Dataset Information

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPAR? 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-2(?adip) 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(?adip) mice. At the molecular level, Fra-2 directly binds to the PPAR?2 promoter and represses PPAR?2 expression. Deletion of Fra-2 leads to increased PPAR?2 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.

SUBMITTER: Luther J

PROVIDER: S-EPMC3950327 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Luther J J Ubieta K K Hannemann N N Jimenez M M Garcia M M Zech C C Schett G G Wagner E F EF Bozec A A

Cell death and differentiation 20140124 4

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 adipo ...[more]

PMID: 24464219

Similar Datasets

Project description:Sepsis is a life-threatening condition characterized by excessive inflammation in its early phase. This is followed by an aberrant resolution phase associated to a prolonged period of immune suppression that can ultimately lead to multiple organ dysfunctions. This immunosuppression can be mediated by the functional reprogramming of gene transcription in monocytes/macrophages in response to prolonged lipopolysaccharide (LPS) exposure. Surprisingly, there is no report on the role of AP-1 transcription factors in this reprogramming process. Herein, we used the endotoxin tolerance model on murine bone marrow-derived macrophages in which tolerant cells stimulated twice with LPS were compared to naïve cells stimulated once. Out of all AP-1 transcription factors tested, Fosl1 gene stood out because of its unique regulation in tolerized cells. Moreover, we could correlate FRA-1 expression to the expression of an essential anti-inflammatory molecule involved in sepsis response, Lipocalin 2 aka NGAL. Identical results were obtained in human PBMC following the endotoxin tolerance model. When using FRA-1 deficient macrophages, we could confirm that FRA-1 regulates NGAL expression during the tolerant state. Interestingly, ChIP-seq and ChIP-qPCR revealed the binding of FRA-1 on Lcn2 promoter after LPS stimulation in these cells. Finally, we used an in vivo septic model of consecutive injection of LPS, in which the second stimulation is performed before the resolution of inflammation, in wild type and FRA-1 deficient mice. NGAL secretion was elevated in lung, spleen and serum of wild type tolerant mice, whereas it was significantly lower in tolerant FRA-1 deficient mice. Moreover, an increased inflammatory state likely dependent of the low level of NGAL was observed in these FRA-1 deficient mice. This was characterized by an increase of neutrophil infiltration in lung and an increase of apoptotic follicular cells in spleen. This suggests that FRA-1 expression supports resolution of inflammation in this model. Collectively, our data indicate that FRA-1 is involved in myeloid cell tolerance responses by mediating the functional reprogramming of Lcn2 transcription in response to prolonged LPS exposure. In conclusion, FRA-1 may have a protective role in the tolerance response of sepsis through the regulation of NGAL, leading to resolution of inflammation.

Dataset Information

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPAR? and hypoxia.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets