The Transcriptional Coactivator Peroxisome
Proliferator–Activated Receptor (PPAR)
Coactivator-1 and the Nuclear Receptor PPAR
Control the Expression of Glycerol Kinase and
Metabolism Genes Independently of PPAR Activation in
Human White Adipocytes
Anne Mazzucotelli,
1,2
Nathalie Viguerie,
1,2,3
Claire Tiraby,
1,2
Jean-Se´ bastien Annicotte,
4
Aline Mairal,
1,2
Eva Klimcakova,
1,2,3
Emmanuelle Lepin,
1,2
Paul Delmar,
5
Se´ bastien Dejean,
6
Genevie` ve Tavernier,
1,2
Corinne Lefort,
1,2
Juan Hidalgo,
7
Thierry Pineau,
8
Lluis Fajas,
4
Karine Cle´ ment,
9
and Dominique Langin
1,2,3,10
OBJECTIVE—The purpose of this work was to determine the
pattern of genes regulated by peroxisome proliferator–activated
receptor (PPAR) coactivator 1 (PGC-1) in human adipocytes
and the involvement of PPAR and PPAR in PGC-1 transcrip-
tional action.
RESEARCH DESIGN AND METHODS—Primary cultures of
human adipocytes were transduced with a PGC-1 adenovirus and
treated with PPAR and PPAR agonists. Variation in gene expres-
sion was assessed using pangenomic microarrays and quantitative
RT-PCR. To investigate glycerol kinase (GyK), a target of PGC-1,
we measured enzymatic activity and glycerol incorporation into
triglycerides. In vivo studies were performed on wild-type and
PPAR
/
mice. The GyK promoter was studied using chromatin
immunoprecipitation and promoter reporter gene assays.
RESULTS—Among the large number of genes regulated by
PGC-1 independently of PPAR, new targets involved in metab-
olism included the gene encoding GyK. The induction of GyK by
PGC-1 was observed at the levels of mRNA, enzymatic activity,
and glycerol incorporation into triglycerides. PPAR was also
upregulated by PGC-1. Its activation led to an increase in GyK
expression and activity. PPAR was shown to bind and activate
the GyK promoter. Experiments in mice confirmed the role of
PGC-1 and PPAR in the regulation of GyK in vivo.
CONCLUSIONS—This work uncovers novel pathways regu-
lated by PGC-1 and reveals that PPAR controls gene expres-
sion in human white adipocytes. The induction of GyK by PGC-1
and PPAR may promote a futile cycle of triglyceride hydrolysis
and fatty acid reesterification. Diabetes 56:2467–2475, 2007
T
he accumulation of white adipose tissue (WAT)
predisposes to the development of an array of
metabolic disturbances leading to type 2 diabe-
tes and cardiovascular disease. In a search for
new therapies, it has been postulated that targeting mo-
lecular pathways that regulate thermogenesis may provide
a plausible means of increasing energy expenditure (1). In
that context, the opposite role of WAT specialized in
energy storage in the form of triglycerides and brown
adipose tissue (BAT) specialized in adaptive thermogene-
sis is of great interest. In humans, BAT depots and brown
adipocytes are sparsely distributed in the body and are not
thought to contribute to a significant part of adaptive
thermogenesis (2,3). Conversion of human white adipo-
cytes into fat cells with some properties of brown adipo-
cytes is an attractive therapeutic strategy (4). Stimulation
of lipolysis in WAT without the concomitant use of re-
leased fatty acids may be detrimental because fatty acids
in excess will be deposited in other organs and may induce
insulin resistance and cardiovascular complications. In-
stead, simultaneous activation of lipolysis and fatty acid
utilization within white adipocytes could allow a decrease
or a stabilization of fat mass without systemic side effects.
The transcriptional coactivator peroxisome prolifera-
tor–activated receptor (PPAR) coactivator 1 (PGC-1)
was initially described as a metabolic regulator of adaptive
thermogenesis in BAT (5). PGC-1 cooperates with the
From the
1
Institut National de la Sante´ et de la Recherche Me´ dicale (INSERM)
U858, Obesity Research Laboratory, Toulouse, F-31432, France;
2
Paul Sabatier
University, Louis Bugnard Institute, Institut Fe´de´ ratif de Recherche 31,
Toulouse, F-31432, France;
3
INSERM, Franco-Czech Laboratory for Clinical
Research on Obesity, Prague, CZ-10100, Czech Republic;
4
INSERM U834,
Metabolism and Cancer Laboratory, Montpellier, F-34090, France; the
5
Math-
e´ matiques Applique´es aux Syste´ mes Laboratory, Ecole Centrale Paris, Chat-
enay Malabry, F-92295, France; the
6
Centre National de la Recherche
Scientifique, Statistics and Probality Laboratory, Paul Sabatier University,
Toulouse, F-31400, France; the
7
Institute of Neurosciences, Department of
Cellular Biology, Physiology and Immunology, Faculty of Sciences, Autono-
mous University of Barcelona, Barcelona, 08193, Spain; the
8
Institut National
de la Recherche Agronomique, Pharmacology and Toxicology Laboratory,
Toulouse, France;
9
INSERM U872, Human Research Center on Nutrition,
Hoˆ tel Dieu, Paris, F-75181, France; and the
10
Centre Hospitalier Universitaire
de Toulouse, Biochemistry Laboratory, Biology Institute of Purpan, Toulouse,
F-31059, France.
Address correspondence and reprint requests to Dominique Langin,
INSERM U858, IFR31 Institute, BP 84225, 31432 Toulouse Cedex 4, France.
E-mail: langin@toulouse.inserm.fr.
Received for publication 18 October 2006 and accepted in revised form 8
July 2007.
Published ahead of print at http://diabetes.diabetesjournals.org on 23 July
2007. DOI: 10.2337/db06-1465.
Additional information for this article can be found in an online appendix at
http://dx.doi.org/10.2337/db06-1465.
BAT, brown adipose tissue; GFP, green fluorescent protein; GSEA, Gene Set
Enrichment Analysis; GyK, glycerol kinase; PANTHER, Protein Analysis
Through Evolutionary Relationships; PGC-1, peroxisome proliferator–acti-
vated receptor coactivator 1; PPAR, peroxisome proliferator–activated
receptor; PPRE, PPAR responsive element; ROS, reactive oxygen species;
RXR, retinoic acid X receptor-; SLC25A4, solute carrier family 25 member
4; UCP, uncoupling protein; WAT, white adipose tissue.
© 2007 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
ORIGINAL ARTICLE
DIABETES, VOL. 56, OCTOBER 2007 2467
Downloaded from http://diabetesjournals.org/diabetes/article-pdf/56/10/2467/385884/zdb01007002467.pdf by guest on 04 November 2022