title: Adiponectin resistance and proinflammatory changes in the visceral adipose tissue induced by fructose consumption via ketohexokinase-dependent pathway.
abstract: An epidemic of obesity and type 2 diabetes is linked with the increase in consumption of fructose-containing sugars, such as sucrose and high-fructose corn syrup. In mammalian cells, fructose is metabolized predominantly via phosphorylation to fructose-1 phosphate by ketohexokinase (KHK) or by alternative pathways. Here we demonstrate that a KHK-dependent pathway mediates insulin resistance and inflammatory changes in the visceral fat in response to high fructose. We used mice (males, C57BL/6 background) including littermate wild-type control and mice lacking both isoforms of KHK (KHK-null). Fructose diet induced metabolic syndrome, including visceral obesity, insulin resistance, proinflammatory changes in the visceral fat (production of proinflammatory adipokines and macrophage infiltration), the endoplasmic reticulum stress signaling, and decrease of the high-molecular weight adiponectin followed by decrease in the downstream signaling. KHK-KO mice consuming the same high-fructose diet remained lean, with normal insulin sensitivity and healthy visceral adipose tissue with normal adiponectin function not distinguishable from the control by any of the tested parameters. This study demonstrates that blocking KHK and redirecting fructose metabolism to alternative pathways is an effective way to prevent visceral obesity and insulin resistance induced by high fructose, a widespread component of Western diets.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL.
authors.forename: George
authors.initials: G
authors.lastname: Marek
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL.
authors.forename: Varinderpal
authors.initials: V
authors.lastname: Pannu
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Shanmugham
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL.
authors.forename: Brianna
authors.initials: B
authors.lastname: Pancione
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL.
authors.forename: Dominic
authors.initials: D
authors.lastname: Mascia
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL.
authors.forename: Sean
authors.initials: S
authors.lastname: Crosson
authors.affiliation: Department of Medicine, University of Colorado Denver, Denver, CO.
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL yuri.sautin@medicine.ufl.edu.
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D004040:Dietary Carbohydrates / Q000494:pharmacology; D005631:Fructokinases / Q000235:genetics / Q000378:metabolism*; D005632:Fructose / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D007333:Insulin Resistance; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015430:Weight Gain
chemical_list: D052242:Adiponectin; D004040:Dietary Carbohydrates; D012333:RNA, Messenger; D005632:Fructose; D005631:Fructokinases; C021475:ketohexokinase