The application of peroxisome proliferator-activated receptor (PPAR-γ) agonists, thiazolidinediones, has been one of the major advances in the treatment of type 2 diabetes in recent years. However, in recent years, the tendency of GO to worsen after the application of thiazolidinediones in diabetic patients with combined Graves’ ophthalmopathy (GO) has been reported one after another [1-4], thus the relationship between PPAR-γ and the development of Graves’ ophthalmopathy has attracted increasing attention. 1. PPAR-γ and adipocyte differentiation PPAR-γ is an important factor regulating adipocyte gene expression and differentiation. the expression of PPAR-γ occurs during the differentiation phase of preadipocytes and is expressed before the transcriptional activation of most adipocytes. During adipocyte differentiation, the expression level of PPAR-γ increases through positive feedback regulation, reaching a maximum at the time of mature adipocyte formation. Activation of PPAR-γ can eventually lead to the activation of genes associated with the end of adipose differentiation. Transfection of mouse fibroblasts (NIH3T3) with PPAR-γ retroviral expression vector resulted in their transformation into adipocytes in a PPAR-γ ligand-dependent manner [5]. The use of PPAR-γ agonists thiazolidinediones significantly increased the rate of adipocyte differentiation, while PPAR-γ antagonists inhibited adipocyte differentiation. It can be seen that PPAR-γ is a key transcription factor for adipose differentiation and is an essential gene for adipocyte differentiation. The increase in fat volume due to abnormal adipocyte proliferation and differentiation in the orbit is also closely related to the occurrence and development of GO. It has been reported in the literature that type 2 diabetic patients with combined GO have increased protrusion of the eye after treatment with rosiglitazone or pioglitazone, PPAR-γ agonists [2,4], therefore, PPAR-γ agonists should be used with caution in diabetic patients with combined GO. GO or thyroid-associated ophthalmopathy (TAO) is another common condition that has long plagued the endocrine community. Most patients with TAO have both increased intraorbital fat and enlarged extraocular muscles, and the increase in adipose tissue volume may contribute more to the formation of proptosis than the increase in extraocular muscle volume [6]. The presence of precursor adipocytes in human orbital fat/connective tissue has been demonstrated, and fibroblasts that can differentiate into adipocytes have been isolated from neonatal vascular stroma and adult fat or connective tissue from different parts of the body, and are called “fibrogenic precursor adipocytes”, a subpopulation of fibroblasts [7]. The level of PPAR-γ in the adipose/connective tissue of patients with active GO is significantly higher than that of normal controls by RT PCR, but there is no significant difference between inactive GO and normal controls, so PPAR-γ can be considered as an indicator of GO disease activity [8]. The PPAR-γ antagonist bisphenol propane diepoxide propyl ether (BADGE) can antagonize the effect of rosiglitazone [8], and in vitro studies have also demonstrated that the PPAR-γ antagonist GW9662 can inhibit adipocyte differentiation and formation [1]. Therefore, it can be speculated that drugs that can specifically block PPAR-γ may be another promising treatment for GO. 3. PPAR-γ and TSHR expression in precursor adipocytes PPAR-γ agonists can promote the differentiation and maturation of orbital fibroblastic precursor adipocytes in vitro while causing a significant increase in the expression levels of thyrotropin receptor (TSHR) and PPAR-γ mRNA in differentiated mature cells, and TSHR, PPAR-γ, leptin and lipocalin in mature adipocytes mRNA levels in mature adipocytes were approximately 10-fold higher than those in undifferentiated cells [8]. Activation of TSHR can stimulate adipose precursor cell differentiation at an early stage and inhibit it at the end stage. Activation of TSHR increases the level of endogenous PPAR-γ agonist cAMP in adipose precursor cells, thus indirectly promoting adipogenesis [10]. It is suggested that the increased expression of PPAR-γ, followed by the increased expression of TSHR, may be related to the development of GO, and it may be important to avoid the increase of TSH level during GO treatment for the control of proptosis. PPAR-γ and the regulation of the inflammatory response in orbital tissues The most significant pathophysiological features of active severe ophthalmopathy are inflammation and fat formation in orbital tissues, and PPAR-γ is closely related to the regulation of the inflammatory response. The increased expression of PPAR-γ in parallel with the progression of inflammation may promote increased ocular adipose tissue formation. Compared to chronic inactive GO, active in-frame tissues of ocular disease exhibit overexpression of stearoyl coenzyme A desaturase (SCD) and cyclooxygenase 2 (COX-2) genes, rosiglitazone only increases COX-2 expression in growth arrested precursor adipocytes transiently (48h), while SCD causes a persistent increase in PPAR-γ expression during adipogenesis (2-7d ) [12]. Treatment of human thyroid follicular cells, orbital fibroblasts or adipose precursor cells with rosiglitazone revealed a decrease in mRNA and protein levels of various chemokines induced by interferon-γ (IFN-γ), and the release of CXCR3-transfected chemotactic lymphocytes was also inhibited. It is suggested that PPAR-γ may inhibit the expression of IFN-γ-induced chemokines in autoimmune thyroid disease and GO, and its agonist may attenuate the aggregation of activated T cells in areas of Th1-mediated inflammation [13]. Therefore, it has been suggested that increased intraorbital adipose tissue in GO patients may be the result of overexpression of PPAR-γ when it exerts anti-inflammatory effects during the inflammatory process, and that PPAR-γ has a dual role in GO, both exerting anti-inflammatory effects to attenuate the GO inflammatory response and promoting fat formation to exacerbate proptosis. Therefore, it is impossible to use PPAR-γ agonist for anti-inflammatory treatment of GO if its effect of promoting posterior bulbar adipogenesis cannot be eliminated. T cells and PPAR-γ ligands The formation of intraorbital adipose tissue is a PPAR-γ-dependent process, and may be the result of the combined action of the PPAR-γ ligand prostaglandin D2 (PGD2) family. PGJ family members including 15d-PGJ2, prompting PPAR-γ-expressing ocular fibroblasts to differentiate into adipocytes, and these adipogenic processes can be inhibited by non-selective small molecule Cox-1/Cox-2 inhibitors and selective Cox-2 inhibitors [14]. synthesis of inflammatory mediators such as IL-8. Thus, T cells themselves possess an autoimmune pathway through which T cells can synthesize PPAR-γ ligands and further activate T cells. Co-culture of T cells with orbital fibroblasts in vitro induced adipogenic differentiation, while isolation of T cells from fibroblasts still induced adipogenesis, suggesting a close relationship between secretory mediators PGs and adipogenesis. As a cyclooxygenase inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, antagonizes the effect of PPAR-γ while reducing the number of mature adipocytes by 50% [12]. These exciting findings strongly support the notion that activated T cells are capable of stimulating the differentiation of human fibroblasts into adipocytes, and suggest that T cells are responsible for the pathogenesis of TAO, while orbital fibroblasts expressing PPAR-γ are the basis for adipogenic differentiation and intraorbital tissue reconstruction. Prospect: The determination of PPAR-γ ligands produced by human orbital tissues will be a hot spot for future research. Future facts may demonstrate that PPAR-γ antagonists or drugs that inhibit the PPAR-γ signaling system will provide new therapeutic targets for GO patients in the active phase.