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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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    • "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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    • "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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