Preprint
Intestinal catabolism of dietary fructose promotes obesity and insulin resistance via ileal lacteal remodeling
bioRxiv
Cold Spring Harbor Laboratory, 1.1
08/22/2025
DOI: 10.1101/2025.08.18.670963
PMID: 40894608
Abstract
High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and metabolic syndrome, yet the underlying mechanisms are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we unexpectedly found that inhibition of fructose catabolism specifically in the small intestine mitigates fructose-induced obesity and insulin resistance. Mechanistically, blocking intestinal fructose catabolism reduces dietary fat absorption, which is associated with a decrease in the surface area of the ileal lacteals and alterations in gut microbiome. Fecal transplantation experiments revealed that such a microbiome stimulates the intestine-resident macrophages, promoting lacteal growth and boosting dietary fat absorption. Given the preclinical and clinical studies reporting the effect of fructose catabolism suppression on mitigating diet-induced obesity, our data suggest that such effects are partly mediated by intestinal lacteal remodeling.
Here, we uncover a previously unappreciated link between intestinal fructose catabolism and ileal lacteal remodeling, suggesting the mechanisms by which fructose intake promotes obesity. Using mice lacking the fructose-processing enzyme specifically in the intestine, we show that blocking intestinal fructose metabolism protects against diet-induced obesity by reducing fat absorption. Changes in gut microbiome and immune cell interactions drive this effect.
Details
- Title: Subtitle
- Intestinal catabolism of dietary fructose promotes obesity and insulin resistance via ileal lacteal remodeling
- Creators
- Miranda L. Lopez - University of California, IrvineTaekyung Kang - University of California, IrvineAna Espeleta - University of California, IrvineVarvara I. Rubtsova - University of California, IrvineJongwon Baek - University of California, IrvineJakob Songcuan - University of California, IrvineElena M. Moyer - University of California, IrvineJoohwan Kim - University of California, IrvineWon-Suk Song - University of California, IrvineSunhee Jung - University of California, IrvineNicholas D’Sa - University of California, IrvineAlexis Anica - University of California, IrvineElise Tran - University of California, IrvineYujin Chun - University of California, IrvineWonsuk Choi - University of California, IrvineKi-Hong Jang - University of California, IrvineMiranda E. Kelly - University of California, IrvineIan J Tamburini - University of California, IrvineYasmine H. Alam - University of California, IrvineJohnny Le - University of California, IrvineCuauhtemoc B. Ramirez - University of California, IrvineRaghu P. Kataru - Memorial Sloan Kettering Cancer CenterSeon Pyo Hong - Institute for Basic ScienceDequina A. Nicholas - University of California, IrvineKatherine S. Xue - University of California, IrvineGina Lee - University of California, IrvineHosung Bae - University of California, IrvineCholsoon Jang - University of California, Irvine
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- Edition
- 1.1
- DOI
- 10.1101/2025.08.18.670963
- PMID
- 40894608
- NLM abbreviation
- bioRxiv
- ISSN
- 2692-8205
- eISSN
- 2692-8205
- Publisher
- Cold Spring Harbor Laboratory
- Number of pages
- 25
- Language
- English
- Date posted
- 08/22/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985216994402771