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Teperino, R. ; Adamová, M.* ; Aljabali, S. M. ; Pai, S. ; Gerlini, R. ; Paez-Perez, I.* ; Matz-Soja, M.* ; Heyne, S.* ; Lempradl, A.* ; Basilicata, M.F.* ; Hrabě de Angelis, M. ; Gebhardt, R.* ; Schleicher, E.* ; Häring, H.U.* ; Pospisilik, J.A.*

Liver-derived Indian Hedgehog (Ihh) couples fast-feed transition to thermogenic and metabolic homeostasis.

Mol. Metab. 106:102339 (2026)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND & AIMS: Obesity and type 2 diabetes are global health challenges driven by genetic and environmental factors, including diet. While intermittent fasting improves metabolic health, the hepatic mechanisms linking feeding transitions to systemic metabolic regulation remain unclear. We investigated whether Indian Hedgehog (Ihh), a liver-derived hepatokine, coordinates metabolic responses to nutritional transitions. METHODS: We employed genetic and epigenetic tools, including liver-specific deletion of the PRC2 component Eed, to study Ihh regulation. In vivo metabolic phenotyping, thermogenic gene profiling, and Ihh immunoneutralization assessed its function. VLDL-associated Ihh levels were measured and their correlations with metabolic traits were analyzed in humans. RESULTS: Ihh is induced upon feeding and promotes adipose thermogenesis, enhancing metabolic flexibility. The Ihh locus in hepatocytes resides in a bivalent chromatin state; hepatic Eed deletion derepresses Ihh, conferring resistance to diet-induced obesity and insulin resistance. Immunoneutralization of Ihh reverses this protection, confirming its necessity. Ihh circulates in complex with VLDL. Human Ihh-VLDL levels decline with age and correlate with improved metabolic parameters, including insulin sensitivity, HDL/LDL ratio, and reduced adiposity. CONCLUSIONS & IMPLICATIONS: Ihh is a liver-derived, epigenetically regulated hepatokine that links nutrient timing to systemic metabolic control by stimulating thermogenesis and promoting glucose homeostasis. These findings identify Ihh as a key inter-organ signal coupling hepatic chromatin dynamics to energy balance. The age-related decline in circulating Ihh and its strong association with metabolic health suggest that enhancing Ihh signaling may represent a novel therapeutic avenue for obesity and type 2 diabetes.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Polycomb Repressive Complex 2; Hedgehog; Hepatokine; Browning; VLDL; Metabolism; Signaling Pathway; Messenger-rna; Prc2; Brown; Adipocytes; Expression; Mutations; Zonation; Cilia; White
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Quellenangaben Volume: 106, Issue: , Pages: , Article Number: 102339 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Grants European Research Council
Max Planck Society
Helmholtz Association (Helmholtz ERC Recognition Award)
Minerva Association (ARCHES Prize)
German Diabetes Center
Marie-Curie Action
Italian Association for Cancer Research (AIRC)
Planck Institute for Immunobiology and Epigenetics in Freiburg