Transcription factor activating enhancer-binding protein-2beta. A negative regulator of adiponectin gene expression.
We previously reported the association between the activating enhancer-binding protein-2beta (AP-2beta) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with the disease-susceptible allele of AP-2beta showed stronger expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2beta leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study we demonstrated that overexpression of AP-2beta in 3T3-L1 adipocytes decreased the expression and secretion of adiponectin and increased those of interleukin-6 (IL-6). Interestingly, the effects of AP-2beta on the expressions of adiponectin and IL-6 and the mechanisms by which AP-2beta modulated their expressions were different. We found that the promoter activity of adiponectin gene was inhibited by AP-2beta overexpression and enhanced by knockdown of endogenous AP-2beta, whereas IL-6 was unaffected. Electrophoretic mobility shift assays revealed the existence of putative responsive elements for AP-2beta and NF-YA in human and mouse adiponectin promoter regions, and mutation of this AP-2beta binding site abolished the inhibitory effect of AP-2beta. Furthermore, chromatin immunoprecipitation assays demonstrated that AP-2beta and NF-YA competitively bind to the same region of the adiponectin promoter. Our results clearly demonstrated that AP-2beta directly inhibits adiponectin gene expression by displacing NF-YA and binding to its promoter. We conclude that AP-2beta might modulate the expression of adiponectin by directly inhibiting its transcriptional activity.
Ikeda
Kazuhiro
K
Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192 Japan.
Maegawa
Hiroshi
H
Ugi
Satoshi
S
Tao
Yukari
Y
Nishio
Yoshihiko
Y
Tsukada
Shuichi
S
Maeda
Shiro
S
Kashiwagi
Atsunori
A
D041721:3T3-L1 Cells; D052242:Adiponectin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001692:Biological Transport; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D011401:Promoter Regions, Genetic; D050656:Transcription Factor AP-2 / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D052242:Adiponectin; D015850:Interleukin-6; D008055:Lipids; D050656:Transcription Factor AP-2