Journal Article

DKFZ-2026-02333

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Westernized diet related arachidonic acid metabolism expands DNA error-prone growth factor-dependent colonic quiescent stem cells in adolescent mice.

Christiansen, L. ; Ragab, M. ; Nickel, L. ; Sünderhauf, A. ; Jegodzinski, L. ; Hicken, M. ; Schlichting, H. ; Weikamp, R. ; Schmelter, F. ; Margis, D. ; Mertel, S. ; Richerzhagen, I. ; Wenk, H. ; Pötter, L. ; Tornow, S. ; Buchmann, N. ; Vondran, D. ; Gottschild, C. ; Raschdorf, A. ; Nogueira de Almeida, L. ; consortium, O.-C. (Collaboration Author) ; Künstner, A. ; Busch, H. ; Gemoll, T. ; Sadik, C. D. ; Castven, D. ; Marquardt, J. U. ; Divanovic, S. ; Raasch, W. ; Sina, C. ; Derer, S. ; von Bubnoff, N. (Contributor) ; Katalinic, A. (Contributor) ; Oberländer, M. (Contributor) ; Deck, R. (Contributor) ; Sültmann, H. (Contributor)DKFZ* ; Hutzenlaub, T. (Contributor) ; Jülg, P. (Contributor)

2026
Nature Publishing Group London [u.a.]

Abstract: Given the association between early-onset colorectal cancer (eoCRC) and insulin resistance (IR), we investigated the effects of westernized diet (WD)-induced IR on intestinal stem cells (ISCs) by in-depth phenotyping three adolescent mouse models of escalating WD-driven IR. WD-related hyperlipidaemia and hyperglycaemia enhanced ω6-polyunsaturated fatty acid (PUFA) metabolism, while inhibiting glucose metabolism, resulting in colonic epithelial cell (EC) energy deficiency, hypoproliferation, and quiescent ISCs (qISC) expansion. WD-induced systemic IR provoked colonic EC IR, reduced ω6-PUFA metabolism, which was compensated by aberrated triglyceride metabolism and growth factor receptor signalling, causing hyperproliferation of expanded qISCs. Combined with single-cell transcriptomic data and colonic 3D-organoid analysis we revealed that the ω6-PUFA arachidonic acid inhibited glucose uptake, favouring colonic EC IR driven expansion of the lipid-dependent inherently DNA-mismatch prone qISC compartment in expense of the insulin-dependent LGR5+ ISCs. Overall, our findings may open new alleys for targeted nutritional interventions in eoCRC prevention.

Keyword(s): Animals (MeSH) ; Arachidonic Acid: metabolism (MeSH) ; Stem Cells: metabolism (MeSH) ; Colon: metabolism (MeSH) ; Colon: pathology (MeSH) ; Colon: cytology (MeSH) ; Mice (MeSH) ; Diet, Western: adverse effects (MeSH) ; Insulin Resistance (MeSH) ; Cell Proliferation (MeSH) ; Glucose: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Arachidonic Acid ; Glucose

Note: #DKTKZFB26# / #NCTZFB26#

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Contributing Institute(s):

1. Krebsgenomforschung (B063)
2. DKTK HD zentral (HD01)
3. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2026

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Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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