Genes that control the early stages of adipogenesis remain largely unknown. Here, we show that murine GATA-2 and GATA-3 are specifically expressed in white adipocyte precursors and that their down-regulation sets the stage for terminal differentiation. Constitutive GATA-2 and GATA-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. This effect is mediated, at least in part, through the direct suppression of peroxisome proliferator-activated receptor gamma. GATA-3-deficient embryonic stem cells exhibit an enhanced capacity to differentiate into adipocytes, and defective GATA-2 and GATA-3 expression is associated with obesity. Thus, GATA-2 and GATA-3 regulate adipocyte differentiation through molecular control of the preadipocyte-adipocyte transition.
We have previously demonstrated that GATA-2 and GATA-3 are expressed in adipocyte precursors and control the preadipocyte-to-adipocyte transition. Constitutive expression of both GATA-2 and GATA-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor ␥ (PPAR␥) promoter and suppression of its basal activity. In the present study, we demonstrate that both GATA-2 and GATA-3 form protein complexes with CCAAT/enhancer binding protein ␣ (C/EBP␣) and C/EBP, members of a family of transcription factors that are integral to adipogenesis. We mapped this interaction to the basic leucine zipper domain of C/EBP␣ and a region adjacent to the carboxyl zinc finger of GATA-2. The interaction between GATA and C/EBP factors is critical for the ability of GATA to suppress adipocyte differentiation. Thus, these results show that in addition to its previously recognized function in suppressing PPAR␥ transcriptional activity, interaction of GATA factors with C/EBP is necessary for their ability to negatively regulate adipogenesis.Adipocyte differentiation is a process controlled by multiple regulators, principally the CCAAT/enhancer binding protein (C/EBP) family of transcription factors and the peroxisome proliferator-activated receptor ␥ (PPAR␥), a nuclear hormone receptor (12, 15). Upon hormonal stimulation, the expression of C/EBP and C/EBP␦ temporally increases (3), followed by expression of PPAR␥ and C/EBP␣ (3, 16). A cooperative interaction between PPAR␥ and C/EBP␣ drives the expression of genes that are necessary for the generation and maintenance of the adipogenic phenotype, such as genes producing morphological changes, lipid accumulation, and insulin sensitivity (22).The C/EBP family of transcription factors contains a highly conserved basic leucine zipper domain (bZip) that mediates homo-or heterodimerization with other isoforms in this protein family. Gain-or loss-of-function studies of preadipocyte cell lines and loss-of-function experiments in vivo all indicate that C/EBP␣ is a key regulator of adipogenesis (6,20,23,25). Furthermore, two other members of this family, C/EBP and C/EBP␦, are also highly expressed in adipose tissue and have been demonstrated to be vital components of the signaling cascade which initiates adipocyte differentiation (13). Clearly, the coordinated activity of these three members of the C/EBP family makes key contributions to adipogenesis.We have previously demonstrated that the zinc finger transcription factors GATA-2 and GATA-3 are expressed predominantly in white and not brown adipose tissue in vivo and that their expression is restricted to preadipocytes and down-regulated upon adipocyte differentiation. Constitutive expression of both GATA-2 and GATA-3 suppressed adipocyte differentiation and trapped cells at the preadipocyte stage, as found when morphology and gene expression were assessed. This effect was mediated, at least in part, through direct binding of PPAR␥ and inhibition of its basal promoter activity. However, ...
Frequency of Foclor V (1691 G-A) Mutotion in Turkish Populotion Dear Sir, A mutation in the Factor V gene (1691G-+ A in exon 10) was identified that formed the molecular explanation for the phenotype of APC-resistance in the large majority of affected individuals (1). This mutation, which is associated with a significant increase in tluombotic risk, has been found in 30-5070 of selected families with thrombophilia and in 20Vo of consecutive patients with venous tluombosis (2,3).The prevalence of the FV: Q506 allele is between2To and l07o in Western societies but it varies widely depending on the geographic location and the ethnic background of the population. However, the mutated allele is not found in certain populations, such as the Japanese, Chinese, Africans and native Americans (a-6).
Sleep apnea causes cognitive deficits and is associated with several neurologic diseases. Intermittent hypoxia (IH) is recognized as a principal mediator of pathophysiology associated with sleep apnea, yet the basis by which IH contributes to impaired cognition remains poorly defined. Using a mouse model exposed to IH, this study examines how the transcription factor, hypoxia inducible factor 1a (HIF1a), contributes to disrupted synaptic physiology and spatial memory. In wild-type mice, impaired performance in the Barnes maze caused by IH coincided with a loss of NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) in area CA1 and increased nuclear HIF1a within the hippocampus. IH-dependent HIF1a signaling caused a two-fold increase in expression of the reactive oxygen species (ROS) generating enzyme NADPH oxidase 4 (NOX4). These changes promoted a pro-oxidant state and the downregulation of GluN1 within the hippocampus. The IH-dependent effects were not present in either mice heterozygous for Hif1a (HIF1a +/− ) or wild-type mice treated with the antioxidant manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP). Our findings indicate that HIF1a-dependent changes in redox state are central to the mechanism by which IH disrupts hippocampal synaptic plasticity and impairs spatial memory. This mechanism may enhance the vulnerability for cognitive deficit and lower the threshold for neurologic diseases associated untreated sleep apnea.
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