Cheng Lu, Hu Jing, Zhang Ling, Shen Ning, Chen Hui, Zhang Fang
National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Shanghai Key Laboratory of Fundus Diseases, Shanghai 200080, China.
Pharmaceuticals (Basel). 2022 Oct 22;15(11):1305. doi: 10.3390/ph15111305.
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.
甲状腺眼病（TED）是成人中最常见的眼眶疾病。针对手术切除的眼眶脂肪组织（OAT）增生具有治疗潜力。然而，由于缺乏对OAT特征的解读，尚无针对OAT的药物。在此，我们旨在研究OAT扩张的机制，并确定一种针对TED中OAT的药物。我们发现，与对照组相比，TED来源的OAT中脂肪细胞数量增加且体积较小，这表明增生而非肥大导致了TED中OAT的增大。值得注意的是，TED患者来源的OAT中典型的较小尺寸脂肪细胞位于血管周围。RNA测序显示，从TED来源的基质血管成分（SVF）的前脂肪细胞分化而来的脂肪细胞中，血管内皮生长因子受体（VEGFR）基因富集。同样，TED患者的OAT也表达更高水平的VEGFR-1和-2。我们用或不用乐伐替尼（一种FDA批准的小分子VEGFR抑制剂）诱导TED来源的SVF中的脂肪生成。乐伐替尼以剂量依赖性方式显著抑制脂质积累。总之，我们的研究揭示了乐伐替尼对TED患者OAT的潜在抗脂肪生成作用。除了提出一种用于TED治疗的药物外，本研究还显示了靶向VEGF途径的抗脂肪生成药物的治疗潜力。
