Phosphorylation of GATA2 by akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: A novel pathway linking obesity to atherosclerosis

Department of Internal Medicine, University of Rome Tor Vergata, Policlinico Tor Vergata-PTV University Hospital, Rome, Italy.
Circulation (Impact Factor: 14.95). 05/2005; 111(15):1946-53. DOI: 10.1161/01.CIR.0000161814.02942.B2
Source: PubMed

ABSTRACT Obesity-related inflammation is emerging as a major cause of insulin resistance and cardiovascular diseases. GATA2 transcription factor is an inhibitor of adipogenesis and an activator of vascular cells. We hypothesized that GATA2 activity is controlled by insulin during adipogenesis, linking metabolic homeostasis and inflammation.
We show that insulin induces GATA2 phosphorylation on serine 401 in a PI-3K/Akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs GATA2 translocation to the nucleus and its DNA binding activity. A GATA2 mutant not phosphorylable by Akt (GATA2(S401A)) acts similarly to wild-type GATA2. In contrast, a GATA2 mutant that mimics Akt phosphorylation (GATA2(S401D)) is restrained in the cytoplasm. Cultured preadipocytes bearing GATA2(S401A) do not convert to adipocytes and express high levels of inflammatory cytokines like monocyte chemotactic protein-1 (MCP-1). On the contrary, GATA2(S401D) preadipocytes differentiate to adipocytes. When GATA2(S401A) preadipocytes are injected in mice fed a high-fat diet, they do not differentiate adequately into adipocytes, maintaining the expression of inflammatory markers like MCP-1. In contrast, injection of GATA2(S401D) preadipocytes in mice fed a high-fat diet results in development of adipocytes and no expression of inflammatory markers.
GATA2 could be a new target in the prevention and treatment of obesity-related inflammation and its complications.

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    • "is not a critical signaling component down - stream of insulin for proper upregulation of the adipogenic factors and the induction of adipogenesis . Under these conditions , other branches of Akt signaling , such as forkhead protein 1 ( FOXO1 ; Nakae et al . , 2003 ) , hepatocyte nuclear factors ( Foxa ; Wolfrum et al . , 2003 ) and GATA factors ( Menghini et al . , 2005 ) are play - ing roles in promoting adipogenesis ( Rosen and MacDougald , 2006 ) . Therefore , the Akt branches related to insulin signaling play complementary and , perhaps , partially redundant roles in driving adipocyte differentiation . Despite the observed functional differences between ghrelin and insulin system under ␤ - arrestin"
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    ABSTRACT: β-Arrestins were identified as scaffold-proteins that have the capacity to desensitize G protein-coupled receptors. However, it has been found that β-arrestins activate signaling pathways independent of G protein activation. The diversity of these signaling pathways has also been recognized for receptor tyrosine kinase. The aim of the present study was to validate the β-arrestin-dependent signaling mechanism(s) responsible for regulation of adipogenesis. Two signal models were selected, ghrelin and insulin, based on its β-arrestin-associated Akt activity. Herein, we found that β-arrestin 1 and 2 were essential molecules for adipocyte differentiation. More specifically, the role of these scaffolding proteins was demonstrated by depletion of β-arrestin 1 and 2 during ghrelin-induced adipogenesis in 3T3-L1 cells, which decreased the adipocyte differentiation and the expression levels of master regulators of early, the CCAAT/enhancer-binding protein β (C/EBPβ) and the CCAAT/enhancer-binding protein δ (C/EBPδ), and terminal, the peroxisome proliferator-activated receptor (PPARγ) and the CCAAT/enhancer-binding protein α (C/EBPα), adipogenesis. Accordingly ghrelin-induced Akt activity and its downstream targets, the mammalian target of rapamycin complex 1 (mTORC1) and the ribosomal protein S6 kinase beta-1 (S6K1), were inhibited by β-arrestin 1 and 2 siRNAs. By contrast, assays performed during insulin-activated adipogenesis showed an intensifying effect on the adipocyte differentiation as well as on the expression of C/EBPβ, C/EBPδ, PPARγ and C/EBPα⋅ The increase in insulin-induced adipogenesis by β-arrestin knock-down was concomitant to a decrease in the insulin receptor susbtrate-1 (IRS-1) serine phosphorylation, proving the loss of the negative feedback loop on IRS-1/phosphoinositide 3-kinase (PI3K)/Akt. Therefore, β-arrestins control the extent and intensity of the lipogenic and adipogenic factors associated to Akt signaling, although the mechanistic and functional principles that underlie the connection between signaling and β-arrestins are specifically associated to each receptor type.
    The international journal of biochemistry & cell biology 04/2013; DOI:10.1016/j.biocel.2013.03.014 · 4.24 Impact Factor
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    • "Akt phosphorylation of the transcription factor GATA2, a negative regulator of PPARg expression and adipogenesis (Menghini et al, 2005). ProF might also have a role outside of the Akt signalling pathway. "
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    ABSTRACT: We have previously identified a protein, consisting of seven WD-repeats, forming a putative beta-propeller, and an FYVE domain, ProF, which is highly expressed in 3T3-L1 cells, a cell line that can be differentiated into adipocytes. We recently found ProF to interact with the kinases Akt and protein kinase Czeta. Here we demonstrate that ProF is a positive regulator of adipogenesis. Knockdown of ProF by RNA interference leads to decreased adipocyte differentiation. This is shown by reduced lipid accumulation, decreased expression of the differentiation markers PPARgamma and C/EBPalpha, and reduced glucose uptake in differentiated cells. Furthermore, ProF overexpression leads to increased adipogenesis. ProF binds to the transcription factor Foxo1 (Forkhead box O1), a negative regulator of insulin action and adipogenesis, and facilitates the phosphorylation and thus inactivation of Foxo1 by Akt. Additionally, dominant-negative Foxo1 restores adipogenesis in ProF knockdown cells. Thus, ProF modulates Foxo1 phosphorylation by Akt, promoting adipocyte differentiation. Furthermore, ProF might be involved in metabolic disorders such as diabetes.
    The EMBO Journal 06/2008; 27(9):1399-410. DOI:10.1038/emboj.2008.67 · 10.75 Impact Factor
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    • "These indicate that up-regulation of DGAT1 gene may have certain functional effect upon the adipocyte development in beef cattle. Furthermore , PIK3CA (phosphoinositide-3-kinase catalytic, alpha polypeptide) in insulin signaling is detected as one of the up-regulated genes as well as known to be a downstream effect of insulin stimulated adipogenesis through the activation of insulin receptor [17]. PPAR-c has been considered to regulate adipogenesis by imparting insulin sensitivity to fat cells [18]. "
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    ABSTRACT: Bovine perimuscular fat (PMF) preadipocytes were induced to undergo adipogenesis in vitro in our recent study to define the expression patterns of genes involved in the differentiation process. Based on the understanding of the interaction among adipogenic genes, a broad overview of gene expression profile in the differentiating PMF preadipocytes was evaluated using bovine specific DNA microarray from day 2 to 8 post-differentiation induction. A total of 100 significantly differentially expressed genes were detected between differentiated and control cells including those involved in several biochemical pathways and cellular/molecular signaling. In addition, quantitative real-time PCR validated that typical adipogenic genes were up-regulated at early differentiation in the preadipocytes. These results suggest that the PMF preadipocyte system is available as a novel in vitro model for molecular adipogenesis studies in the bovine and that a series of genes are switched on/off during early events associated with adipogenesis.
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