Kupffer cell programming by maternal obesity triggers fatty liver disease

• 成果类型: Article
• 署名作者: Huang, Hao; Balzer, Nora R.; Seep, Lea; Splichalova, Iva; Blank-Stein, Nelli; Viola, Maria Francesca; Franco Taveras, Eliana; Acil, Kerim; Fink, Diana; Petrovic, Franzisca; Makdissi, Nikola; Bayar, Seyhmus; Mauel, Katharina; Radwaniak, Carolin; Zurkovic, Jelena; Kayvanjoo, Amir H.; Wunderling, Klaus; Jessen, Malin; Yaghmour, Mohamed H.; Kenner, Lukas; Ulas, Thomas; Grein, Stephan; Schultze, Joachim L.; Scott, Charlotte L.; Guilliams, Martin; Liu, Zhaoyuan; Ginhoux, Florent; Beyer, Marc D.; Thiele, Christoph; Meissner, Felix; Hasenauer, Jan; Wachten, Dagmar; Mass, Elvira
• 署名单位: University of Bonn; University of Bonn; University of Bonn; University of Bonn; University of Bonn; Medical University of Vienna; Medical University of Vienna; University of Veterinary Medicine Vienna; Umea University; Medical University of Vienna; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Bonn; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Bonn; Ghent University; Ghent University; Flanders Institute for Biotechnology (VIB); Ghent University; Flanders Institute for Biotechnology (VIB); Chinese Academy of Sciences; Shanghai Jiao Tong University; Universite Paris Saclay; Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Gustave Roussy; Agency for Science Technology & Research (A*STAR); A*STAR - Singapore Immunology Network (SIgN); Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Bonn
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2429
• DOI: 10.1038/s41586-025-09190-w
• 发表日期: 2025-08-21
• 关键词: developmental origins; microglia derive; macrophages; expression; metabolism; activation; precursors; sequence; exposure; platform

摘要

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, 2-3. 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-alpha (HIF1 alpha) 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.