Intestinal fructose catabolism promotes obesity and insulin resistance via ileal lacteal remodeling
High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and diabetes, yet the underlying mechanisms, especially at the specific organ level, 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 report that inhibition of fructose catabolism specifically in the murine small intestine unexpectedly mitigates fructose-induced obesity and insulin resistance. Such phenotypes are attributed to decreased dietary fat absorption by the shortening of ileal lacteals. Fecal transplantation experiments revealed that the microbiome altered by blunted host intestinal fructose catabolism decreases ileal macrophages essential for lacteal growth. Thus, altered intestinal lacteal architecture likely contributes to the synergistic effects of high fat and sugar on metabolic disorders. It may also be relevant to the clinical evidence that pharmacologic suppression of fructose catabolism mitigates diet-induced obesity.
Authors
- Hosung Bae (ORCID: https://orcid.org/0000-0001-5848-7972)
- Varvara I. Rubtsova (ORCID: https://orcid.org/0000-0003-3912-4820)
- Yasmine H. Alam
- Sunhee Jung (ORCID: https://orcid.org/0000-0001-5396-4813)
- Cholsoon Jang (ORCID: https://orcid.org/0000-0001-6651-4213)
- Wonsuk Choi (ORCID: https://orcid.org/0000-0002-0523-0839)
- Seon Pyo Hong (ORCID: https://orcid.org/0000-0002-9923-8099)
- Yujin Chun
- Katherine S. Xue (ORCID: https://orcid.org/0000-0002-4094-3615)
- Thomas Q. de Aguiar Vallim (ORCID: https://orcid.org/0000-0001-7642-5046)
- Ki-Hong Jang (ORCID: https://orcid.org/0000-0002-9914-8480)
- Joo‐Hwan Kim (ORCID: https://orcid.org/0000-0002-2999-4411)
- Gina Lee (ORCID: https://orcid.org/0000-0002-8120-9169)
- Raghu P. Kataru (ORCID: https://orcid.org/0000-0003-1315-7982)
- Sungji Cho (ORCID: https://orcid.org/0000-0002-1311-0191)
- Dequina Nicholas (ORCID: https://orcid.org/0000-0003-4996-2190)
- Cuauhtemoc B. Ramirez (ORCID: https://orcid.org/0000-0001-7182-1859)
- Johnny Le (ORCID: https://orcid.org/0000-0002-0245-5848)
- Rochelle W. Lai (ORCID: https://orcid.org/0000-0003-1423-197X)
- Miranda Lopez
- Jongwon Baek
- M. Kelly
- Taekyung Kang
- Ian Tamburini
- Elena M. Moyer
- Nicholas D’Sa
- Jakob Songcuan
- Won-Suk Song
- Amy R. Lantz
- Elise Tran (ORCID: https://orcid.org/0009-0003-3798-9852)
- Alexis Anica
- Aiyana Binuya
- Ana M. Espeleta
- Christopher H. Lee (ORCID: https://orcid.org/0009-0008-9805-3835)
Institutions
- University of Iowa (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- University of California, Irvine (US)
- Institute for Basic Science (KR)
- Irvine University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-08-28
- DOI
- https://doi.org/10.1126/sciadv.aec0481
- Primary Topic
- Diet, Metabolism, and Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Research Foundation of Korea
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases