Breast-feeding, Adipokines, and Childhood Obesity
Gillman, Matthew W.*; Mantzoros, Christos S.†
From the *Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care, Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; and †Division of Endocrinology Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Submitted 24 July 2007; accepted 1 August 2007.
Supported by NIH grants HL 068041 and DK58785.
Correspondence: M.W. Gillman, DACP, HMS/HPHC, 133 Brookline Ave., 6th floor, Boston, MA 02215. E-mail: firstname.lastname@example.org.
One mechanism by which breast-feeding may protect against the development of childhood obesity is through the activity of components of breast milk. In an article published in this issue of Epidemiology, Weyermann et al found that overweight at age 2 years was associated with higher levels of adiponectin, a hormone secreted by fat cells, in the breast milk of mothers who breast-fed their infants for at least 6 months. This finding is surprising for several reasons: it is doubtful that infants absorb ingested adiponectin; prior literature suggests that adiponectin would reduce, rather than increase, risk for overweight; and the authors did not find associations with breast milk leptin, another adipokine. It is possible that adipokine exposure in infancy determines later weight status, but fundamental research is needed on associations of circulating adipokines with excess weight gain and on determinants of adipokine levels.
The obesity epidemic has ensnared even our youngest children, highlighting the need to prevent obesity at the earliest stages of human development.1 One potential strategy is to optimize infant feeding. In the United States, rates of breast-feeding initiation and duration have been rising over the past 30 years,2 so that lack of breast-feeding cannot explain the obesity epidemic. Nevertheless, if having been breast-fed lowers the risk of obesity, increasing breast-feeding rates even further could be one way to blunt the epidemic.
The extent to which breast-feeding protects against obesity is not settled. Meta-analysis suggests a 10%–20% decreased risk of obesity (dichotomous outcome) among those who had been breast-fed compared with those who were not breast-fed (dichotomous exposure),3,4 and a 4% reduction for each additional month of breast-feeding duration (continuous exposure).5 The only meta-analysis examining a continuous outcome, mean body mass index, suggested that confounding by sociocultural factors can explain the apparent protective effects.6 But the lack of covariate information from many component studies and the difference in outcomes among the meta-analyses render a simple overall conclusion slippery. Within-family studies can be informative, but even the largest published study, with over 2000 siblings discordant for breast-feeding duration, was not large enough for precise inferences.7 Also, the results from a large randomized controlled trial of breast-feeding promotion are not yet available past the age of 1 year.8
If consensus does not exist on the protective effect of breast-feeding on obesity, is it worth examining the mechanisms of such an effect? We believe it is. The best evidence to date does show a reduction in risk, and no meta-analysis suggests harm. Further, it is possible that breast-feeding reduces obesity risk for some infants but not for others.
At least 2 types of pathways could explain how having been breast-fed improves later weight status. One is behavioral. Compared with bottle feeding, the act of breast-feeding could lead to infants better recognizing satiety signals, resulting in enhanced self-regulation of energy intake growing up.9,10
Another hypothesized pathway is through the biologic activity of components of breast milk. Very few studies have addressed this pathway, and thus the contribution of Weyermann et al11 in this issue of Epidemiology is a welcome addition to the literature. For 674 infants still breast-fed at around 6 weeks of age, the authors measured both leptin and adiponectin in the mothers' breast milk samples. The main finding was that risk of overweight at age 2 years was higher among children whose mothers had higher concentrations of breast milk adiponectin, but only among children who had been breast-fed for at least 6 months. They did not find an association of leptin with overweight.
Before considering causality, one should bear in mind alternative explanations. We believe that chance is likely, for 2 related reasons. The first is questionable biologic plausibility for an effect of adiponectin in breast milk. The second is that the major finding was limited to 1 of the 2 hormones studied and to 1 subgroup, and is in the opposite direction from what many researchers would hypothesize.
The prevailing view of adipose tissue has changed in the past decade from that of an inert energy storage organ, to that of an active endocrine system involved in sensing, metabolizing, and secreting numerous metabolically active compounds. Leptin is the prototype adipocyte-secreted cytokine (adipokine).12 Leptin administration decreases food intake and body weight in leptin-deficient ob/ob mice and humans.13,14 Most of obese adolescents and adults, however, have high circulating leptin levels and do not respond to exogenously administered leptin, likely owing to leptin resistance in peripheral tissues and in the hypothalamus, the part of the brain most involved in appetite regulation.15–17 In contrast to older individuals, infants are still in early, presumably leptin-sensitive, developmental stages of hypothalamic development. It is reasonable to hypothesize that leptin resistance has not yet taken hold and that circulating leptin among infants could have beneficial effects on limiting future excess weight gain. One study of rodents shows that subcutaneous leptin administration at a critical period of postnatal brain development can virtually eliminate the risk of obesity-related consequences that are prenatally programmed by manipulation of maternal diet.18
Weyermann et al,11 however, do not show a relationship between breast milk leptin and child weight status. One explanation for the null results is the likelihood that little or no ingested breast milk leptin enters the infant's circulation. Leptin is a rather large molecule, consisting of 167 amino acids. Because of its size, gastric absorption is nil, at least in adults. Two studies of newborn rodents shows some absorption in the developing gastrointenstinal tract, but no study of humans exists.19,20 Also, some, but not all, studies show that formula-fed infants have higher blood leptin levels than breast-fed infants, even though infant formula contains no leptin.21 That finding suggests that factors other than breast milk are the chief determinants of circulating leptin levels.
Another adipokine, adiponectin, is a protein that is produced and secreted almost exclusively by differentiated adipocytes.22 Most researchers now think that adiponectin represents an important mediator between adipose tissue and insulin sensitivity.23–25 In contrast to leptin, adiponectin decreases with increasing adiposity, especially intra-abdominal adiposity, among adults. Higher levels of adiponectin are associated with less insulin resistance and lower risk of developing cardiovascular disease in adults.26,27
No data exist on the extent to which adiponectin from breast milk enters the circulation of an infant. But adiponectin is a larger molecule—244 amino acids—than leptin, making gastrointestinal absorption doubtful. As in the case of leptin, blood levels of adiponectin are probably more biologically relevant than breast milk because they reflect the adipokine levels to which developing tissues are exposed.
Given these questions about the biology, it is understandable that the authors did not express a strong prior hypothesis about the relationship of breast milk adiponectin with the development of childhood obesity. Both the observed direction of adiponectin effect and the presence of the effect only with longer duration of breast-feeding are counterintuitive. It will be instructive to see whether other studies replicate these findings. To strengthen the credibility of the results, investigators would also need to answer many fundamental questions. For example, to what extent is breast milk adiponectin absorbed into the infant circulation? Do higher levels of circulating adiponectin in infants predict excess weight gain, in contradistinction to the situation in adults? Why would this be the case only among infants who are breast-fed for longer versus shorter periods? Are levels of adiponectin in human milk a proxy for maternal, environmental, or other factors that themselves determine adiposity-related outcomes in the child?
These and other research questions about the roles of adipokines in infancy in the risk of developing obesity are biologically interesting and potentially important for health. They will need answers before any clinical and public health implications of the findings of Weyermann et al are perceptible. The best advice remains that all women should strive to breast-feed their children for at least 12 months, with the first 4–6 months consisting of exclusive breast-feeding.28,29
ABOUT THE AUTHORS
MATTHEW W. GILLMAN is Director of the Obesity Prevention Program at the Department of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care. His research on the developmental origins of health and disease includes epidemiologic studies of infant feeding and obesity. CHRISTOS S. MANTZOROS is an endocrinologist with a special interest in the biology and epidemiology of adipokines, including leptin and adiponectin, across the life course.
1. Kim J, Peterson KE, Scanlon KS, et al. Trends in overweight from 1980 through 2001 among preschool-aged children enrolled in a health maintenance organization. Obesity
2. Ryan AS, Wenjun Z, Acosta A. Breastfeeding continues to increase into the new millennium. Pediatrics
3. Arenz S, Ruckerl R, Koletzko B, et al. Breast-feeding and childhood obesity—a systematic review. Int J Obes Relat Metab Disord
4. Owen CG, Martin RM, Whincup P, et al. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics
5. Harder T, Bergmann R, Kallischnigg G, et al. Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol
6. Owen CG, Martin RM, Whincup PH, et al. The effect of breastfeeding on mean body mass index throughout life: a quantitative review of published and unpublished observational evidence. Am J Clin Nutr
7. Gillman MW, Rifas-Shiman SL, Berkey CS, et al. Breastfeeding and overweight in adolescence: within-family analysis. Epidemiology
8. Kramer MS, Guo T, Platt RW, et al. Breastfeeding and infant growth: biology or bias? Pediatrics
9. Taveras EM, Scanlon KS, Birch L, et al. Association of breastfeeding with maternal control of infant feeding at age 1 year. Pediatrics
10. Taveras EM, Rifas-Shiman SL, Scanlon KS, et al. To what extent is the protective effect of breastfeeding on future overweight explained by decreased maternal feeding restriction? Pediatrics
11. Weyermann M, Brenner H, Rothenbacher D. Adipokines in human milk and risk of overweight in early childhood: a prospective cohort study. Epidemiology
. 2007;18: XXX–XXX.
12. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature
13. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med
14. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest
15. Chan JL, Matarese G, Shetty GK, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci U S A
16. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet
17. Brennan AM, Mantzoros CS. Drug insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications. Nat Clin Pract Endocrinol Metab
18. Vickers MH, Gluckman PD, Coveny AH, et al. Neonatal leptin treatment reverses developmental programming. Endocrinology
19. Pico C, Oliver P, Sanchez J, et al. The intake of physiological doses of leptin during lactation in rats prevents obesity in later life. Int J Obes (Lond).
2007;Epub ahead of print.
20. Casabiell X, Pineiro V, Tome MA, et al. Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake. J Clin Endocrinol Metab
21. Petridou E, Mantzoros CS, Belechri M, et al. Neonatal leptin levels are strongly associated with female gender, birth length, IGF-I levels and formula feeding. Clin Endocrinol (Oxf)
22. Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A
23. Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med
24. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med
25. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med
26. Brennan AM, Mantzoros CS. Leptin and adiponectin: their role in diabetes. Curr Diab Rep
27. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA
28. Gartner LM, Morton J, Lawrence RA, et al. Breastfeeding and the use of human milk. Pediatrics
29. American Academy of Pediatrics Committee on Nutrition. Pediatric Nutrition Handbook
. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003.
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