Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia

Abstract

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-2Dadip 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 Dadip mice. At the molecular level, Fra-2 directly binds to the PPARc2 promoter and represses PPARc2 expression. Deletion of Fra-2 leads to increased PPARc2 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.

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…HIFs directly impact on the control of tissue oxygen delivery, by regulating angiogenesis and vascular remodelling, and on the cellular homeostasis by regulating glucose metabolism and redox balance (Jeong et al, 2014;Luther et al, 2014;Semenza, 2014;Sun et al, 2014;Zhang et al, 2014). HIFs acts as transcriptional factors, activating gene transcription by binding to the core DNA sequence 5 -RCGTG-3 (R = A or G), included in a DNA binding consensus sequence defined hypoxia response element (HRE) (Semenza et al, 1996).…”

The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field

“…Although several transcriptional targets have been identified for Fosl2 (Bozec et al, 2010(Bozec et al, , 2008Luther et al, 2014) and crucial regulators of SHF differentiation have been described (Rochais et al, 2009), we are not aware of any genes that fit into both categories. With regard to cellular differentiation, Fosl2 transcriptionally activates osteocalcin (Bozec et al, 2010) and members of the epidermal differentiation complex (Wurm et al, 2015) to positively regulate osteoclast and epidermal differentiation, respectively.…”

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

“…Fos-related antigen 1 and 2 (Fra-1 and Fra-2) are able to regulate adipocyte differentiation. Fra-1 impairs adipocyte differentiation by inhibiting C/EBPα 8 , whereas Fra-2 controls adipocyte turnover 9 . Fra-2 thereby not only decreases the adipocyte number by repressing PPARγ2 expression during adipocyte differentiation, but also decreases adipocyte apoptosis through direct repression of hypoxia-inducible factors (HIFs) expression.…”

“…Further key transcriptional factors are the CCAAT/enhancer-binding protein (C/EBP) family members (i.e., C/EBPα, C/ EBPβ, and C/EBPδ), kruppel-like factors (KLFs), cAMP responsive element binding protein (CREB) and early growth response 20 (Krox20) 6 . Recently, it has been shown that the activator protein-1 (AP-1) family is involved in the adipocyte differentiation process 8,9 . The AP-1 family is formed by a dimeric protein complex, composed of Fos, Jun and/or activating transcription factor (ATF) members.…”

“…It shows how apoptosis, proliferation and differentiation of adipocytes in vivo and in vitro can be regulated by hypoxia. To do so, we use mice with adipocyte specific deletion of Fra-2 generated by crossing mice carrying the Fra-2 floxed alleles with Fabp4-CreERT mice 9 . By using Fabp4-Cre ERT mice, the deletion is adipocyte specific and inducible by tamoxifen injection 14 .…”