EDITORIAL OPINIONS

Higher Levels of Inflammation inObese Children

INTRODUCTION

The prevalence of obesity is increasing in Western countries. Asimilar trend is being observed for children.1 In the United States,the prevalence of overweight has increased from 5.0% between1963 and 1965 to 13.6% between 1988 and 1994 among children6 to 11 y. In adolescents, these numbers are 5.0% and 11.4%,respectively.2 Even in preschool children aged 4 to 5 y, an increas-ing prevalence of overweight was observed between 1971 and1974 (5.8%) and between 1988 and 1994 (10%).3 Although thehealth risks of obesity in adulthood are well characterized, muchless is known about the (long-term) health risks of obesity at youngages.

METABOLIC CORRELATES OF CHILDHOOD OBESITY

Obesity in children has been associated with the presence of themetabolic cardiovascular syndrome.4,5 Compared with leaner chil-dren, fatter children have higher systolic and diastolic blood pres-sures, higher fasting levels of glucose and insulin, higher total andlow-density lipoprotein cholesterol, lower high-density lipoproteincholesterol, and higher factor VIIc.6,7 Further, prospective researchhas shown that increases in adiposity at a young age are associatedwith increases in total and low-density lipoprotein cholesterol anddecreases in high-density lipoprotein cholesterol, suggesting anincreasingly atherogenic lipoprotein profile.8

INFLAMMATION AND CHILDHOOD OBESITY

Recent studies have found that overweight and obesity in childrenalso is associated with higher levels of inflammation. In thesestudies, the serum concentration of acute-phase proteins such asC-reactive protein (CRP) and fibrinogen were used as sensitivemarkers of inflammation status. My colleagues and I reported astrong association between overweight and inflammation in chil-dren.9 Serum CRP levels were collected from 3512 children aged8 to 16 y who were participants in the third National Health andNutrition Examination Study and a representative sample of theU.S. population. Overweight was defined as having a body massindex or a sum of three skinfolds above the sex-specific 85thpercentile. After adjustment for potential confounders includingsmoking and health status, overweight boys were 3.7 to 5.1 timesmore likely to have elevated CRP ($0.22 mg/dL) and overweightgirls were 2.9 to 3.2 times more likely to have elevated CRP.Moreover, the overweight children had higher white blood cellcounts than normal-weight children, indicating a higher inflamma-tion status.

Results from the Ten Towns Children’s Study, which used datafrom 699 children aged 10 to 11 y, support our findings.7 Apositive relationship between the Ponderal index (weight/height3)and CRP was found. CRP levels were 270% higher in the topquintile of Ponderal index than in the lowest quintile. Adiposity at10 to 11 y (current age) was a stronger determinant of CRP levelsthan obesity at 5 to 7 y, suggesting that the effect on CRP is dueto current adiposity. Further, obesity was a stronger determinant ofCRP levels than other factors that increase CRP levels such asHelicobacter pyloriinfection and environmental exposure to to-bacco smoke as measured by salivary cotinine levels.

A positive association between body mass index or Ponderalindex and fibrinogen levels also was found in children, indicatinglow-grade systemic inflammation in obese children.10,11

OBESITY AND INFLAMMATION: A CAUSALRELATIONSHIP?

Obesity has been repeatedly associated with higher inflammationlevels in adults.12–14 However, many factors correlated with obe-sity can cause higher inflammation levels, including smoking,arthritis, cardiovascular disease, and diabetes mellitus. Whetherobesity and inflammation are causally related or whether theassociation is indirect through other obesity-related factors is notclear. The recent findings of an association between obesity andinflammation in children support a direct relationship because theprevalence of smoking, atherosclerosis,15 and preexisting diseaseis low in children and is unlikely to confound the relationship.However, more research is warranted to test whether the associa-tion between obesity and inflammation is causal.

ADIPOSE TISSUE AS AN ENDOCRINE ORGAN

Results of several (experimental) studies have suggested thatinterleukin-6 is the link between obesity and inflammation.Interleukin-6 is expressed in adipose tissue16–18and released intothe circulation.18,19 Proinflammatory cytokines, includinginterleukin-6, stimulate the production of acute-phase proteins inthe liver.20,21 Further, higher adipose-tissue content ofinterleukin-6 has been associated with higher serum CRP concen-trations in obese persons.22 Moreover, a decrease in serum andadipose-tissue interleukin-6 was found after weight loss in 14obese non-diabetic women.23 The release of interleukin-6 fromadipose tissue might induce elevated levels of acute-phase proteinsin persons with excess body fat, leading to low-grade systemicinflammation.

CHILDHOOD OBESITY, INFLAMMATION, AND HEALTHRISKS

In adults, higher CRP or fibrinogen levels are predictive of futuremyocardial infarction, peripheral arterial disease, ischemic stroke,and diabetes mellitus.24,25 Whether higher inflammation levels inoverweight and obese children predispose them to disease at olderages is not known. However, body weight and weight gain duringchildhood are related to adult cardiovascular risk and mortalityrisk.26,27 Obese children at 7 y are four times more likely to havemetabolic syndrome in adulthood.28 The risk for this syndrome isstill twice as high after adjustment for body weight in adulthood.Similar results were obtained in the Harvard Growth Study in

The research of Dr. Visser was made possible by a fellowship from theRoyal Netherlands Academy of Arts and Sciences.

Correspondence to: Marjolein Visser, MD, Institute for Research in Ex-tramural Medicine, Faculty of Medicine, Vrije Universiteit, Van der Bo-echorststraat 7, 1081 BT Amsterdam, Netherlands. E-mail: m.visser.emgo@med.vu.nl

Nutrition 17:480–484, 2001 0899-9007/01/$20.00©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved.

which adolescents were followed for 55 y. Overweight at adoles-cence was a strong predictor of coronary heart disease and athero-sclerosis during adulthood, independent of body weight duringadulthood.29 The presence of higher inflammation levels duringchildhood might in part explain the increased risk for cardiovas-cular disease in adulthood among obese children.

Because overweight is associated with various risk factorsamong children, successful prevention and treatment of obesity inchildhood might reduce the adult incidence of cardiovasculardisease. Because obese children as young as 5 to 8 y already havehigher inflammation levels and several risk factors for cardiovas-cular disease, efforts to prevent overweight should begin in earlychildhood.

Marjolein Visser, PhDInstitute for Research in Extramural Medicine Vrije

Universiteit AmsterdamNetherlands

REFERENCES

1. Chinn S, Rona RJ. Prevalence and trends in overweight and obesity in three crosssectional studies of British children, 1974–94. BMJ 2001;322:24

2. MacKay AP, Fingerhut LA, Duran CR.Adolescent health chartbook. Health,United States, 2000. Hyattsville, MD: National Center for Health Statistics, 2000

3. Ogden CL, Troiano RP, Briefel RR, et al. Prevalence of overweight amongpreschool children in the United States, 1971 through 1994. Pediatrics 1997;99(4). Available from: http://www.pediatrics.org/cgi/content/full/99/4/e1

4. Morrison JA, Sprecher DL, Barton BA, Waclawiw MA, Daniels SR. Overweight,fat patterning, and cardiovascular disease risk factors in black and white girls: theNational Heart, Lung, and Blood Institute Growth and Health Study. J Pediatr1999;135:458

5. Csabi G, Torok K, Jeges S, Molnar D. Presence of metabolic cardiovascularsyndrome in obese children. Eur J Pediatr 2000;159:91

6. Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of over-weight to cardiovascular risk factors among children and adolescents: the Boga-lusa Heart Study. Pediatrics 1999;103:1175

7. Cook DG, Mendall MA, Whincup PH, et al. C-reactive protein concentration inchildren: relationship to adiposity and other cardiovascular risk factors. Athero-sclerosis 2000;149:139

8. Freedman DS, Burke GL, Harsha DW, et al. Relationship of changes in obesityto serum lipid and lipoprotein changes in childhood and adolescence. JAMA1985;254:515

9. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Low-gradesystemic inflammation in overweight children. Pediatrics 2000;107(1). Availablefrom: http://www/pediatrics.org/cgi/content/full/107/1/e13

10. Cook DG, Whincup PH, Miller G, et al. Fibrinogen and factor VII levels arerelated to adiposity but not fetal growth or social class in children aged 10–11years. Am J Epidemiol 1999;150:727

11. Shea S, Isasi CR, Couch S, et al. Relations of plasma fibrinogen level in childrento measures of obesity, the (G24553A) mutation in theb-fibrinogen promotorgene, and family history of ischemic heart disease. Am J Epidemiol 1999;150:737

12. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive proteinand its relation to cardiovascular risk factors: a population based cross-sectionalstudy. Br Med J 1996;312:1061

13. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. ElevatedC-reactive protein levels in overweight and obese adults. JAMA 1999;282:2131

14. Hak AE, Stehouwer CD, Bots ML, et al. Associations of C-reactive protein withmeasures of obesity, insulin resistance, and subclinical atherosclerosis in healthy,middle-aged women. Arterioscler Thromb Vasc Biol 1999;19:1986

15. Stary HC. Lipid and macrophage accumulations in arteries of children and thedevelopment of atherosclerosis. Am J Clin Nutr 2000;72(suppl):1297S

16. Purohit A, Ghilchik MW, Duncan L, et al. Aromatase activity and interleukin-6production by normal and malignant breast tissues. J Clin Endocrinol Metab1995;80:3052

17. Crichton MB, Nichols JE, Zhao Y, Bulun SE, Simpson ER. Expression oftranscripts of interleukin-6 and related cytokines by human breast tumors, breastcancer cells, and adipose stromal cells. Mol Cell Endocrinol 1996;118:215

18. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutaneous adipose tissuereleases interleukin-6, but not tumor necrosis factor-a, in vivo. J Clin EndocrinolMetab 1997;82:4196

19. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues

of obese subjects release interleukin-6: depot difference and regulation by glu-cocorticoid. J Clin Endocrinol Metab 1998;83:847

20. Banks RE, Forbes MA, Shorr M, et al. The acute phase response in patientsreceiving subcutaneous IL-6. Clin Exp Immunol 1995;102:217

21. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The patho-physiologic roles of interleukin-6 in human disease. Ann Intern Med 1998;128:127

22. Bastard JP, Jardel C, Delattre J, et al. Evidence for a link between adipose tissueinterleukin-6 content and serum C-reactive protein concentrations in obese sub-jects. Circulation 1999;99:2221

23. Bastard JP, Jardel C, Bruckert E, et al. Elevated levels of interleukin 6 arereduced in serum and subcutaneous adipose tissue of obese women after weightloss. J Clin Endocrinol Metab 2000;85:3338

24. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactiveprotein, albumin, or leukocyte count with coronary heart disease. JAMA 1998;279:1477

25. Schmidt MI, Duncan BB, Sharrett AR, et al. Markers of inflammation andprediction of diabetes mellitus in adults (Atherosclerosis Risk in Communitiesstudy): a cohort study. Lancet 1999;353:1649

26. DiPietro L, Mossberg HO, Stunkard AJ. A 40-year history of overweight childrenin Stockholm: life-time overweight, morbidity, and mortality. Int J Obes RelMetab Disord 1994;18:585

27. Sinaiko AR, Donahue RP, Jacobs DR Jr, Prineas RJ. Relation of weight and rateof increase in weight during childhood and adolescence to body size, bloodpressure, fasting insulin, and lipids in young adults. The Minneapolis Children’sBlood Pressure Study. Circulation 1999;99:1471

28. Vanhala MJ, Vanhala PT, Keina¨nen-Kiukaanniemi SM, Kumpusalo EA, TakalaJK. Relative weight gain and obesity as a child predict metabolic syndrome as anadult. Int J Obes 1999;23:656

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A Good Start in Life: Breast Is Best,but Complementary Foods ShouldNot Be WorseOptimum nutrition and feeding of infants and young children areamong the most important determinants of their health, growth,and development. They can prevent malnutrition and early growthretardation, which are common in many parts of the world.1 Poorlyfed children have higher rates and severity of enteric and otherinfections, and they are at greater risk of dying prematurely. Thereis evidence that poor fetal and infant nutrition have long-termhealth consequences and play a role in the genesis of some chronicnon-communicable diseases in adults. Furthermore, micronutrientdeficiencies, especially of iron and iodine, might be associatedwith delayed motor development and impaired cognitive function.Thus, improvements in the nutrition of young children are desir-able, not only for their positive effects on physical health andgrowth but also to reduce the risk of infection, ensure optimalpsychomotor development and school performance and, in thelong-term, improve adult life opportunities, health, and productivity.

The period of transition, from an exclusively milk diet to one inwhich an increasing variety of foods is required to satisfy nutri-tional needs, is a particularly vulnerable time. Despite recognitionof the public-health importance of infant and young-child nutritionand feeding practices, there are few guidelines based on scientificevidence for this critical weaning period.2,3 The World HealthOrganization (WHO) is aiming to reach consensus on the optimumduration of exclusive breast feeding and age of introduction ofcomplementary feeds and, with UNICEF, to develop a globalstrategy for infant and young-child feeding.4

Correspondence to: Lawrence Weaver, MD, Department of Child Health,University of Glasgow, Royal Hospital for Sick Children, Yorkhill, Glas-gow G3 8SJ, UK. E-mail: lweaver@clinmed.gla.ac.uk

Nutrition Volume 17, Number 6, 2001 481Editorial Opinions