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 June 3, 2019; First 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 7

AKG-mediated signaling to adipocytes is inactivated at BeAT/WAT transition.

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AKG-mediated signaling to adipocytes is inactivated at BeAT/WAT transiti...
(A) ATMs were treated with vehicle or AKGs for 30 minutes, and PAF levels were measured in the cell culture media. ATMs were pretreated with vehicle or 10 ng/ml IL-4 for 18 hours. (B) Transcript levels of Agmo in mouse ATMs isolated at P3, P7, P14, and P56. One data point represents pooled ATM samples from 9 to 11 neonate (P3, P7, P14) and 3 to 4 adult (P56) mice. ##P < 0.01, 1-way ANOVA with Dunnett’s post hoc test. (C) FACS histogram showing ATM expression of AGMO and LPCAT2 at P3 and P56 and following 3-months HFD feeding in mouse. (D) Plasma NPFF levels in C57/BL6 mouse at P3 and P10 and at weaning. **P < 0.01, Student’s 2-tailed unpaired t test. (E) Left: effect of NPFF on Agmo transcription in ATMs and 3T3-L1 adipocytes. Cells were treated with vehicle or 1 nM NPFF for 18 hours in vitro. Another data set of NPFF-induced transcriptional changes in macrophages has been published previously (62) (GEO GSE90658). Right: NGS analysis of 3T3-L1 adipocytes treated with vehicle or NPFF for 18 hours. Ontology of significantly upregulated transcripts (P < 0.001) is shown. Pink bars, combined score ranking; gray bars, rank-based ranking of GO terms. TEM images of 3T3-L1 adipocytes treated with vehicle or 1 nM NPFF for 18 hours. Arrowheads show mitophagosome membranes. mb, multilamellar body. Scale bars: 5 μm; 1 μm (insets). (F) Schematic of AKG-mediated signaling in AT. (a) Breast milk AKGs are metabolized by ATMs into PAF. (b) In an autocrine loop, PAF triggers IL-6 release from ATMs. (c) The secreted IL-6 activates adipocyte JAK/STAT3 signaling. (d) This triggers BeAT gene transcription and prevents a premature BeAT/WAT transition. (e) Under physiological conditions, AKG signaling in AT is active only in infancy and is inactivated in lean adult AT.