Lopez Miranda L, Kang Taekyung, Espeleta Ana, Rubtsova Varvara I, Baek Jongwon, Songcuan Jakob, Moyer Elena M, Kim Joohwan, Song Won-Suk, Jung Sunhee, D'Sa Nicholas, Anica Alexis, Tran Elise, Chun Yujin, Choi Wonsuk, Jang Ki-Hong, Kelly Miranda E, Tamburini Ian J, Alam Yasmine H, Le Johnny, Ramirez Cuauhtemoc B, Kataru Raghu P, Hong Seon Pyo, Nicholas Dequina A, Xue Katherine S, Lee Gina, Bae Hosung, Jang Cholsoon
Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA 92617.
Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92617.
bioRxiv. 2025 Aug 22:2025.08.18.670963. doi: 10.1101/2025.08.18.670963.
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.
食用高果糖玉米糖浆（HFCS）是肥胖和代谢综合征的一个风险因素，但其潜在机制尚未完全明确。膳食果糖的分解代谢主要发生在小肠和肝脏，肝脏中的果糖分解具有病理性，而小肠对果糖的清除则可保护肝脏。在此，我们意外地发现，特异性抑制小肠中的果糖分解代谢可减轻果糖诱导的肥胖和胰岛素抵抗。从机制上讲，阻断肠道果糖分解代谢可减少膳食脂肪吸收，这与回肠乳糜管表面积的减少以及肠道微生物群的改变有关。粪便移植实验表明，这样的微生物群会刺激肠道驻留巨噬细胞，促进乳糜管生长并增加膳食脂肪吸收。鉴于临床前和临床研究报告了果糖分解代谢抑制对减轻饮食诱导的肥胖的作用，我们的数据表明，这种作用部分是由肠道乳糜管重塑介导的。
