Estradiol stimulates adipogenesis and Slc2a4/GLUT4 expression via ESR1-mediated activation of CEBPA

Luciana A Fatima; Raquel S Campello; João N Barreto-Andrade; Marisa Passarelli; Roberta S Santos; Deborah J Clegg; Ubiratan F Machado

doi:10.1016/j.mce.2019.05.006

Estradiol stimulates adipogenesis and Slc2a4/GLUT4 expression via ESR1-mediated activation of CEBPA

Mol Cell Endocrinol. 2019 Dec 1:498:110447. doi: 10.1016/j.mce.2019.05.006. Epub 2019 May 14.

Authors

Luciana A Fatima¹, Raquel S Campello¹, João N Barreto-Andrade¹, Marisa Passarelli², Roberta S Santos³, Deborah J Clegg³, Ubiratan F Machado⁴

Affiliations

¹ Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
² Lipids Laboratory (LIM 10), Medical School, University of São Paulo, São Paulo, Brazil; Graduate Studies Program in Medicine, University Nove Nove de Julho, São Paulo, Brazil.
³ Biomedical Research Department, Diabetes and Obesity Research Division, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴ Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: [email protected].

PMID: 31100494
DOI: 10.1016/j.mce.2019.05.006

Abstract

The ability of adipose tissue to expand is dependent on adipocyte differentiation and adipose tissue glucose disposal. The CCAAT/enhancer-binding protein alpha (CEBPA) enhances the expression of the Slc2a4 gene and GLUT4 protein, which are markers of adipocyte differentiation/glucose disposal. We hypothesized estradiol (E2) facilitates adipocyte differentiation/glucose disposal by an estrogen receptor 1 (ESR1)-dependent and CEBPA-mediated mechanism. Our results suggest that E2 (10 nM) has a positive effect on 3T3-L1 adipocyte differentiation (days 2-8), lipid accumulation, Slc2a4 and Cebpa mRNA expression, total GLUT4 and nuclear CEBPA contents, and CEBP/Slc2a4-binding activity. Esr1 silencing (∼50%) in mature adipocytes abrogates the 24-h E2 effects on nuclear CEBPA content, Slc2a4/GLUT4 expression and GLUT4 translocation to the cell membrane. Thus, E2 stimulates adipocyte differentiation and Slc2a4/GLUT4 expression in an ESR1/CEBPA-mediated pathway. Our data provide mechanistic insight demonstrating E2 participates in adipose-tissue differentiation and glucose transporter expression which ultimately can improve adipose tissue expandability and glycemic control.

Keywords: 3T3-L1 adipocytes; Adipogenesis; CEBPA; ESR1-Silencing; GLUT4; Slc2a4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / cytology*
Adipocytes / drug effects
Adipocytes / metabolism
Adipogenesis / drug effects*
Animals
CCAAT-Enhancer-Binding Proteins / genetics
CCAAT-Enhancer-Binding Proteins / metabolism*
Cell Differentiation
Estradiol / pharmacology*
Estrogen Receptor alpha / physiology*
Estrogens / pharmacology
Female
Gene Expression Regulation / drug effects*
Glucose Transporter Type 4 / genetics
Glucose Transporter Type 4 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Promoter Regions, Genetic

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, mouse
Esr1 protein, mouse
Estrogen Receptor alpha
Estrogens
Glucose Transporter Type 4
Slc2a4 protein, mouse
Estradiol