; 143:235-40.
20. Do R, Bailey SD, Desbiens K, et al. Genetic variants of FTO influence adiposity, insuline sensitivity, leptin levels and resting metabolic rate in the Quebec family study. Diabetes 2008;57:1147-50.
21. Jacobsson JA, Danilesson P, Svensson V, et al. Major gender differences in association of FTO gene variant among severely obese children with obesity and obesity-related phenotypes. Biochem Biophys Res Commun 2008;368:476-82.
22. Lin RCY, Wang YS, Morris BJ. High penetrance, overweight and glucocorticoid receptor variant: case-control study. BMJ 2000;319: 1337.
23. Wang GJ, Volkow ND, Logan J. Brain dopamine and obesity. Lancet 2001;357:354.
24. Xinli W, Xiaomei T, Meihua P, Song L. Association of a mutation in beta3-adrenergic receptor gene with obesity and response to dietary intervention in Chinese children. Acta Paediatr 2001;90:1233. Rapporto gene-ambiente
25. Soerensen TH, Sabroe S, Rothman KJ. Relation between weight and leght at birth and body mass index in young adulthood: cohort study. BJM 1997;315:1137-43.
26. Hanson MA, Gluckman PD. Developmental origins of health and disease: new insight. Basic Clin Pharmacol Toxicol 2008;102:90-3.
27. Vickers MH. Developmental programming and adult obesity. The role of leptine. Curr Opinion Endocrinol Diabetes Obes 2007;14: 17-22.
28. Whithaker RC, Dietz WH. Role of perinatal environment in the development of obesity. J Pediatr 1998;132:768-73.
29. Ravelli ACJ, van der Meulen JHP, Michels RPJ. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998;351:173-6.
30. Fioretto ML, Davis TA, Schocknecht P. Both maternal over-and-undernutrition during gestation increases the adiposity of young adults pregnancy in rats. Obes Res 1995;3: 131-8.
31. Kinra S, Baumer JH, Daver Smith G. Early growth and childhood obesity. A historical cohort study. Arch Dis Child 2005;90:1122-7.
32. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5-20.
33. Hesse V, Voigt M, Salzler A. Alteration in height, weight, and body mass index of newborn, children, and young adults in Eastern germany, after German reunification. J Pediatr 2003;142:259-65. Epigenetica
34. Waddington CH. The epigenotype. Endeavour 1942;1:18-20.
35. Jablonka E, Lamb MJ. The changing concept of epigenetics. Ann NY Acad Sci 2002; 981:82-96.
36. Bird A. Perceptions of epigenetics. Nature 2007;447:396-8.
37. Roloff TC, Nuber UA. Chromatin, epigenetics and stem cells. Eur J Cell Biol 2005;84: 123-35.
38. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet 2000;1:11-9.
39. von Kries R, Koletzko B, Sauerwald T, et al. Breast feeding and obesity: cross sectional study. BMJ 1999;319:147-50.
40. Gillman MW, Rifas-Shiman SL, Frazier AL, et al. Family dinner and diet quality among older children and adolescents. Arch Fam Med 2000;9:235-40.
41. Robinson TN. Reducing children’s television viewing to prevent obesity: a randomized controlled trial. JAMA 1999;282:1561-7.
42. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome. Diabetes 2005;54:1899-906.
43. Dabalea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risk for type 2 diabetes and obesity. A study of discordant sibships. Diabetes 2000;49: 2208-11.
44. Issa JP. Epigenetic variation and human diseases. J Nutr 2002;132:2388S-92S.
45. Frontiera M, Dickins B, Plagge A, Kelsey G. Imprinted genes, postnatal adaptation and enduring effects on energy homeostasis. Adv Exp Med Biol 2008;626:41-61. Fattori di rischio
46. Washington RL. Evidence-based medicine and the obesogen environment. J Pediatr 2006;149:5-7.
47. Davidson KK, Marshall SJ, Birch LL. Cross-sectional and longitudinal association between TV-viewing and girl’s body mass index. J Pediatr 2006;149-32-8.
48. Dencker M, Thomson O, Karlsson MK. Daily physical activity related to body fat in children aged 8-11 years. J Pediatr 2006;49:38- 41.
49. Tosche AM, Vignerova J, Lhostka L. Overweight and obesity in 6-14-year-old Czech children in 1991. Protective effect of breast feeding. J Pediatr 2002;141:764-9.
50. Gillman MW. Breast feeding and obesity. J Pediatr 2002;141:749-50.
51. Li L, Parson TJ, Power C. Breast feeding and obesity in childhood: cross sectional study. BMJ 2003;327:904-9.
52. Victora CG, Barros F, Lima RC, et al. Anthropometry and body composition of 18-yearold men according to the duration of breast feeding: birth cohort study from Brazil. BMJ 2003;327:879-83.
53. Reilly JJ, Armstrong J, Dorosty AR. Early life risk factors for obesity in childhood: cohort study. BMJ 2005;330:1357-63.
54. Davson KK, Francis LA, Birch LL. Links between parents’ and girls’ television viewing behaviors: a longotudinal study. J Pediatr 2005;147:436-70.
55. Viner RM, Cole IJ. Television viewing in early childhood predicts adult body mass index. J Pediatr 2005;147:429-35.
56. Kuepper-Nybelen J, lamerz A, Bruning N. Major differences in prevalence of overweight according to nationality in preschool children living in Germany: determinants and public health implications. Arch Dis Child 2005;90: 359-65.
57. Sherry B, Mei Z, Seanlon S. Trends in state-specific prevalence of overweight and underweight in 2-through 4-year-old children from low-income families, from 1989 through
2000. Arch Pediatr Adolesc Med 2004;158: 1116-20.
58. Ordovas JM. Why study gene-environment interactions? Curr Opin Lipidol 2008;19: 158-67.
59. Corl BA, Mathews Olivier SA, Lin X, et al. Conjugated linoleic acid reduces body fat accretion and lipogenic gene expression in neonatal pigs fed low or high-fat formula. J Nutr 2008;138:449-54.
Corrispondenza: franco@panizon.it