J Korean Med Assoc.  2014 Mar;57(3):234-240. 10.5124/jkma.2014.57.3.234.

A developmental perspective on the origins of obesity and metabolic syndrome

• Choi YS
• Hwang IT

• KMID: 2064880
• DOI: http://doi.org/10.5124/jkma.2014.57.3.234

Abstract

Metabolic syndrome comprises central obesity, dyslipidemia, hypertension, glucose intolerance, and insulin resistance. Children sometimes develop metabolic syndrome, and it is strongly associated with the same syndrome in adulthood. Recently, there is evidence that obesity and metabolic syndrome originate from fetal life. Possible explanations of fetal and developmental origin of metabolic syndrome are the thrifty genotype and thrifty phenotype hypothesis, which together confer insulin resistance on developing fetus. Poor nutrition in utero as well as extrauterine growth restriction of preterm infants are important triggers of this hypothesis. Like metabolic syndrome in adulthood, the high levels of inflammatory cytokines and adipokines are certainly characteristic in pediatric patients. Increased fat mass was also observed in these patients, although their birth weight was lower than average. The mitochondrial genome is responsible for the inheritance of obesity from the maternal line. This can be a key as to why the phenotypes of obesity and metabolic syndrome start in fetal life with an association with poor maternal nutrition. In such circumstances, catch-up growth with an over-nutrition strategy can aggravate those features, suggesting that rapid catch-up growth in early infancy should not be encouraged.

Keyword

Metabolic syndrome; Pediatric obesity; Small for gestational age infant; Fetal nutrition disorders

MeSH Terms

Adipokines
Birth Weight
Child
Cytokines
Dyslipidemias
Fetal Nutrition Disorders
Fetus
Genome, Mitochondrial
Genotype
Glucose Intolerance
Humans
Hypertension
Infant, Newborn
Infant, Premature
Insulin Resistance
Obesity*
Obesity, Abdominal
Pediatric Obesity
Phenotype
Wills
Adipokines
Cytokines

Figure

• 

  Figure 1 Hypothesis proposed to explain the development of insulin resistance associated with reduced fetal growth. Thrifty phenotype and genotype are the major underlying mechanisms together with gene-environmental interaction to develop insulin resistance and later metabolic syndrome. SGA, small for gestational age.

Reference

1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012; 82:1–8.

2. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365:1415–1428.

3. Campion J, Milagro FI, Martinez JA. Individuality and epigenetics in obesity. Obes Rev. 2009; 10:383–392.

4. Dietz WH. Health consequences of obesity in youth: childhood predictors of adult disease. Pediatrics. 1998; 101:518–525.

5. Styne DM. Childhood and adolescent obesity. Prevalence and significance. Pediatr Clin North Am. 2001; 48:823–854.

6. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004; 350:2362–2374.

7. Ozanne SE, Hales CN. Early programming of glucose-insulin metabolism. Trends Endocrinol Metab. 2002; 13:368–373.

8. King JC. Maternal obesity, metabolism, and pregnancy outcomes. Annu Rev Nutr. 2006; 26:271–291.

9. Elahi MM, Cagampang FR, Mukhtar D, Anthony FW, Ohri SK, Hanson MA. Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice. Br J Nutr. 2009; 102:514–519.

10. Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hyper-tension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia. 1993; 36:62–67.

11. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992; 35:595–601.

12. Wells JC. Commentary: the thrifty phenotype and the hierarchical preservation of tissues under stress. Int J Epidemiol. 2013; 42:1223–1227.

13. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991; 303:1019–1022.

14. Barker DJ. The fetal origins of adult hypertension. J Hypertens Suppl. 1992; 10:S39–S44.

15. Barker DJ, Martyn CN. The maternal and fetal origins of cardiovascular disease. J Epidemiol Community Health. 1992; 46:8–11.

16. Newsome CA, Shiell AW, Fall CH, Phillips DI, Shier R, Law CM. Is birth weight related to later glucose and insulin metabolism?: a systematic review. Diabet Med. 2003; 20:339–348.

17. Han DY, Murphy R, Morgan AR, Lam WJ, Thompson JM, Wall CR, Waldie KE, Mitchell EA, Ferguson LR. Reduced genetic influence on childhood obesity in small for gestational age children. BMC Med Genet. 2013; 14:10.

18. Neel JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? 1962. Bull World Health Organ. 1999; 77:694–703.

19. Yoo EG. Consequences of being born small for gestational age: more than being small. Korean J Pediatr. 2009; 52:152–158.

20. Cohen MP, Stern E, Rusecki Y, Zeidler A. High prevalence of diabetes in young adult Ethiopian immigrants to Israel. Diabetes. 1988; 37:824–828.

21. Dowse GK, Zimmet PZ, Finch CF, Collins VR. Decline in incidence of epidemic glucose intolerance in Nauruans: implications for the "thrifty genotype". Am J Epidemiol. 1991; 133:1093–1104.

22. Lee HK. Evidence that the mitochondrial genome is the thrifty genome. Diabetes Res Clin Pract. 1999; 45:127–135.

23. Surani MA. Imprinting and the initiation of gene silencing in the germ line. Cell. 1998; 93:309–312.

24. Lee YY, Park DJ, Shin CS, Park KS, Lee HK, Jun JK, Yoon BY, Song JY, Kang BS. Relationship of insulin-like growth factor (IGF)-1, IGF-2, IGF binding protein (IGFBP)-3, and mitochondrial DNA amount in the umbilical cord blood to birth weight. J Korean Diabetes Assoc. 1999; 23:36–45.

25. Velho G, Byrne MM, Clement K, Sturis J, Pueyo ME, Blanche H, Vionnet N, Fiet J, Passa P, Robert JJ, Polonsky KS, Froguel P. Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu (UUR) gene mutation. Diabetes. 1996; 45:478–487.

26. Rahier J, Wallon J, Henquin JC. Cell populations in the endocrine pancreas of human neonates and infants. Diabetologia. 1981; 20:540–546.

27. Ozanne SE, Olsen GS, Hansen LL, Tingey KJ, Nave BT, Wang CL, Hartil K, Petry CJ, Buckley AJ, Mosthaf-Seedorf L. Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. J Endocrinol. 2003; 177:235–241.

28. Eriksson J, Lindi V, Uusitupa M, Forsen T, Laakso M, Osmond C, Barker D. The effects of the Pro12Ala polymorphism of the PPARgamma-2 gene on lipid metabolism interact with body size at birth. Clin Genet. 2003; 64:366–370.

29. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998; 19:268–270.

30. Ortiz-Espejo M, Perez-Navero JL, Olza J, Munoz-Villanueva MC, Aguilera CM, Gil-Campos M. Changes in plasma adipokines in prepubertal children with a history of extrauterine growth restriction. Nutrition. 2013; 29:1321–1325.

31. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006; 117:1253–1261.

32. De Blasio MJ, Gatford KL, McMillen IC, Robinson JS, Owens JA. Placental restriction of fetal growth increases insulin action, growth, and adiposity in the young lamb. Endocrinology. 2007; 148:1350–1358.

33. Monteiro PO, Victora CG. Rapid growth in infancy and childhood and obesity in later life: a systematic review. Obes Rev. 2005; 6:143–154.

34. Euser AM, Finken MJ, Keijzer-Veen MG, Hille ET, Wit JM, Dekker FW. Dutch POPS-19 Collaborative Study Group. Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm. Am J Clin Nutr. 2005; 81:480–487.

35. Joss-Moore LA, Wang Y, Campbell MS, Moore B, Yu X, Callaway CW, McKnight RA, Desai M, Moyer-Mileur LJ, Lane RH. Uteroplacental insufficiency increases visceral adiposity and visceral adipose PPARgamma2 expression in male rat offspring prior to the onset of obesity. Early Hum Dev. 2010; 86:179–185.

36. Bol VV, Reusens BM, Remacle CA. Postnatal catch-up growth after fetal protein restriction programs proliferation of rat preadipocytes. Obesity (Silver Spring). 2008; 16:2760–2763.

37. Rolland-Cachera MF, Deheeger M, Bellisle F, Sempe M, Guilloud-Bataille M, Patois E. Adiposity rebound in children: a simple indicator for predicting obesity. Am J Clin Nutr. 1984; 39:129–135.

38. Modi N, Thomas EL, Uthaya SN, Umranikar S, Bell JD, Yajnik C. Whole body magnetic resonance imaging of healthy newborn infants demonstrates increased central adiposity in Asian Indians. Pediatr Res. 2009; 65:584–587.

39. Young L, Embleton ND, McCormick FM, McGuire W. Multi-nutrient fortification of human breast milk for preterm infants following hospital discharge. Cochrane Database Syst Rev. 2013; 2:CD004866.

40. Bocca-Tjeertes IF, Reijneveld SA, Kerstjens JM, de Winter AF, Bos AF. Growth in small-for-gestational-age preterm-born children from 0 to 4 years: the role of both prematurity and SGA status. Neonatology. 2013; 103:293–299.