title: Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity.
abstract: Insulin resistance is a key pathophysiological feature of metabolic syndrome. However, the initial events triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed an HFD before the onset of insulin resistance through discrete mechanism. In the liver, an HFD up-regulated genes involved in sterol regulatory element binding protein 1c-related fatty acid synthesis and peroxisome proliferator-activated receptor alpha-related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Furthermore, increased ROS production preceded the elevation of tumor necrosis factor-alpha and free fatty acids in the plasma and liver. The ROS may be an initial key event triggering HFD-induced insulin resistance.
authors.affiliation: Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Matsuzawa-Nagata
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kurita
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Misu
authors.forename: Tsuguhito
authors.initials: T
authors.lastname: Ota
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D004041:Dietary Fats / Q000008:administration & dosage*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species