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Keywords:

  • Adipokines;
  • adiponectin;
  • breast milk;
  • body composition;
  • leptin;
  • weight gain

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

Background

Adipokines in breast milk have been associated with infant growth trajectories.

Objective

We aimed to explore the relationship of leptin and adiponectin in breast milk with infant weight gain and body composition up to the age of 2 years.

Methods

Breast milk samples were collected from exclusively or partially breastfeeding mothers at 6 weeks (n = 152) and 4 months (n = 120) post-partum. Leptin and adiponectin were determined in skim breast milk and related to infant growth and fat mass assessed by skin-fold thickness measurements. A total of 118 infants were examined at 2 years.

Results

The levels of both milk adipokines were slightly lower at 4 months compared with 6 weeks post-partum. Breast milk leptin was largely unrelated to infant anthropometric measures up to 2 years. Milk adiponectin tended to be inversely related to early infant anthropometry up to 4 months, but beyond was positively associated with weight gain and the sum of skin-folds up to 2 years.

Conclusions

Our results suggest that higher adiponectin levels in breast milk might be associated with greater weight gain and higher fat mass in the offspring up to 2 years.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

The perinatal nutritional environment is suggested to have a programming effect on an individual's susceptibility to develop obesity [1]. Breastfeeding is suggested to be protective against later obesity [2], which could partly be attributable to bioactive compounds present in breast milk, but absent in infant formula [3]. However, the specific components of breast milk accounting for these effects have not yet been identified. Since the discovery of the adipocyte-secreted factors leptin and adiponectin in breast milk [4, 5], both adipokines have been proposed as strong candidates [6]. Leptin is mainly produced in adipose tissue, but also by other tissues including the mammary gland [7]. It is released from adipose tissue in amounts proportionate to the body fat depots and plays a fundamental role in the hypothalamic regulation of energy homeostasis by decreasing food intake and increasing energy expenditure [8]. In contrast, adiponectin is down-regulated in obesity and exerts insulin-sensitizing and anti-inflammatory effects [9].

Several animal and human studies have suggested a role of oral leptin administration or the amount of adipokines in breast milk in the regulation of early weight gain or growth trajectory [10-17]. However, the majority of available human studies merely focused on rather global measures of infant overweight such as body mass index (BMI) or simple weight development and did not include more specific measurements of fat mass. We therefore aimed to explore the relationship of the adipokines leptin and adiponectin in breast milk with infant weight gain and body composition assessed by skin-fold thickness measurements.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

Data came from the INFAT study, a randomized controlled trial originally designed to examine the effect of reducing the maternal dietary n-6/n-3 fatty acid ratio during pregnancy and lactation on infant fat mass. The study design and the clinical results on infant body composition over the first year of life were previously published [18, 19]. Briefly, a total of 208 healthy pregnant women with a pre-pregnancy BMI between 18 and 30 kg m−2 were randomly assigned to either an intervention or a control group from the 15th week of gestation until 4 months post-partum. The dietary intervention consisted of a dietary supplementation with 1200 mg n-3 long-chain polyunsaturated fatty acids (LCPUFA) per day and a nutritional counselling to normalize the consumption of arachidonic acid to a moderate level of intake (∼90 mg per day). In contrast, women of the control group were advised to keep a healthy diet according to current recommendations. The study protocol was approved by the ethical committee of the Technische Universität München and all participants gave written informed consent.

Collection of biosamples

Breast milk samples of the lactating mothers were collected with an electric breast pump after an overnight fast at 6 weeks (n = 152) and 4 months (n = 120) post-partum. Approximately, 20 mL of a complete breast expression were kept, aliquoted and stored at −80°C until analysis. Maternal EDTA plasma samples were taken after an overnight fast at the same time points. Plasma was separated from red blood cells by centrifugation at 2000 × g at 4°C for 10 min, aliquoted and stored at −80°C until analysis.

Maternal and infant characteristics

Maternal height, pre-pregnancy weight and weight development over the course of pregnancy were retrieved from the maternity records issued to the women by their gynecologists. Maternal skin-fold thickness measurements were performed at four sites (biceps, triceps, subscapular and suprailiacal) by a Holtain Caliper (Holtain Ltd, Croswell, Crymych, UK) at the 15th and 32nd week of gestation. The mean of triplicate measurements per site was used for analysis. Maternal body fat percentage was calculated according to Durnin and Wormersley [20] and van Raaij et al [21]. Infants were examined at birth (n = 188), at 6 weeks (n = 180), 4 months (n = 174), 1 year (n = 170) and 2 years (n = 118) post-partum. Weight, length and skin-fold thicknesses at four body sites were measured as previously described [19]. Percentage body fat was calculated according to Weststrate and Deurenberg [22]. Infant weight gain between the time point of milk collection and later time points of follow-up was also calculated. If infants could not be clinically examined at 2 years, parents were asked to provide weight and height as assessed in the routine pediatric ‘well-child check-up visit’ at 24 months (n = 52). Infant feeding practices (fully breastfed, partially breastfed, formula) were documented at each visit over the first year of life. The individuals lost to follow-up did not differ from those remaining in the study with regard to the major sociodemographic and clinical parameters, such as maternal age, education, parity, pre-pregnancy BMI or infant feeding practices (data not shown). The infants of the intervention group (treatment with n-3 LCPUFA) did not differ from the control group in growth or body composition, neither over the first year of life, except higher birth weight and ponderal index due to prolonged pregnancy duration [19], nor at 2 years of age (data not shown). For the present analysis, only the mother–infant pairs with available breast milk sample at 6 weeks or 4 months post-partum were included.

Laboratory analyses

For the analysis of leptin and total adiponectin, milk samples were pre-treated as follows: milk samples were thawed at room temperature and vortexed. The whole milk was sonicated three times for a 5-s burst by using an ultrasound stick (ultrasonic processor UP100H, 100 W, 30 kHz, 100% amplitude; Hielscher Ultrasonics GmbH, Teltow, Germany). Skim milk was prepared by centrifugation of whole milk (14000 rpm, 30 min). Leptin and adiponectin were detected in skim milk by commercially available radioimmunoassays (leptin: Mediagnost, Reutlingen, Germany; adiponectin: Millipore, St. Charles, MO, USA). Leptin and high molecular weight (HMW) adiponectin in maternal plasma were quantified using enzyme-linked immunosorbent assay (Leptin: Mediagnost, Reutlingen, Germany; HMW adiponectin: ALPCO Diagnostics, Salem, MA, USA) in a subsample of n = 82 women.

Statistical analyses

Statistical analyses were performed with the R software package (version 2.8.1; R Foundation for Statistical Computing, http://www.r-project.org) and PASW software (version 20.0; SPSS Inc, Chicago, IL, USA). Changes of parameters over time within the groups were assessed by Wilcoxon tests. Mann Whitney-U tests were performed to explore differences in the parameters between the control and the intervention group at the individual time points. Correlations between breast milk and plasma adipokines as well as with maternal anthropometric variables were explored by Spearman correlation coefficients. To analyze associations of breast milk adipokines with infant growth and body composition up to 2 years of age, multiple regression models adjusting for maternal pre-pregnancy BMI, gestational weight gain, pregnancy duration, sex, ponderal index at birth, group and degree of breastfeeding (full vs. partial) were performed. A two-sided P-value ≤ 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

Adipokines in breast milk and maternal plasma

As no differences in maternal or milk adipokines between the original intervention and control group were found at any time point (data not shown), pooled data from both groups are presented. Median concentrations of leptin and total adiponectin in breast milk at 6 weeks post-partum were 0.11 (interquartile range: 0.19) ng mL−1 and 10.93 (8.34) ng mL−1, respectively (Table 1). Both leptin and adiponectin concentrations in breast milk were slightly lower at 4 months compared with 6 weeks, with a significant difference over time only for total adiponectin. Median plasma levels of leptin and HMW adiponectin showed the same pattern (Table 1). Maternal plasma leptin levels over the course of pregnancy and lactation were previously reported [23]. Concentrations of both adipokines were substantially lower in breast milk compared with plasma (P < 0.001) with a high correlation between plasma and milk levels at both time points (e.g. at 6 weeks: leptin: r = 0.55; adiponectin: r = 0.52, both P < 0.001).

Table 1. Concentrations of the adipokines, leptin and adiponectin in breast milk at 6 weeks and 4 months post-partum
 6 weeks post-partum4 months post-partumP (over time)P
Median (IQR*)nMedian (IQR*)n
  1. *IQR, interquartile range. Change over time by Wilcoxon test. Comparison of the respective adipokine levels in breast milk vs. plasma (Wilcoxon test).

Milk leptin (ng mL−1)0.11 (0.19)1520.09 (0.18)1200.65P < 0.001
Plasma leptin (ng mL−1)9.52 (8.56)828.30 (10.64)820.29
Milk total adiponectin (ng mL−1)10.93 (8.34)15110.36 (9.40)1200.03P < 0.001
Plasma HMW adiponectin (μg mL−1)2.13 (1.43)822.03 (1.32)820.01

Correlations of breast milk adipokines with maternal anthropometry

Leptin levels in breast milk were strongly correlated with pre-pregnancy BMI and maternal anthropometry during pregnancy, including BMI and fat mass, both at the 15th and 32nd week of gestation (all P < 0.001). Results were similar for leptin levels at 6 weeks and at 4 months post-partum; therefore, only correlations for the 6-week data are presented (Table 2). In contrast, no significant correlations were found between milk total adiponectin and maternal anthropometry (data not shown).

Table 2. Correlations of breast milk leptin with maternal anthropometry
Anthropometric variablenR*P
  1. *Spearman correlation coefficient. SFT, skin-fold thickness; wk gest, week of gestation.

Pre-pregnancy BMI1520.49<0.001
BMI (15th wk gest)1520.52<0.001
Sum 4 SFTs (15th wk gest)980.57<0.001
Percentage body fat (15th wk gest)1150.54<0.001
BMI (32nd wk gest)1490.57<0.001
Sum 4 SFTs (32nd wk gest)1080.61<0.001
Percentage body fat (32nd wk gest)1170.61<0.001

Breast milk adipokines in relation to infant outcomes up to 2 years

Of the infants included in the present analysis, 85% were exclusively and 15% were partially breastfed until 6 weeks; 83% and 17%, respectively, were exclusively or partially breastfed until 4 months post-partum.

Milk leptin at 6 weeks post-partum was not related to any of the infant clinical outcomes from 6 weeks until the age of 2 years (data not shown). However, milk leptin concentration at 4 months post-partum was significantly inversely associated with infant weight (adjusted regression coefficient beta [95% CI]: −604.96 g [−1166.19; −43.72], P = 0.037) and lean body mass (−400.95 g [−777.64; −24.25], P = 0.039) at the age of 4 months, but not at later time points, in the model corrected for maternal pre-pregnancy BMI, gestational weight gain, pregnancy duration, sex, ponderal index at birth and mode of infant feeding (Supporting Information Table S1).

Milk adiponectin at 6 weeks was significantly inversely associated with lean body mass at 4 months (−11.43 g [−20.51; −2.34], P = 0.015) and tended to be inversely related to infant weight at 4 months (−13.25 g [−26.61; 0.11], P = 0.054) in the adjusted analysis. In contrast, the associations were positive for infant weight gain (23.70 g [1.23; 46.17], P = 0.041) up to 1 year, the sum of four skin-folds (0.09 mm [0.01; 0.18], P = 0.037), percentage body fat (0.06% [0; 0.12], P = 0.037) and fat mass (8.86 g [0.25; 17.47], P = 0.046) at 1 year and, in the unadjusted model only, up to 2 years (e.g. weight gain: 27.01 g [3.34;50.69], P = 0.027; sum of skin-folds: 0.10 mm [0; 0.21], P = 0.047) (Table 3). Likewise, higher milk adiponectin at 4 months was associated with greater weight gain up to 2 years (29.48 g [3.29; 55.05], P = 0.026) (Fig. 1a) and higher infant fat mass expressed as the sum of four skin-folds (badj: 0.14 mm [0.02; 0.25], P = 0.023) (Fig. 1b), percentage body fat (0.10% [0.02; 0.18], P = 0.020), and absolute body fat (17.42 g [0.43; 34.41], P = 0.048) at 2 years in the adjusted model, also after exclusion of outliers. No relevant interactions by the treatment with n-3 LCPUFA or maternal pre-pregnancy BMI in the reported associations were found.

Table 3. Breast milk total adiponectin (ng mL−1) at 6 weeks post-partum in relation to infant clinical outcomes up to the age of 2 years
Outcome variablenUnadjusted analysisAdjusted analysis*
Beta (95% CI)PBeta (95% CI)P
  1. Data are presented as the regression coefficient beta (95% confidence interval) from linear regression analyses. *adjusted for maternal pre-pregnancy BMI, gestational weight gain, pregnancy duration, sex, ponderal index at birth, group and mode of infant feeding (exclusively or partially breastfed) at 4 months post-partum. P-values ≤ 0.05 are given in bold. LBM, lean body mass; mo, months; pp, post-partum; SFT, skin-fold thickness; wk, week.

4 months pp     
Weight (g)147−8.61 (−22.37; 5.15)0.222−13.25 (−26.61; 0.11)0.054
BMI (kg m−2)147−0.01 (−0.04; 0.01)0.264−0.02 (−0.05; 0)0.096
Sum 4 SFT (mm)1470.01 (−0.07; 0.1)0.7460.01 (−0.07; 0.10)0.726
Body fat (%)1470.01 (−0.04; 0.06)0.7000.01 (−0.05; 0.07)0.679
Fat mass (g)146−1.32 (−6.76; 4.11)0.634−2.17 (−7.94; 3.61)0.463
LBM (g)146−7.59 (−17.53; 2.34)0.136−11.43 (−20.51; −2.34)0.015
Weight gain (6 wks – 4 mo pp)147−8.47 (−17.08; 0.13)0.056−8.40 (−19.3; 2.51)0.133
1 year pp     
Weight (g)14521.11 (0.97; 41.25)0.04211.32 (−8.39; 31.03)0.262
BMI (kg m−2)1450.02 (0; 0.05)0.0980.01 (−0.02; 0.04)0.446
Sum 4 SFT (mm)1400.09 (0.01; 0.17)0.0290.09 (0.01; 0.18)0.037
Body fat (%)1400.06 (0.01; 0.12)0.0280.06 (0; 0.12)0.037
Fat mass (g)14010.77 (2.49; 19.05)0.0128.86 (0.25; 17.47)0.046
LBM (g)14011.66 (−2.45; 25.77)0.1084.15 (−9.17; 17.46)0.543
Weight gain (6 wks – 1 year pp)14521.51 (4.11; 38.9)0.01723.70 (1.23; 46.17)0.041
2 years pp     
Weight (g)14426.85 (0.58; 53.11)0.04716.28 (−10.54; 43.10)0.236
BMI (kg m−2)1440.01 (−0.01; 0.04)0.3540.00 (−0.03; 0.03)0.924
Sum 4 SFT (mm)960.10 (0; 0.21)0.0470.09 (−0.02; 0.20)0.117
Body fat (%)960.07 (0; 0.14)0.0460.06 (−0.02; 0.13)0.126
Fat mass (g)9614.68 (−0.67; 30.02)0.06411.57 (−4.85; 27.98)0.171
LBM (g)9615.22 (−14.32; 44.76)0.31510.45 (−18.98; 39.88)0.488
Weight gain (6 wks – 2 years pp)14427.01 (3.34; 50.69)0.02717.73 (−6.20; 41.66)0.149
figure

Figure 1. Association of breast milk total adiponectin at 4 months post-partum (pp) with (a) weight gain up to 2 years (N = 117) and (b) infants' sum of 4 skin-folds at 2 years (N = 78) by linear regression. Solid line = regression line without exclusion of outliers; Dashed line = regression line after exclusion of outliers (excluded values for total milk adiponectin: 50.16 ng/ml and 37.20 ng/ml).

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

In this study, we explored the relationship of leptin and adiponectin in breast milk with infant weight gain and body composition based on skin-fold thickness measurements up to 2 years of life. Whereas milk leptin measured at 4 months was inversely related to concurrent infant weight, BMI and lean body mass, no associations with infant growth and body composition at later follow-up were found. In contrast, milk adiponectin tended to be inversely related to infant anthropometry in the early postnatal period (up to 4 months), but afterwards was positively associated with infant weight gain and even fat mass up to 2 years of life.

Several previous studies reported inverse associations between breast milk leptin levels and infant weight gain or BMI, suggesting a role for milk-borne leptin in the early regulation of body weight [10, 14, 16, 24]. In contrast, we could not demonstrate associations of milk leptin concentrations with infant weight gain or adiposity, despite a transient inverse relationship with infant BMI and lean body mass at 4 months. This is in agreement with other human studies [25, 26], including one large observational study showing no clear relationship between milk leptin content at 6 weeks post-partum and the odds of overweight up to 2 years in infants breastfed for at least 6 months [12].

Regardless of the somewhat inconsistent findings from human studies, animal studies provided some evidence for a direct cause–effect of orally supplied leptin in regulating food intake and weight gain [11, 27]. These and other observations indicate a role for exogenous leptin supply in the short- and long-term regulation of food intake and further metabolic adaptations, resulting in decreased fat mass and markers of the metabolic syndrome [11, 13, 28]. Such a function of oral leptin could also be conceivable in breastfed infants, especially in early life, when the appetite regulatory system is still immature [16, 27]. However, our data do not support a sustained effect in the longer term up to 2 years of life.

The relationship of breast milk adiponectin with infant anthropometry is less well studied. Previously, three studies have addressed associations of human milk adiponectin with infant growth and body weight/BMI [12, 15, 17]. In a large cohort study, higher levels of milk adiponectin were related to greater odds of overweight at the age of 2 years [12]. In contrast, another study showed higher milk adiponectin concentrations to be associated with lower infant weight-for-age z-score over the first 6 months of life [15]. Interestingly, follow-up of the infants revealed that exposure to higher milk adiponectin was associated with increased weight trajectory in the second year of life, indicating a reversal of the effect seen in early infancy [17]. Our results are in agreement with these findings, suggesting that breast milk adiponectin may exert differential effects on weight gain during the period of active breastfeeding compared with later infancy [17]. It was further suggested that the association of high milk adiponectin with accelerated growth trajectories over the second year of life might reflect catch-up growth after less pronounced weight gain in the early postnatal period [17]. Here, we extend previous findings in demonstrating that higher adiponectin in breast milk was not only associated with more pronounced weight gain, but also with higher fat mass assessed by skin-fold thickness measurements up to 2 years. A potential mechanistic link for our findings might be provided by the central effects of adiponectin, as it was shown to stimulate food intake and decrease energy expenditure in the hypothalamus [29].

Generally, the potential of breast milk adipokines to affect infant growth and metabolism depends on their bioavailability. However, due to their molecular size, absorption of both milk adipokines is questionable [3, 6]. In rats, orally ingested leptin was shown to be absorbed by the immature stomach of the suckling pups and transferred to the infant circulation [4, 27]. For adiponectin, the transport across the intestinal mucosa into the serum was demonstrated in mice after administering adiponectin through orogastric intubation [30]. However, in humans, it is currently unclear whether or to which extent these milk proteins reach the infant circulation and are transferred to the target organs in its biologically active form [30].

A strength of our study is the longitudinal design including a comprehensive assessment of infant growth and body composition over the first two years of life. Importantly, we here provide additional data on infant body composition beyond the rather general growth parameters, although skin-fold measurements also have limitations. Weaknesses of our study are the considerable loss to follow-up until 2 years of life and the treatment with n-3 LCPUFA in one part of the studied population, which could be masking or affecting the relation between adipokines in breast milk and infant outcomes. However, as no significant interactions by study group were observed, this seems unlikely. It should also be considered that both milk samples collected within the study reflect mature milk. Therefore, we could have missed the influence of adipokines in earlier stages of lactation mediated by colostrum or transitional milk.

In conclusion, milk leptin did not show a clear relationship with infant growth and body composition up to 2 years despite a transient inverse association with infant growth up to 4 months, whereas adiponectin was positively associated with infant fat mass and weight gain up to 2 years of life. Although the latter finding is compatible with previous studies [12, 17], the underlying mechanisms for such an effect remain to be elucidated.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

Funding: Else Kröner-Fresenius Foundation, Bad Homburg, Germany; the International Unilever Foundation, Hamburg, Germany; the EU-funded EARNEST consortium (FOOD-CT-2005–007036); and the German Ministry of Education and Research via the Competence Network Obesity (Kompetenznetz Adipositas, 01GI0842).

We thank the technical staff of the Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany, for assistance in performing the laboratory analyses. We thank Dr. Tibor Schuster and Ina Rondak, Institute for Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany, for statistical advice.

Author contributions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information

HH, UAG and BLB designed the research; SB, DS, KZ and DM were responsible for data collection and trial management; BK performed the statistical analyses; SB wrote the manuscript; JK was responsible for laboratory analyses; all authors contributed to the critical revision of the manuscript.

References

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  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. Acknowledgements
  9. Author contributions
  10. References
  11. Supporting Information
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Table S1. Breast milk leptin (ng mL−1) at 4 months post-partum in relation to infant clinical outcomes up to the age of 2 years.

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