Brown Fat-Activating Lipokine 12,13-diHOME in Human Milk Is Associated With Infant Adiposity

Abstract

Context: Little is known about the specific breastmilk components responsible for protective effects on infant obesity. Whether 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), an oxidized linoleic acid metabolite and activator of brown fat metabolism, is present in human milk, or linked to infant adiposity, is unknown.

Objective: To examine associations between concentrations of 12,13-diHOME in human milk and infant adiposity.

Design: Prospective cohort study from 2015 to 2019, following participants from birth to 6 months of age.

Setting: Academic medical centers.

Participants: Volunteer sample of 58 exclusively breastfeeding mother-infant pairs; exclusion criteria included smoking, gestational diabetes, and health conditions with the potential to influence maternal or infant weight gain.

Main outcome measures: Infant anthropometric measures including weight, length, body mass index (BMI), and body composition at birth and at 1, 3, and 6 months postpartum.

Results: We report for the first time that 12,13-diHOME is present in human milk. Higher milk 12,13-diHOME level was associated with increased weight-for-length Z-score at birth (β = 0.5742, P = 0.0008), lower infant fat mass at 1 month (P = 0.021), and reduced gain in BMI Z-score from 0 to 6 months (β = -0.3997, P = 0.025). We observed similar associations between infant adiposity and milk abundance of related oxidized linoleic acid metabolites 12,13-Epoxy-9(Z)-octadecenoic acid (12,13-epOME) and 9,10-Dihydroxy-12-octadecenoic acid (9,10-diHOME), and metabolites linked to thermogenesis including succinate and lyso-phosphatidylglycerol 18:0. Milk abundance of 12,13-diHOME was not associated with maternal BMI, but was positively associated with maternal height, milk glucose concentration, and was significantly increased after a bout of moderate exercise.

Conclusions: We report novel associations between milk abundance of 12,13-diHOME and adiposity during infancy.

Trial registration: ClinicalTrials.gov NCT02535637.

Keywords: 12; 13-diHOME; breastmilk; brown fat activators; infant adiposity; infant metabolism; thermogenic metabolites.

Figure 1.

Associations of milk 12,13-diHOME and anthropometry measures in infancy. A, Linear association between log(12,13-diHOME) in milk and BMI Z-score at birth, P = 0.005. B, Infant adiposity (% fat assessed by ADP) at 1 month by milk 12,13-diHOME tertile. P = 0.077; P(adjusted) = 0.021 (covariates: infant sex, gestational age, maternal pregravid BMI, gestational weight gain, and parity) C, Linear association between milk log(12,13-diHOME) and change in infant BMI Z-score from 0 to 6 months, P = 0.025. D, Change in infant weight-for-age (WFA) Z-score according to tertile of milk 12,13-diHOME. E, Change in infant length-for-age (LFA) Z-score according to tertile of milk 12,13-diHOME. F, Change in infant weight-for-length (WFL) Z-score according to tertile of milk 12,13-diHOME. * denotes P < 0.05, ** denotes P < 0.01.

Figure 2.

Associations of milk Ephx1-4 metabolites and anthropometry measures in infancy. A, Biosynthetic pathway for 12,13-diHOME. B, Linear association between log(9,10-diHOME) in milk and infant BMI Z-score at birth, P = 0.007. C, Change in WFL Z-score from 0 to 6 months according to tertile of log(9,10-diHOME) in milk. D, Linear association between milk log(9,10-diHOME) and change in WFL Z-score from 0 to 6 months, P = 0.029. E, Linear association between log(12,13-epOME) in milk and infant BMI Z-score at birth, P = 0.026. F, Change in WFL Z-score from 0 to 6 months according to tertile of log(12,13-epOME) in milk. G, Linear association between milk log(12,13-epOME) and change in WFL Z-score from 0 to 6 months, P = 0.064. * denotes P < 0.05, ** denotes P < 0.01.

Figure 3.

Breast milk 12,13-diHOME concentration rises after a moderate exercise bout. Change in 12,13-diHOME concentrations at baseline and 90 minutes after a bout of moderate exercise at 1 month postpartum. N = 16. **P = 0.0076, 2-sided paired t test, pre- vs post-exercise.