title: Insulin-like growth factor 1 promotes the proliferation and adipogenesis of orbital adipose-derived stromal cells in thyroid-associated ophthalmopathy.
abstract: Thyroid-associated ophthalmopathy (TAO) is characterised by increased volume of the orbital contents involving adipose tissue, but the factors responsible for stimulation of orbital adipogenesis remain uncertain. Previous studies have shown that insulin-like growth factor 1 (IGF-1) is increased in the orbital fatty connective tissues of patients with TAO. The present study was conducted to investigate the effects of IGF-1 on orbital adipose-derived stromal cells (OADSCs) derived from TAO patients and to identify the signalling mechanisms involved. Our results showed that IGF-1 significantly promoted the cell proliferation and lipid accumulation of TAO OADSCs. The mRNA expression of adipogenic markers (adiponectin, leptin, adipocyte fatty acid binding protein [AP2] and fatty acid synthase [FAS]) was increased in TAO cultures treated with IGF-1. Further research demonstrated that the protein levels of peroxisome proliferator-activated receptor-γ (PPARγ) were up-regulated when OADSCs were treated with IGF-1. We also found that the inhibition of either IGF-1 receptor (IGF-1R) or phosphoinositide 3-kinase (PI3K) activity decreased the levels of IGF-1-stimulated mRNA encoding adiponectin, leptin, AP2, and FAS, as well as PPARγ protein levels. Moreover, the expression of phosphorylated Akt (p-Akt) protein in TAO cells was up-regulated by IGF-1, while a specific PI3K inhibitor (LY294002) or an antibody of IGF-1R blocked this effect. These results indicate that IGF-1 is a pro-proliferative and pro-adipogenic factor in TAO OADSCs. IGF-1 enhances the adipogenesis of TAO OADSCs by up-regulation of PPARγ via the activation of the IGF-1R and PI3K pathways, suggesting that the blocking of IGF-1R or inhibition of PI3K signalling might be a potential novel therapeutic approach to TAO.
authors.affiliation: Department of Ophthalmology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Pingqian
authors.initials: P
authors.lastname: Zhao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Deng
authors.forename: Ping
authors.initials: P
authors.lastname: Gu
authors.forename: Yefei
authors.initials: Y
authors.lastname: Wang
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhou
authors.forename: Yamin
authors.initials: Y
authors.lastname: Hu
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Xianqun
authors.initials: X
authors.lastname: Fan
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D019138:Antibodies, Blocking; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D019299:Decompression, Surgical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049970:Graves Ophthalmopathy / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D006801:Humans; D016130:Immunophenotyping; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D050356:Lipid Metabolism; D009915:Orbit / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000276:immunology; D012844:Sincalide / Q000378:metabolism; D017154:Stromal Cells
chemical_list: D019138:Antibodies, Blocking; D015415:Biomarkers; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D012844:Sincalide