Echeverria, C. E. | bioRxiv Science

bioRxiv2026

Intestinal fructose metabolism drives unsaturated fat absorption and synergizes with GLP-1 receptor agonism to promote weight loss

High-fat, high-sucrose (HFHS) diets are established risk factors for obesity. In the intestine, sucrose is hydrolyzed into glucose and fructose, with fructose being taken up by epithelial cells and phosphorylated by ketohexokinase (KHK). We hypothesized that KHK is required for the obesogenic effects of HFHS diets and performed genetic and pharmacologic experiments in mice using diet-induced obesity (DIO) models. We show that genetic loss of KHK prevents HFHS-induced weight gain and intestinal villus elongation. Moreover, pharmacologic inhibition of KHK (KHKi) promotes weight and fat loss during continued HFHS feeding in DIO mice and enhances weight loss and weight maintenance during and after incretin-mimetic therapy. The anti-obesogenic effects of KHKi were associated with delayed intestinal lipid absorption, reprogramming of lipid metabolism in the distal intestinal epithelium, and reduced absorption of unsaturated dietary fats. Together, these findings identify fructose metabolism as a key regulator of intestinal lipid handling and suggest that fructose promotes obesity, in part, by enhancing intestinal lipid absorption and metabolism.

cell biology↗

bioRxiv2025

Metabolic Adaptations of Prostate Cancer Cells Under Chronic Fructose Stimulation

BackgroundDietary sugars, particularly fructose, are increasingly implicated in cancer progression through their impact on tumor metabolism. However, the specific metabolic adaptations driven by fructose in prostate cancer (PCa) remain unexplored. MethodsWe investigated the metabolic consequences of chronic fructose exposure in androgen-sensitive (LNCaP) and androgen-independent (PC-3) PCa cell lines. We evaluated the expression, localization, and function of the fructose transporter Glut-5 and assessed metabolic fluxes, enzyme expression, lipid accumulation, and global metabolite profiles using molecular, imaging, and metabolomic approaches. ResultsGlut-5 was primarily localized to early endosomes under basal and fructose-stimulated conditions, suggesting a non-canonical role potentially consistent with transceptor function. Chronic fructose exposure significantly upregulated Glut-5 expression and enhanced fructose uptake, but did not alter substantially its subcellular localization. Functionally, fructose reduced lactate production and mitochondrial ATP output, indicating a metabolic shift away from glycolysis and oxidative phosphorylation. In LNCaP cells, fructose induced robust activation of de novo lipogenesis (DNL), evidenced by upregulation of FASN and G6PD, increased lipid droplet accumulation, and enhanced levels of key fatty acid metabolites (e.g., TG, EPA, DHA). In contrast, PC-3 cells exhibited a distinct metabolic response, characterized by increased ceramide and amino acid metabolites. Notably, pharmacological inhibition of lipid metabolism using etomoxir abrogated proliferation in both cell lines under fructose stimulation. ConclusionsThese findings reveal that fructose promotes a metabolic reprogramming in PCa cells that is cell type- and AR-dependent, enhancing lipogenesis and potentially contributing to tumor progression. Our study identifies Glut-5-mediated fructolysis and lipid metabolic pathways as key vulnerabilities in PCa, offering potential avenues for metabolic intervention.

cell biology↗