Stimulation of Adipogenesis, Peroxisome Proliferator-Activated Receptor-γ (PPARγ), and Thyrotropin Receptor by PPARγ Agonist in Human Orbital Preadipocyte Fibroblasts

Abstract

The symptoms and signs of Graves' ophthalmopathy (GO) result from both an accumulation of hydrated hyaluronan in the orbital muscles and connective tissues and an expansion of the orbital adipose tissues. Recent studies have suggested a link between the stimulation of adipogenesis within the orbit in GO and the expression in these tissues of TSH receptor (TSHR), the putative orbital autoantigen. To further investigate this association, we treated orbital fibroblasts from patients with GO with rosiglitazone, a thiazolidinedione agonist of the PPARgamma receptor that stimulates adipocyte differentiation. We found this compound to be a potent stimulator of functional TSHR expression as well as TSHR and PPARgamma mRNA levels in differentiated cultures. In addition, rosiglitazone treatment stimulated recruitment and differentiation of a subset of cells within these cultures into mature lipid-laden adipocytes. These results suggest that TSHR expression in GO orbital preadipocyte fibroblasts is linked to adipogenesis, and that ligation of the PPARgamma receptor results in differentiation of these cells. It is possible that endogenous PPARgamma ligands play a role in stimulating orbital adipogenesis in GO, and that future treatments may be aimed at antagonism of various components of the PPARgamma signaling system.

Platelet-Derived Growth Factor: A Key Factor in the Pathogenesis of Graves' Ophthalmopathy and Potential Target for Treatment

“…Orbital fibroblasts express TSHR, which increases when orbital fibroblasts differentiate into adipocytes [12,13]. TSHR stimulatory autoantibodies stimulate the production of cytokines, hyaluronan and adipocyte differentiation by orbital fibroblasts [14,15,16,17,18].…”

Adjuvant Treatment of Graves' Disease with Diclofenac: Safety, Effects on Ophthalmopathy and Antibody Concentrations

“…One pathogenic mechanism in GO is increased orbital adipogenesis, and glitazones are known to increase the volume of subcutaneous adipose tissue [9]. Orbital fibroblasts from patients with ophthalmopathy have been shown to differentiate to adipocytes in response to rosiglitazone [10]. Glitazones are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists and it is therefore of interest to study if PPAR-γ antagonists have preventive effects on the development of GO.…”

Pathogenesis of Graves Ophthalmopathy: Implications for Prediction, Prevention, and Treatment

“…Levels of TSHR mRNA, as well as leptin and adiponectin mRNA (encoding genes expressed exclusively by mature adipocytes, used here as markers of differentiation), are approximately tenfold higher in cultures containing mature adipocytes than in undifferentiated cultures. 18,19 Similarly, expression of these genes is increased in orbital adipose tissue specimens from GO patients, compared with normal tissue specimens, and significant positive correlations exist between mRNA levels corresponding to TSHR and those encoding leptin and adiponectin. 20 Taken together, these results suggest that adipogenesis is enhanced in the orbits of patients with GO and that increased TSHR expression is a consequence of this process.…”

“…20 PPAR-γ ligation is important in the initiation of adipogenesis, and PPAR-γ agonists have been shown to stimulate both adipogenesis and TSHR expression in cultured orbital preadiopocytes. 19 Therefore, agents that might be developed to specifically block PPAR-γ ligation would hold therapeutic promise for GO. Of related interest is a report of a patient with GO in whom increased proptosis developed after treatment of diabetes mellitus type 2 with the PPAR-γ agonist rosiglitazone.…”