Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages
Haidong Yu, … , Jeffrey Bryant Travers, Tamás Röszer
Haidong Yu, … , Jeffrey Bryant Travers, Tamás Röszer
Published May 13, 2019
Citation Information: J Clin Invest. 2019;129(6):2485-2499. https://doi.org/10.1172/JCI125646.
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Research Article Immunology Metabolism

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages

Abstract

Prevalence of obesity among infants and children below 5 years of age is rising dramatically, and early childhood obesity is a forerunner of obesity and obesity-associated diseases in adulthood. Childhood obesity is hence one of the most serious public health challenges today. Here, we have identified a mother-to-child lipid signaling that protects from obesity. We have found that breast milk–specific lipid species, so-called alkylglycerol-type (AKG-type) ether lipids, which are absent from infant formula and adult-type diets, maintain beige adipose tissue (BeAT) in the infant and impede the transformation of BeAT into lipid-storing white adipose tissue (WAT). Breast milk AKGs are metabolized by adipose tissue macrophages (ATMs) to platelet-activating factor (PAF), which ultimately activates IL-6/STAT3 signaling in adipocytes and triggers BeAT development in the infant. Accordingly, lack of AKG intake in infancy leads to a premature loss of BeAT and increases fat accumulation. AKG signaling is specific for infants and is inactivated in adulthood. However, in obese adipose tissue, ATMs regain their ability to metabolize AKGs, which reduces obesity. In summary, AKGs are specific lipid signals of breast milk that are essential for healthy adipose tissue development.

Authors

Haidong Yu, Sedat Dilbaz, Jonas Coßmann, Anh Cuong Hoang, Victoria Diedrich, Annika Herwig, Akiko Harauma, Yukino Hoshi, Toru Moriguchi, Kathrin Landgraf, Antje Körner, Christina Lucas, Susanne Brodesser, Lajos Balogh, Julianna Thuróczy, Gopal Karemore, Michael Scott Kuefner, Edwards A. Park, Christine Rapp, Jeffrey Bryant Travers, Tamás Röszer

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Figure 3

Macrophages are necessary for the effect of AKGs on adipocytes.

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Macrophages are necessary for the effect of AKGs on adipocytes. (A) Sche...
(A) Schematic of a Transwell assay with ATMs and 3T3-L1 adipocytes. (B–G) Adipocytes were treated with vehicle or AKGs for 24 hours, without ATMs (–ATMs) or in the presence of ATMs (+ATMs). Each data point represents 1 Transwell assay (B, E–G) or 1 adipocyte (D). (B) MFI of MitoTracker Green in adipocytes after treatment. (C) MitoTracker Red staining and transmission electron microscopy (TEM) images of 3T3-L1 cells treated in the presence of ATMs. Asterisks show lipid droplets; arrowheads show mitochondria. Scale bars: 25 μm (MitoTracker Red); 5 μm (TEM). (D) Mitochondrial content of 3T3-L1 cells, determined with image analysis. (E) Relative NADH-DH activity of adipocytes. (F) Ucp1 transcription in adipocytes. (G) Oxygen consumption of adipocytes treated with conditioned media of ATMs for 18 hours. ATMs were treated with vehicle or AKGs for 4 hours before cell culture media was collected and used for treating adipocytes. (H) CIM representation of BeAT-marker gene transcription in iAT of HFD-fed mice treated with vehicle or AKGs. ATMs were depleted with clodronate liposomes 24 hours before treatment in 1 group of mice (n = 5). (I) AT from human and M. mulatta infants, labeled for CD163 and Iba1. Scale bars: 10 μm (upper panels); 25 μm (lower panels). **P < 0.01; ***P < 0.001, Student’s 2-tailed unpaired t test (B, E–G) 1-way ANOVA with Dunnett’s post hoc test (D).