PPAR-g GENE EXPRESSION IN GRAVES’ OPHTHALMOPATHY
849
patient had hypothyroidism and another hyperthyroidism
while 7 patients were euthyroid.
3. Valysasevi RW, Harteneck D, Dutton DM, Bahn RS 2002 Stim-
ulation of adipogenesis, peroxisome proliferator-activated re-
ceptor-[gamma] (PPAR[gamma]), and thyrotropin receptor
by PPAR[gamma] agonist in human orbital preadipocyte fi-
broblasts. J Clin Endocrinol Metab 87:2352–2358.
Because PPAR-g has been demonstrated by immunofluo-
rescence to be present in orbital preadipocytes and its role
in adipogenesis has been well documented (5,10), an in-
creased amount of this transcription factor in the orbit of pa-
tients with GO can be considered an expected finding. Re-
cently, Starkey and colleagues (20) documented worsening
of proptosis and increase in fat volume of the orbit in a pa-
tient with previously stable GO after the introduction of
PPAR-g agonist thiazolidinedione. Their findings emphasize
the importance of PPAR-g in the pathogenesis of the disease.
GO is, however, generally a self-limiting condition and dif-
ferentiation of fibroblasts to adipocytes probably occurs only
during a certain period of time, while progression of eye
symptoms occur. The higher expression levels of PPAR-g in
orbital tissues from patients with the active stage of GO com-
pared with those from patients with the non-active stage of
the disease and normal orbital adipose/connective tissue
specimens are in accordance with such an expectation.
PPAR-g decrease probably correlate with clinical stabiliza-
tion of symptoms.
The main factors leading to PPAR-g increase in the orbit
of patients with GO not taking PPAR-g agonists are un-
known. Our study, showing high expression of the tran-
scription factor in orbital tissues from patients in the active
stage of GO indicate a possible relationship between elevated
PPAR-g levels and the inflammatory process that is triggered
by the autoimmune process that is present in the active con-
gestive stage of GO (25). This assumption is in accordance
with recent experimental reports that link PPAR-g with an
anti-inflammatory action. For instance, some studies indi-
cated that PPAR-g ligands reduced the colonic inflammatory
process in animal models and inhibited induced cytokine
synthesis of mononuclear cells in vitro (26,27). Furthermore,
Feinstein and coworkers (27) reported that oral use of the
PPAR-g agonist pioglitazone prevents experimental autoim-
mune encephalomyelitis in mice. Their study indicates that
PPAR-g exerts an anti-inflammatory effect on glial cells and
reduces the proliferation and activation of T cells (28). Be-
4. Bahn RS 1995 The fibroblast is the target cell in the connec-
tive tissue manifestations of Graves’ disease. Int Arch Al-
lergy Immunol 106:213–218.
5
. Sorisky A, Pardasani D, Gagnon A, Smith TJ 1996 Evidence
of adipocyte differentiation in human orbital fibroblasts in
primary culture. J Clin Endocrinol Metab 81:3428–3431.
6
. Crisp MS, Lane C, Halliwell M, Wynford-Thomas D,
Ludgate M 1997 Thyrotropin receptor transcripts in human
adipose tissue. J Clin Endocrinol Metab 82:2003–2005.
7. Wu SL, Yang CSJ, Wang HJ, Liao CL, Chang TJ, Chang TC
1
999 Demonstration of thyrotropin receptor mRNA in or-
bital fat and eye muscle tissues from patients with Graves’
ophthalmopathy by in situ hybridization. J Endocrinol In-
vest 22:289–295.
8. Chen X, Hausman DB, Dean RG, Hausman GJ 1997 Differ-
entiation-dependent expression of obese (ob) gene by
preadipocytes and adipocytes in primary cultures of porcine
stromal-vascular cells. Biochim Biophys Acta 1359:136–142.
9. Tontonoz P, Hu E, Spielgeman BM 1994 Stimulation of adi-
pogenesis in fibroblasts by PPAR gamma 2, a lipid-activated
transcription factor. Cell 79:1147–1156.
0. Smith TJ, Koumas L, Gagnon A, Bell A, Sempowski GD,
Phipps RP, Sorisky A 2002 Orbital fibroblast heterogeneity
may determine the clinical presentation of thyroid associ-
ated ophthalmopathy. J Clin Endocrinol Metab 87:385–392.
1. Rangwala SM, Lazar MA 2000 Transcriptional control of adi-
pogenesis. Annu Rev Nutr 20:535–559.
1
1
1
1
1
1
2. Gregoire MF, Smas CM, Sul HS 1998 Understanding
adipocyte differentiation. Physiol Rev 78:783–809.
3. Lowell BB. 1999 PPAR-g: An essential regulator of adipo-
genesis and modulator of fat cell function. Cell 99:239–242.
4. Spiegelman BM 1998 PPAR-g: Adipogenic regulator and thi-
azolidinedione receptor. Diabetes 47:507–514.
5. Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA 1994
Peroxisome proliferator-activated receptor (PPAR) g:
Adipose-predominant expression and induction early in
adipocyte differentiation. Endocrinology 135:798–800.
cause PPAR-g seems to have anti-inflammatory action it is 16. Mouritz MP, Koorneef L, Wiersinga WM, Prummel MF,
likely that the high levels observed in the active stage of GO
is induced by the inflammation produced by the autoim-
mune process. Orbital adipose tissue enlargement could
Berghout A, Van der Gaag R 1989 Clinical criteria for the as-
sessment of disease activity in Graves’ ophthalmopathy: A
novel approach. Br J Ophthalmol 73:639–644.
therefore occur as a secondary event, resulting from raised 17. Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP,
Staels B, Suwerx J, Laville M, Vidal H 1997 Tissue dis-
tribuition and quantification of the expression of mRNAs of
peroxisome proliferator-activated receptors and liver X re-
ceptor-a in humans. Diabetes. 46:1319–1327.
levels of PPAR-g.
Acknowledgments
This work was supported by FAPESP grant 98/14199-1 18. Pasquali D, Exposito D, Vassalo P, Bonavolonta G, Bel-
and CNPq grant 300145/93-4.
lastella A, Smisi AA 1999 PPAR g2 expression is increased
in cultured orbital fibroblasts from patients with Graves’
ophthalmopathy. The Endocrine Society 81st Annual Meet-
ing, Califórnia, p. 423.
We are indebted to Hubert Vidal for kindly providing the
plasmid with the mutant form of PPAR-g cDNA and for his
assistance with the development of the methodology.
1
9. Feliciello A, Porcellini A, Ciullo L, Bonavolonta G, Avvedi-
mento E, Fenzi G 1993 Expression of thyrotropin receptor
mRNA in healthy and Graves’ disease retro-orbital tissue.
Lancet 342:337–338.
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