Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity.
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.
Matsuzawa-Nagata
Naoto
N
Department of Medicinal Informatics, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.
Takamura
Toshinari
T
Ando
Hitoshi
H
Nakamura
Seiji
S
Kurita
Seiichiro
S
Misu
Hirofumi
H
Ota
Tsuguhito
T
Yokoyama
Masayoshi
M
Honda
Masao
M
Miyamoto
Ken-ichi
K
Kaneko
Shuichi
S
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
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species