Visfatin in adipocytes is upregulated by hypoxia through HIF1alpha-dependent mechanism.
Obesity is associated with metabolic disorders, such as insulin resistance. Visfatin is an adipose-derived secretory factor to exert insulin-mimetic effects. Plasma visfatin levels and mRNA levels of visfatin in adipose tissues are increased in obesity. However, the mechanism that mediates induction of visfatin mRNA in adipose tissue of obesity remains unknown. Recent studies have reported that fat tissue is hypoxia in obesity. In this study, we investigated the effects of hypoxia on mRNA expression of visfatin in adipocytes. Hypoxia increased visfatin mRNA expression. Desferoxamine and Cobaltous chloride, two hypoxia mimetic compounds, also increased visfatin mRNA levels. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF1alpha), mimicked the hypoxia-mediated upregulation of visfatin, and YC1, an inhibitor of HIF1 cancelled the hypoxia-induced upregulation of visfatin mRNA. We identified two functional hypoxia responsive elements (HRE) in mouse visfatin promoter. Hypoxic treatment and overexpression of HIF1alpha increased the promoter activity, and mutation of the HRE blunted hypoxia-induced activation of visfatin promoter. Our results suggest that visfatin mRNA expression is upregulated in the fat tissue of obesity through the activation of HIF1alpha pathway due to hypoxia.
Segawa
Katsumori
K
Department of Medicine and Pathophysiology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Fukuhara
Atsunori
A
Hosogai
Naomi
N
Morita
Kentaro
K
Okuno
Yosuke
Y
Tanaka
Masaki
M
Nakagawa
Yasuhiko
Y
Kihara
Shinji
S
Funahashi
Tohru
T
Komuro
Ryutaro
R
Matsuda
Morihiro
M
Shimomura
Iichiro
I
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D054409:Nicotinamide Phosphoribosyltransferase; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation
D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse