Kupffer cell programming by maternal obesity triggers fatty liver disease

Hao Huang, Nora R. Balzer, Lea Seep, Iva Splichalova, Nelli Blank-Stein, Maria Francesca Viola, Eliana Franco Taveras, Kerim Acil, Diana Fink, Franzisca Petrovic, Nikola Makdissi, Seyhmus Bayar, Katharina Mauel, Carolin Radwaniak, Jelena Zurkovic, Amir H. Kayvanjoo, Klaus Wunderling, Malin Jessen, Mohamed H. Yaghmour, Lukas Kenner, Thomas Ulas, Stephan Grein, Joachim L. Schultze, Charlotte L. Scott, Martin Guilliams, Zhaoyuan Liu, Florent Ginhoux, Marc D. Beyer, Christoph Thiele, Felix Meissner, Jan Hasenauer, Dagmar Wachten and Elvira Mass ()
Additional contact information
Hao Huang: University of Bonn
Nora R. Balzer: University of Bonn
Lea Seep: University of Bonn
Iva Splichalova: University of Bonn
Nelli Blank-Stein: University of Bonn
Maria Francesca Viola: University of Bonn
Eliana Franco Taveras: University of Bonn
Kerim Acil: University of Bonn
Diana Fink: University of Bonn
Franzisca Petrovic: University of Bonn
Nikola Makdissi: University of Bonn
Seyhmus Bayar: University of Bonn
Katharina Mauel: University of Bonn
Carolin Radwaniak: University of Bonn
Jelena Zurkovic: University of Bonn
Amir H. Kayvanjoo: University of Bonn
Klaus Wunderling: University of Bonn
Malin Jessen: University of Bonn
Mohamed H. Yaghmour: University of Bonn
Lukas Kenner: Medical University of Vienna
Thomas Ulas: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) e.V.
Stephan Grein: University of Bonn
Joachim L. Schultze: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) e.V.
Charlotte L. Scott: Ghent University
Martin Guilliams: Ghent University
Zhaoyuan Liu: Shanghai Jiao Tong University School of Medicine
Florent Ginhoux: Shanghai Jiao Tong University School of Medicine
Marc D. Beyer: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) e.V.
Christoph Thiele: University of Bonn
Felix Meissner: University of Bonn
Jan Hasenauer: University of Bonn
Dagmar Wachten: University of Bonn
Elvira Mass: University of Bonn

Nature, 2025, vol. 644, issue 8077, 790-798

Abstract: Abstract Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis1. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions1–3. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism4. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-α (HIF1α) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases5.

Date: 2025
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DOI: 10.1038/s41586-025-09190-w

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