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(Circulation. 2005;111:1946-1953.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces Adipose Tissue–Related Inflammation

A Novel Pathway Linking Obesity to Atherosclerosis

Rossella Menghini, PhD; Valentina Marchetti, BS; Marina Cardellini, MD; Marta L. Hribal, PhD; Alessandro Mauriello, MD; Davide Lauro, MD; Paolo Sbraccia, MD, PhD; Renato Lauro, MD; Massimo Federici, MD

From the Departments of Internal Medicine (R.M., V.M., M.C., M.L.H., D.L., P.S., R.L., M.F.) and Biopathology and Diagnostic Imaging (A.M.), University of Rome Tor Vergata, and Center for Atherosclerosis (D.L., P.S., R.L., M.F.), Policlinico Tor Vergata–PTV University Hospital, Rome, Italy.

Correspondence to Dr Massimo Federici or Dr Renato Lauro, Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail federicm{at}uniroma2.it

Received October 21, 2004; revision received December 29, 2004; accepted January 11, 2005.

Background— 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.

Methods and Results— 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.

Conclusions— GATA2 could be a new target in the prevention and treatment of obesity-related inflammation and its complications.

Key Words: diabetes mellitus • inflammation • insulin • obesity • signal transduction

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