Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia.
Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2(Δadip) mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2(Δadip) mice. At the molecular level, Fra-2 directly binds to the PPARγ2 promoter and represses PPARγ2 expression. Deletion of Fra-2 leads to increased PPARγ2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
J
J
Luther
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
K
K
Ubieta
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
N
N
Hannemann
Genes, Development and Disease Group, Cancer Cell Biology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
M
M
Jimenez
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
M
M
Garcia
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
C
C
Zech
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
G
G
Schett
Genes, Development and Disease Group, Cancer Cell Biology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
E F
EF
Wagner
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
A
A
Bozec
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013629:Tamoxifen / Q000494:pharmacology; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D018931:Antineoplastic Agents, Hormonal; D051792:Basic Helix-Loop-Helix Proteins; D051921:Fos-Related Antigen-2; D051793:Hypoxia-Inducible Factor 1; D047495:PPAR gamma; D013629:Tamoxifen; D000099162:Endothelial PAS Domain-Containing Protein 1