NFATc4 and ATF3 negatively regulate adiponectin gene expression in 3T3-L1 adipocytes.
Expression of adiponectin decreases with obesity and insulin resistance. At present, the mechanisms responsible for negatively regulating adiponectin expression in adipocytes are poorly understood. In this investigation, we analyzed the effects of 5' serial deletion constructs on the murine adiponectin promoter. Here, we identified the repressor region located between -472 and -313 bp of the promoter. Removal of the putative nuclear factor of activated T-cells (NFATs) binding site increased the promoter activity, and overexpression of NFATc4 reduced the promoter activity. Treatment with the calcium ionophore A23187, an activator of NFAT, reduced mRNA as well as promoter activity. The binding of NFATc4 to the promoter was associated with increased recruitment of histone deacetylase 1 and reduced acetylation of histone H3 at the promoter site. In addition, binding of activating transcription factor 3 (ATF3) to the putative activator protein-1 site located adjacent to the NFAT binding site also repressed the promoter activity. Treatment with thapsigargin, an inducer of ATF3, reduced both mRNA and promoter activity. Importantly, the binding activities of NFATc4 and ATF3, increased significantly in white adipose tissues of ob/ob and db/db mice compared with controls. Taken together, this study demonstrates for the first time that NFATc4 and ATF3 function as negative regulators of adiponectin gene expression, which may play critical roles in downregulating adiponectin expression in obesity and type 2 diabetes.
Kim
Hyun Bae
HB
Division of Metabolic Diseases, Center for Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Korea.
Kong
Minyoung
M
Kim
Tae Min
TM
Suh
Young Ho
YH
Kim
Won-Ho
WH
Lim
Joo Hyun
JH
Song
Ji Hyun
JH
Jung
Myeong Ho
MH
D016475:3T3 Cells; D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D017667:Adipocytes / Q000502:physiology*; D052242:Adiponectin / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D005786:Gene Expression Regulation; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection
D051700:Activating Transcription Factor 3; D052242:Adiponectin; C103002:Atf3 protein, mouse; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D012333:RNA, Messenger; D008156:Luciferases