Thyroid eye disease (TED) is the most common orbital disease in adults. Targeting expanded orbital adipose tissue (OAT) removed by surgery has therapeutic potential. However, drugs targeting OAT are unavailable because of the lack of deciphering features of OAT. Here, we aimed to investigate the mechanism underlying OAT expansion and identify a drug targeting OAT in TED. We found an increasing number of adipocytes with smaller size in TED-derived OATs as compared with controls, indicating that hyperplasia rather than hypertrophy contributed to OAT enlargement in TED. Typically smaller-sized adipocytes in TED patient-derived OATs were noted to localize surrounding vessels. RNA sequencing revealed enriched vascular endothelial growth factor receptor (VEGFR) genes in adipocytes differentiated from preadipocytes of TED-derived stromal vascular fraction (SVF). Similarly, OATs in patients with TED also expressed a higher level of VEGFR-1 and -2. We induced adipogenesis in TED-derived SVF with or without Lenvatinib, an FDA-approved small-molecule VEGFR inhibitor. Lenvatinib significantly suppressed lipid accumulation in a dose-dependent manner. In conclusion, our study revealed the potential anti-adipogenic effect of Lenvatinib on the OAT of TED-affected patients. In addition to proposing a drug for TED treatment, this study shows the therapeutic potential of anti-adipogenesis drugs targeting the VEGF pathway.

Background: Thyroid eye disease (TED) is the most frequent orbital disease in adults and is characterized by the accumulation of orbital adipose tissue (OAT). It can lead to eyelid retraction or even vision loss. Orbital decompression surgery serves as the primary treatment for inactive TED by removing the excess OAT. However, there is a lack of alternative treatments to surgery due to the unclear understanding of the pathogenesis, particularly the metabolic features. Accordingly, our study was implemented to explore the content and features of metabolites of OATs from TED patients.Method: The OATs used in the current study were obtained from the orbital decompression surgery of seven patients with inactive TED. We also collected control OATs from eye surgical samples of five individuals with no history of autoimmune thyroid diseases, TED, or under non-inflammatory conditions. The liquid chromatography mass spectrometer was used for the measurements of the targeted metabolites. Afterwards, we performed differential metabolite assay analysis and related pathway enrichment analysis.Results: In our study, a total of 149 metabolite profiles were detected in all participants. There were significant differences in several metabolite profiles between the TED group and the control group, mainly including uric acid, oxidized glutathione, taurine, dGMP, oxidized glutathione 2, uracil, hexose-phosphate, 1-methylnicotinamide, D-sedoheptulose 1,7-bisphosphate, and uridine 5′-monophosphate (all p-value < 0.05). The TED-related pathways identified included purine metabolism, beta-alanine metabolism, glutathione metabolism (p-values < 0.05). Our study found overlaps and differences including uric acid and uracil, which are in accordance with metabolites found in blood of patients with TED from previous study and several newly discovered metabolite by our study such as hexose-phosphate, 1-methylnicotinamide, D-sedoheptulose 1,7-bisphosphate, compared to those tested from blood, OAT, or urine samples reported in previous studies.Conclusion: The findings of our study shed light on the metabolic features of OAT in individuals with TED. These results may help identify new treatment targets for TED, providing potential avenues for developing alternative treatments beyond ophthalmic surgery.