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J. Biol. Chem., Vol. 277, Issue 22, 19754-19761, May 31, 2002
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From the Division of Endocrinology, Diabetes, and Metabolism,
Departments of Medicine and Genetics and The Penn Diabetes Center,
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104
Resistin, also known as Adipocyte
Secreted Factor (ADSF) and Found in
Inflammatory Zone 3 (FIZZ3), is a mouse
protein with potential roles in insulin resistance and adipocyte
differentiation. The resistin gene is expressed almost exclusively in
adipocytes. Here we show that a proximal 264-base pair fragment of the
mouse resistin promoter is sufficient for expression in adipocytes. Ectopic expression of the adipogenic transcription factor
CCAAT/enhancer-binding protein (C/EBP
Mechanisms Regulating Adipocyte Expression of
Resistin*
,,
) was sufficient for
expression in non-adipogenic cells. C/EBP binds specifically to a
site that is essential for expression of the resistin promoter.
Chromatin immunoprecipitation studies of the endogenous gene
demonstrated adipocyte-specific association of C/EBP with the
proximal resistin promoter in adipocytes but not preadipocytes.
C/EBP binding was associated with the recruitment of coactivators
p300 and CREB-binding protein and a dramatic increase in histone
acetylation in the vicinity of the resistin promoter. The antidiabetic
thiazolidinedione (TZD) drug rosiglitazone reduced resistin expression
with an ED50 similar to its Kd
for binding to peroxisome proliferator activated receptor 
(PPAR). Other TZD- and non-TZD PPAR ligands also down-regulated
resistin expression. However, no functional PPAR binding site was
found within 6.2 kb of the transcriptional start site, suggesting that
if PPAR is involved, it is either acting at a long distance from the
start site, in an intron, or indirectly. Nevertheless,
rosiglitazone treatment selectively decreased histone acetylation
at the resistin promoter without a change in occupation by C/EBP,
CREB-binding protein, or p300. Thus, adipocyte specificity of resistin
gene expression is because of C/EBP binding, leading to the
recruitment of transcriptional coactivators and histone acetylation
that is characteristic of an active chromatin environment. TZD reduces
resistin gene expression at least in part by reducing histone
acetylation associated with the binding of C/EBP in mature adipocytes.
*
This work was supported by NIDDK, National Institutes
of Health Grants DK49780 and DK49210 (to M. A. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
To whom correspondence should be addressed: University of
Pennsylvania, School of Medicine, 611 CRB, 415 Curie Blvd.,
Philadelphia, PA 19104-6149. Tel.: 215-898-0198; Fax: 215-898-5408;
E-mail: lazar@mail.med.upenn.edu.
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