Kupffer cell programming by maternal obesity triggers fatty liver disease

Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis<sup>1</sup>. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions<sup>1-3</sup>. 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 metabolism<sup>4</sup>. 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 diseases<sup>5</sup>.

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Journal
Nature
Published
2025-06-18
DOI
https://doi.org/10.1038/s41586-025-09190-w
Citations
24
Primary Topic
Birth, Development, and Health
Type
article
Field-Weighted Citation Impact
83.86
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article

Kupffer cell programming by maternal obesity triggers fatty liver disease

Eliana Franco Taveras, Martin Guilliams, Amir Hossein Kayvanjoo, Thomas Ulas et al.
24 citations
Nature
Birth, Development, and Health
83.86
article

Kupffer cell programming by maternal obesity triggers fatty liver disease

Eliana Franco Taveras, Martin Guilliams, Amir Hossein Kayvanjoo, Thomas Ulas, Jelena Zurkovic, Marc Beyer, Nora Reka Balzer, Katharina Mauel, Klaus Wunderling, Zhaoyuan Liu, Hao Huang, Iva Šplíchalová, Florent Ginhoux, Lukas Kenner, Stephan Grein, Jan Hasenauer, Elvira Mass, Joachim L. Schultze, Felix Meissner, Lea Seep, Charlotte L. Scott, Dagmar Wachten, Nikola Makdissi, Mohamed H. Yaghmour, Maria Francesca Viola, Nelli Blank‐Stein, Carolin Radwaniak, Kerim Acil, Christoph Thiele, Filip Petrović, Malin Jessen, Diana Fink, Seyhmus Bayar
article en
24 citations

Abstract

Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis<sup>1</sup>. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions<sup>1-3</sup>. 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 metabolism<sup>4</sup>. 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 diseases<sup>5</sup>.

NatureVol. 644(8077)
Agency for Science, Technology and Research (SG), University of Bonn (DE), University of Veterinary Medicine Vienna (AT), Inserm (FR), Shanghai Jiao Tong University (CN), Singapore Immunology Network (SG), German Center for Neurodegenerative Diseases (DE), Institut Gustave Roussy (FR), Ghent University (BE), Comprehensive Cancer Center Vienna (AT), SingHealth Duke-NUS Academic Medical Centre (SG), Christian Doppler Laboratory for Thermoelectricity (AT), Center For Biomarker Research In Medicine (AT), VIB-UGent Center for Inflammation Research (BE), Life & Brain (Germany) (DE), Medical University of Vienna (AT), Epigenomics (Germany) (DE), Umeå University (SE)
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