Mauriello, Davide Lauro, Paolo Sbraccia, Renato Lauro and Massimo Federici
Rossella Menghini, Valentina Marchetti, Marina Cardellini, Marta L. Hribal, Alessandro
Related Inflammation : A Novel Pathway Linking Obesity to
Phosphorylation of GATA2 by Akt Increases Adipose Tissue Differentiation and Reduces
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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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
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
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.
Insulin-dependent phosphorylation of serine 401 impairs GATA2 translocation to the nucleus and its DNA binding activity.
that mimics Akt phosphorylation (GATA2S401D) is restrained in the cytoplasm. Cultured preadipocytes bearing GATA2S401A
do not convert to adipocytes and express high levels of inflammatory cytokines like monocyte chemotactic protein-1
(MCP-1). On the contrary, GATA2S401Dpreadipocytes differentiate to adipocytes. When GATA2S401Apreadipocytes 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 GATA2S401Dpreadipocytes 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. (Circulation. 2005;111:1946-1953.)
Key Words: diabetes mellitus ? inflammation ? insulin ? obesity ? signal transduction
adipose tissue upon alteration of energy balance.1Recently, it
has been observed that adipocyte precursors and immuno-
competent cells like macrophages share similar functions.2–4
This link has been strengthened by the observation that both
animal models of obesity and human obesity are character-
ized by accumulation among adipocytes of monocyte/macro-
phages, which in turn would be the main source of proin-
flammatory cytokines and a key cause of adipose-specific and
systemic insulin resistance.5,6The failure of adipocytes to
adapt to the demands of energy storage is associated with the
reduced production of antiatherogenic hormones like adi-
ponectin and increased secretion of proinflammatory cyto-
kines such as tumor necrosis factor-? (TNF-?).7,8Interest-
ingly, an inverse relationship between adipose cell and
macrophage differentiation has been described. Thus, it
appears that when differentiation into adipocytes is enhanced,
an inhibition of macrophage activation occurs.3However,
mechanisms explaining macrophage accumulation among
besity, a major cause of cardiovascular diseases and
type 2 diabetes, is caused by an expansion of white
adipocytes have not been clarified, and factors modulating
metabolic versus inflammatory behavior of preadipocytes are
unknown.9Preadipocytes, located in the stromal vascular
fraction of adipose tissue, differentiate under appropriate
hormonal and nutritional stimuli.10Upon differentiation, they
acquire a different phenotype and become able to store
energy through synthesis of lipids.1,11Insulin is a major
stimulator of adipogenesis through the activation of a path-
way involving insulin receptor (IR), IR substrate-1 (IRS-1),
and the downstream effectors phosphatidylinositol 3-kinase
(PI-3K) and Akt.11–14It has been suggested that Akt controls
adipogenesis and metabolic homeostasis in part by modula-
tion of transcription factor activity, as is the case for
FOXO1.15Thus, when insulin resistance occurs, it causes
impaired activity of the PI-3K/Akt pathway, resulting in
inadequate adipogenesis and adipose tissue metabolism. In-
terestingly, adipogenesis is blocked by GATA2, a transcrip-
tion factor specifically expressed in the stromal vascular
fraction of the adipose tissue where preadipocytes reside. In
fact, GATA2 blocks the transition from preadipocyte to
Received October 21, 2004; revision received December 29, 2004; accepted January 11, 2005.
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 firstname.lastname@example.org
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000161814.02942.B2
by guest on June 4, 2013 http://circ.ahajournals.org/Downloaded from
was not expressed by preadipocytes in vitro, it is conceivable
that it derives from monocytes that migrated near injected cells
in response to the increased MCP-1 expression.
We can speculate that insulin triggers adipogenesis to main-
tain metabolic homeostasis by restraining in preadipocytes both
repressors of metabolic program like FOXO-1, as well as factors
regulating cell cycle and inflammatory properties like GATA2.
Therefore, in insulin resistance, unchecked FOXO1 might in-
hibit energy storage, causing metabolic derangement.15Simul-
taneously, unchecked GATA2 might facilitate monocyte hom-
ing and macrophage differentiation via an increased expression
of factors such as MCP-1, GM-CSF, and IL-4 from preadipo-
cytes.29–32Interestingly, a synthetic inhibitor for GATA2 has
recently been developed and shown to act as an antiinflamma-
Our data suggest that insulin regulating GATA2 can direct
preadipocytes toward an adipogenic program, whereas insulin
resistance, resulting from either genetic or metabolic factors,
would facilitate a GATA2-sustained inflammatory program.
Therefore, the inhibition of GATA2 could be investigated as a
new strategy to lower obesity-related inflammation to prevent
the development of late complications of obesity such as
diabetes and plaque rupture.
This study was supported by grants from the Italian Ministry of
University (PRIN 2003067733-001 to Dr Lauro; PRIN 2003067733-
006 to Dr Federici), Italian Ministry of Health (RFS 2001, 2002, and
2003 to Dr Federici), and a grant to University of Tor Vergata Center
of Excellence on Genomic Risk Assessment (MIUR CE00277884 to
Dr Lauro). Drs Menghini and Hribal are supported by a grant from
the University of Tor Vergata.
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