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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Categories: 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 5

AKG-induced BeAT development is mediated by PAF/IL-6/STAT3 signaling.

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AKG-induced BeAT development is mediated by PAF/IL-6/STAT3 signaling. (A...
(A) Histology at P7 and P10; BeAT and TG content of AT at P10 in WT and Ptafr–/– mice. Arrowheads show BeAT. Scale bars: 65 μm. (B) PAF and BeAT content of AT at P10 and AT histology at P7 and P10 in WT and Pla2g2a-Tg (PLA2G2A-overexpressing) mice. Scale bars: 80 μm. (C) Relative transcription of Ucp1 and Ppargc1a in 3T3-L1 adipocytes treated with vehicle, 50 nM PAF, or carbamyl PAF (Carb-PAF) for 18 hours. (D) MitoTracker Red staining and TEM image of 3T3-L1 adipocytes treated with conditioned media of ATMs for 18 hours. ATMS were treated with vehicle or 50 nM PAF. See also Supplemental Figure 7G. Arrowheads show mitochondria. Scale bars: 5 μm. (E) Mitochondrial content and MFI of MitoTracker Green labeling of 3T3-L1 adipocytes treated with vehicle or 50 nM PAF for 18 hours in the presence of ATMs. SR27417, PTAFR blocker. (F) Transcription of BeAT genes in adipocytes treated with 0.2 ng/ml IL-6 or 50 pg/ml TNF-α for 18 hours. (G) Transcription factor–binding site analysis of BeAT genes. (H) STAT3 phosphorylation in adipocytes treated with vehicle or AKGs for 30 minutes in Transwell assay shown in Figure 3A. (I) ATMs were treated with vehicle (Veh) or AKGs for 4 hours, and culture media were added to adipocytes for a further 18 hours. CIM summarizes transcriptional changes evoked in adipocytes. STAT3 was inhibited with 500 nM cucurbitacin I, JAK/STAT3 with 280 nM ruxolitinib. (J) Schematic of the mechanism by which AKGs trigger BeAT gene transcription in adipocytes. **P < 0.01; ***P < 0.001, Student’s 2-tailed unpaired t test.