Journal Article

DZNE-2026-00116

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Kupffer cells control neonatal hepatic metabolism via Igf1 signaling.

Makdissi, N.Extern* ; Hirschmann, D. J. ; Frolov, A.DZNE* ; Sado, I.Extern* ; Bennühr, B. ; Nikolka, F. ; Cheng, J. ; Blank-Stein, N. ; Viola, M. F. ; Yaghmour, M. ; Arnold, P. ; Bonaguro, L.DZNE* ; Becker, M.DZNE* ; Thiele, C. ; Meissner, F. ; Hiller, K. ; Beyer, M. D.DZNE* ; Mass, E. (Last author)DZNE*

2026
The Company of Biologists Cambridge

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Please use a persistent id in citations: doi:10.1242/dev.204962

Abstract: During perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting neonatal energy demands. Shortly after birth, lipogenesis begins, driven by transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the liver's resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet whether KCs influence neonatal hepatocyte metabolism is unknown. Using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a crucial role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid cycle, a role monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process in part regulated by insulin-like growth factor 1 (Igf1) production. Our findings identify KCs as major source of Igf1, with local production essential for balanced hepatocyte metabolism at birth.

Keyword(s): Animals (MeSH) ; Insulin-Like Growth Factor I: metabolism (MeSH) ; Kupffer Cells: metabolism (MeSH) ; Kupffer Cells: cytology (MeSH) ; Liver: metabolism (MeSH) ; Liver: cytology (MeSH) ; Hepatocytes: metabolism (MeSH) ; Mice (MeSH) ; Signal Transduction (MeSH) ; Animals, Newborn (MeSH) ; Mice, Knockout (MeSH) ; Glycogen: metabolism (MeSH) ; Yolk Sac: metabolism (MeSH) ; Yolk Sac: cytology (MeSH) ; Citric Acid Cycle (MeSH) ; Hepatocytes ; Igf1 ; Kupffer cell ; Liver development ; Macrophage ; Insulin-Like Growth Factor I ; Glycogen ; insulin-like growth factor-1, mouse

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Contributing Institute(s):

1. Platform for Single Cell Genomics and Epigenomics (PRECISE)
2. Immunogenomics and Neurodegeneration (AG Beyer)
3. Molecular and Translational Immunaging (AG Bonaguro)
4. Modular High Performance Computing and Artificial Intelligence (AG Becker)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)
3. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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