Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats.
High consumption of fructose-sweetened beverages has been linked to a high prevalence of chronic metabolic diseases. We have previously shown that a short course of fructose supplementation as a liquid solution induces glucose intolerance in female rats. In the present work, we characterized the fructose-driven changes in the liver and the molecular pathways involved. To this end, female rats were supplemented or not with liquid fructose (10%, w/v) for 7 or 14 days. Glucose and pyruvate tolerance tests were performed, and the expression of genes related to insulin signaling, gluconeogenesis and nutrient sensing pathways was evaluated. Fructose-supplemented rats showed increased plasma glucose excursions in glucose and pyruvate tolerance tests and reduced hepatic expression of several genes related to insulin signaling, including insulin receptor substrate 2 (IRS-2). However, the expression of key gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was reduced. These effects were caused by an inactivation of hepatic forkhead box O1 (FoxO1) due to an increase in its acetylation state driven by a reduced expression and activity of sirtuin 1 (SIRT1). Further contributing to FoxO1 inactivation, fructose consumption elevated liver expression of the spliced form of X-box-binding-protein-1 as a consequence of an increase in the activity of the mammalian target of rapamycin 1 and protein 38-mitogen activated protein kinase (p38-MAPK). Liquid fructose affects both insulin signaling (IRS-2 and FoxO1) and nutrient sensing pathways (p38-MAPK, mTOR and SIRT1), thus disrupting hepatic insulin signaling without increasing the expression of key gluconeogenic enzymes.
Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Avenida Diagonal 643, Barcelona 08028, Spain.
Alba
A
Rebollo
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Núria
N
Roglans
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Miguel
M
Baena
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Anna
A
Padrosa
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Rosa M
RM
Sánchez
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Manuel
M
Merlos
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Marta
M
Alegret
Institute of Biomedicine, University of Barcelona, Barcelona 08028, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain. Electronic address: jclagunae@ub.edu.
Juan C
JC
Laguna
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005632:Fructose / Q000378:metabolism*; D005943:Gluconeogenesis; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats
D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D005632:Fructose
FoxO1; Insulin resistance; SIRT1; XBP-1; mTOR; p38-MAPK