TY  - JOUR
AU  - Huang, Hao
AU  - Balzer, Nora
AU  - Seep, Lea
AU  - Splichalova, Iva
AU  - Blank-Stein, Nelli
AU  - Viola, Maria Francesca
AU  - Franco Taveras, Eliana
AU  - Acil, Kerim
AU  - Fink, Diana
AU  - Petrovic, Franzisca
AU  - Makdissi, Nikola
AU  - Bayar, Seyhmus
AU  - Mauel, Katharina
AU  - Radwaniak, Carolin
AU  - Zurkovic, Jelena
AU  - Kayvanjoo, Amir H
AU  - Wunderling, Klaus
AU  - Jessen, Malin
AU  - Yaghmour, Mohamed H
AU  - Kenner, Lukas
AU  - Ulas, Thomas
AU  - Grein, Stephan
AU  - Schultze, Joachim L
AU  - Scott, Charlotte L
AU  - Guilliams, Martin
AU  - Liu, Zhaoyuan
AU  - Ginhoux, Florent
AU  - Beyer, Marc D
AU  - Thiele, Christoph
AU  - Meissner, Felix
AU  - Hasenauer, Jan
AU  - Wachten, Dagmar
AU  - Mass, Elvira
TI  - Kupffer cell programming by maternal obesity triggers fatty liver disease.
JO  - Nature
VL  - 644
IS  - 8077
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DZNE-2025-00972
SP  - 790 - 798
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Kupffer Cells: metabolism
KW  - Kupffer Cells: pathology
KW  - Kupffer Cells: cytology
KW  - Female
KW  - Mice
KW  - Pregnancy
KW  - Hypoxia-Inducible Factor 1, alpha Subunit: genetics
KW  - Hypoxia-Inducible Factor 1, alpha Subunit: metabolism
KW  - Hypoxia-Inducible Factor 1, alpha Subunit: deficiency
KW  - Pregnancy in Obesity: pathology
KW  - Pregnancy in Obesity: metabolism
KW  - Fatty Liver: pathology
KW  - Fatty Liver: etiology
KW  - Fatty Liver: metabolism
KW  - Male
KW  - Liver: metabolism
KW  - Liver: pathology
KW  - Liver: embryology
KW  - Liver: cytology
KW  - Glycolysis
KW  - Hepatocytes: metabolism
KW  - Animals, Newborn
KW  - Disease Models, Animal
KW  - Oxidative Phosphorylation
KW  - Prenatal Exposure Delayed Effects: pathology
KW  - Mice, Inbred C57BL
KW  - Macrophages: metabolism
KW  - Obesity: complications
KW  - Hypoxia-Inducible Factor 1, alpha Subunit (NLM Chemicals)
KW  - Hif1a protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40533564
C2  - pmc:PMC12367551
DO  - DOI:10.1038/s41586-025-09190-w
UR  - https://pub.dzne.de/record/280788
ER  -