Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients.
Obesity is a major cause of insulin resistance and contributes to the development of type 2 diabetes. The altered expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) has been regarded as a key change in insulin-sensitive organs of patients with type 2 diabetes. This study explores possible molecular signatures of obesity and examines the clinical significance of OXPHOS gene expression in the livers of patients with type 2 diabetes. We analyzed gene expression in the livers of 21 patients with type 2 diabetes (10 obese and 11 nonobese patients; age, 53.0 +/- 2.1 years; BMI, 24.4 +/- 0.9 kg/m(2); fasting plasma glucose, 143.0 +/- 10.6 mg/dl) using a DNA chip. We screened 535 human pathways and extracted those metabolic pathways significantly altered by obesity. Genes involved in the OXPHOS pathway, together with glucose and lipid metabolism pathways, were coordinately upregulated in the liver in association with obesity. The mean centroid of OXPHOS gene expression was significantly correlated with insulin resistance indices and the hepatic expression of genes involved in gluconeogenesis, reactive oxygen species (ROS) generation, and transcriptional factors and nuclear co-activators associated with energy homeostasis. In conclusion, obesity may affect the pathophysiology of type 2 diabetes by upregulating genes involved in OXPHOS in association with insulin resistance markers and the expression of genes involved in hepatic gluconeogenesis and ROS generation.
Takamura
Toshinari
T
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. ttakamura@m-kanazawa.jp
Misu
Hirofumi
H
Matsuzawa-Nagata
Naoto
N
Sakurai
Masaru
M
Ota
Tsuguhito
T
Shimizu
Akiko
A
Kurita
Seiichiro
S
Takeshita
Yumie
Y
Ando
Hitoshi
H
Honda
Masao
M
Kaneko
Shuichi
S
D000410:Alanine Transaminase / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver; D005260:Female; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
D005227:Fatty Acids; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000410:Alanine Transaminase; D005947:Glucose