title: Liquid fructose in Western-diet-fed mice impairs liver insulin signaling and causes cholesterol and triglyceride loading without changing calorie intake and body weight.
abstract: Liquid fructose associates with prevalence of type 2 diabetes mellitus and obesity. Intervention studies suggest that metabolically unfit individuals are more responsive than healthy individuals to liquid fructose. We determined whether mice consuming an obesogenic Western diet were more responsive than chow-fed mice to the alterations induced by liquid fructose supplementation (LFS).
  
  
  
  C57BL/6N mice were fed chow or Western diet±ad libitum 15% fructose solution for 12 weeks. Food and liquid intake and body weight were monitored. Plasma analytes and liver lipids, histology and the expression of genes related to lipid handling, endoplasmic reticulum stress, inflammation and insulin signaling were analyzed.
  
  
  
  Western diet increased energy intake, visceral adipose tissue (vWAT), body weight, plasma and liver triglycerides and cholesterol, and inflammatory markers in vWAT vs. chow-fed mice. LFS did not change energy intake, vWAT or body weight. LFS significantly increased plasma and liver triglycerides and cholesterol levels only in Western-diet-fed mice. These changes associated with a potentiation of the increased liver expression of PPARγ and CD36 that was observed in Western-fed mice and related to the increased liver mTOR phosphorylation induced by LFS. Furthermore, LFS in Western-diet-fed mice induced the largest reduction in liver IRS2 protein and a significant decrease in whole-body insulin sensitivity.
  
  
  
  LFS in mice, in a background of an unhealthy diet that already induces fatty liver visceral fat accretion and obesity, increases liver lipid burden, hinders hepatic insulin signaling and diminishes whole-body insulin sensitivity without changing energy intake.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain; Institute of Biomedicine University of Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Baena
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain; Institute of Biomedicine University of Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Sangüesa
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Hutter
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Beltrán
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain; Institute of Biomedicine University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Sánchez
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain; Institute of Biomedicine University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Roglans
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain; Institute of Biomedicine University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Spain. Electronic address: alegret@ub.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Alegret
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Spain; Institute of Biomedicine University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Spain. Electronic address: jclagunae@ub.edu.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Laguna
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism*; D066273:Diet, Western / Q000009:adverse effects*; D059865:Endoplasmic Reticulum Stress; D002149:Energy Intake; D005632:Fructose / Q000009:adverse effects* / Q000737:chemistry; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D015434:Panniculitis / Q000209:etiology; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007328:Insulin; D014280:Triglycerides; D005632:Fructose; D002784:Cholesterol
keywords: CD36; ChREBP; IRS2; Leptin; PPARγ; Visceral adipose tissue; mTOR