High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice

Author(s)

Sellami, Eya ; Evangelista-Silva, Paulo Henrique ; Teixeira, Caio Jordao ; Diop, Khoudia ; Mitchell, Patricia ; Anhe, Fernando Forato

• Document type: Journal article
• Source: MOLECULAR METABOLISM; v. 93, p. 13-pg., 2025-01-29.

Abstract

Objective: Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis. Methods: Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 % Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively. Results: High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling. Conclusion: Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD. (c) 2025 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). (AU)

• FAPESP's process: 20/06397-3 - Study of cellular senescence in rodents subjected to Obesity
• Grantee: Caio Jordão Teixeira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 22/14545-8 - Determining how high-fat diet derived fatty acids and the gut microbiota interact to engage innate immunity via pattern recognition receptors
• Grantee: Paulo Henrique Evangelista Silva
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 20/12201-4 - Pro-inflammatory cytokines expression and their correlation to nutrient transporters and intestinal permeability in murine treated with fatty acids
• Grantee: Paulo Henrique Evangelista Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/02829-1 - The role of AGEs in activation of PRRs by gut microbiota from mice fed with a high-fat high-sucrose diet
• Grantee: Caio Jordão Teixeira
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor