Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages

Haidong Yu

Sedat Dilbaz

Jonas Coßmann

Anh Hoang

Toru Moriguchi+12 authors

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^{Institute of Neurobiology, and}

^{Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.}

^{Department of Food and Life Science, Azabu University, Sagamihara, Kanagawa, Japan.}

^{Center for Pediatric Research, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.}

^{Lipidomics Facility, CECAD Research Center, University of Cologne, Cologne, Germany.}

^{Department of Nuclear Medicine, National Public Health Center (NPHC), Budapest, Hungary.}

^{Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.}

^{Veterans Affairs Medical Center and the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.}

^{Department of Pharmacology and Toxicology, Wright State University, Dayton, Ohio, USA.}

^{Corresponding author.}

Haidong Yu: ed.mlu-inu@uy.gnodiah; Sedat Dilbaz: ed.mlu-inu@zablid.tades; Jonas Coßmann: ed.mlu-inu@nnamssoc.sanoj; Anh Cuong Hoang: ed.mlu-inu@gnaoh.hna; Victoria Diedrich: ed.mlu-inu@hcirdeid.airotciv; Annika Herwig: ed.mlu-inu@giwreh.akinna; Akiko Harauma: pj.ca.u-ubaza@amuarah; Yukino Hoshi: pj.ca.u-ubaza@ihsoh; Toru Moriguchi: pj.ca.u-ubaza@ihcugirom; Kathrin Landgraf: ed.gizpiel-inu.nizidem@fargdnaL.nirhtaK; Antje Körner: ed.gizpiel-inu.nizidem@renreok.ejtna; Christina Lucas: ed.nleok-ku@sacul.anitsirhc; Susanne Brodesser: ed.nleok-ku@ressedorb.ennasus; Lajos Balogh: uh.iksso@sojal.hgolab; Gopal Karemore: moc.ksidronovon@akpg; Michael Scott Kuefner: ude.cshtu@renfeukm; Edwards A. Park: ude.cshtu@krape; Christine Rapp: ude.thgirw@ppar.enitsirhc; Tamás Röszer: ed.mlu-inu@rezseor.samat

Address correspondence to: Tamás Röszer, Institute of Neurobiology, University of Ulm Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49.0.731.50.22695; Email: ed.mlu-inu@rezseor.samat.

Authorship note: HY and SD contributed equally to this work.

Received 2018 Oct 30; Accepted 2019 Mar 12.

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.

Keywords: Immunology, Metabolism

Keywords: Adipose tissue, Macrophages, Obesity

Abstract

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Abstract

Acknowledgments

This study was supported by the German Research Fund (RO4856/1-2 to TR; CRC1052 C05 to AK), the European Foundation for the Study of Diabetes on New Targets for Type 2 Diabetes, supported by MSD (96403 to TR); the Federal Ministry of Education and Research, Germany (FKZ, 01EO1501 IFB Adiposity Diseases to AK); Horizon 2020 Research and Innovation Program MCIF (655598 to TR); and the PRC Scholarship Council (201808080208 to HY). Nonhuman primate tissues were provided by the Wisconsin National Primate Research Center Nonhuman Primate Biological Materials Distribution Core (award no. P51OD011106). Indirect calorimetry equipment was developed and provided by Gerhard Heldmaier. AT samples were kindly provided by Sarah Strauß (Hannover Medical University). The help of Benjamin Mayer with statistical analyses and the contributions of S.F.H. Waqas, Grace Ampem, and Kristina Geiß are appreciated. We thank Kenneth McCreath for scientific editing. The authors are grateful for the support of Harald Wolf, University of Ulm.

Acknowledgments

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Footnotes

Conflict of interest: GK has an affiliation with Novo Nordisk A/S.

Reference information: J Clin Invest. 2019;129(6):2485–2499.https://doi.org/10.1172/JCI125646.

Footnotes

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