TY  - JOUR
AU  - Makdissi, Nikola
AU  - Hirschmann, Daria J
AU  - Frolov, Aleksej
AU  - Sado, Inaam
AU  - Bennühr, Bastian
AU  - Nikolka, Fabian
AU  - Cheng, Jingyuan
AU  - Blank-Stein, Nelli
AU  - Viola, Maria Francesca
AU  - Yaghmour, Mohamed
AU  - Arnold, Philipp
AU  - Bonaguro, Lorenzo
AU  - Becker, Matthias
AU  - Thiele, Christoph
AU  - Meissner, Felix
AU  - Hiller, Karsten
AU  - Beyer, Marc D
AU  - Mass, Elvira
TI  - Kupffer cells control neonatal hepatic metabolism via Igf1 signaling.
JO  - Development
VL  - 153
IS  - 2
SN  - 0022-0752
CY  - Cambridge
PB  - The Company of Biologists
M1  - DZNE-2026-00116
SP  - dev204962
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Insulin-Like Growth Factor I: metabolism
KW  - Kupffer Cells: metabolism
KW  - Kupffer Cells: cytology
KW  - Liver: metabolism
KW  - Liver: cytology
KW  - Hepatocytes: metabolism
KW  - Mice
KW  - Signal Transduction
KW  - Animals, Newborn
KW  - Mice, Knockout
KW  - Glycogen: metabolism
KW  - Yolk Sac: metabolism
KW  - Yolk Sac: cytology
KW  - Citric Acid Cycle
KW  - Hepatocytes (Other)
KW  - Igf1 (Other)
KW  - Kupffer cell (Other)
KW  - Liver development (Other)
KW  - Macrophage (Other)
KW  - Insulin-Like Growth Factor I (NLM Chemicals)
KW  - Glycogen (NLM Chemicals)
KW  - insulin-like growth factor-1, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41459815
DO  - DOI:10.1242/dev.204962
UR  - https://pub.dzne.de/record/284345
ER  -