NFATc4 and ATF3 negatively regulate adiponectin gene expression in 3T3-L1 adipocytes
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Updated: Aug 9, 2026
Adipocyte-Specific ATAC-Seq with Adipose Tissues Using Fluorescence-Activated Nucleus Sorting
Published on: March 17, 2023
Hyun Bae Kim1, Minyoung Kong, Tae Min Kim
1Division of Metabolic Diseases, Center for Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Korea.
Abstract:
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.
Insights
Obesity and insulin resistance lower adiponectin levels. Nuclear factor of activated T-cells (NFATc4) and activating transcription factor 3 (ATF3) were identified as key repressors of adiponectin gene expression.
Area of Science:
- Molecular Biology
- Metabolic Diseases
- Gene Regulation
Background:
- Adiponectin expression declines in obesity and insulin resistance.
- Mechanisms controlling adiponectin gene regulation in adipocytes remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying adiponectin gene repression in adipocytes.
- To identify specific transcription factors involved in negative regulation of adiponectin.
Main Methods:
- Analysis of 5' serial deletion constructs of the murine adiponectin promoter.
- Investigated the role of nuclear factor of activated T-cells (NFAT) and activating transcription factor 3 (ATF3).
- Assessed protein binding, histone modifications (acetylation, HDAC1 recruitment), and mRNA levels in response to specific treatments and in disease models (ob/ob, db/db mice).
Main Results:
- A repressor region between -472 and -313 bp of the adiponectin promoter was identified.
- NFAT binding sites and ATF3 binding sites were found to repress promoter activity.
- NFATc4 and ATF3 binding increased in adipose tissue of obese mice (ob/ob, db/db).
- NFATc4 binding correlated with reduced histone H3 acetylation and increased histone deacetylase 1 recruitment.
- Activators of NFAT (A23187) and ATF3 (thapsigargin) reduced adiponectin mRNA and promoter activity.
Conclusions:
- NFATc4 and ATF3 act as critical negative regulators of adiponectin gene expression.
- These factors may contribute to the downregulation of adiponectin in obesity and type 2 diabetes.
- Understanding these regulatory pathways offers potential therapeutic targets for metabolic disorders.
