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      A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves' ophthalmopathy

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          Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital tissues associated with elevated serum levels of TSH receptor (TSHR) autoantibodies. Because previous studies have demonstrated evidence of adipogenesis within the GO orbit, we sought to determine whether M22, a human monoclonal antibody directed against TSHR, enhances adipogenesis in orbital fibroblasts from patients with GO and, if so, to identify signaling mechanisms involved. GO orbital fibroblast cultures ( n=10) were treated for 10 days with bovine TSH (1 or 10·0 U/l) or M22 (1 or 10 ng/ml) in serum-free adipocyte differentiation medium. Some cultures also received a phosphoinositide 3-kinase (PI3K) inhibitor or an inhibitor of cAMP production. In other experiments, confluent cultures ( n=8) were treated for between 1 and 30 min with TSH (0·1–10·0 U/l) or M22 (0·1–100 ng/ml) with measurement of cAMP production or levels of phosphorylated AKT (pAKT). We found levels of adiponectin, leptin, and TSHR mRNA to be increased in GO cultures treated for 10 days with either M22 (2·6 mean fold ±0·7; P=0·03) or TSH (13·2±5·8-fold, P=0·048). In other studies, M22 and TSH stimulated cAMP production and pAKT levels in GO cells. Inhibition of PI3K activity during 10 days in culture decreased the levels of M22-stimulated mRNA encoding adiponectin (67±12%; P=0·021), as well as adiponectin and CCAAT/enhancer-binding protein α protein levels. In conclusion, M22 is a pro-adipogenic factor in GO orbital preadipocytes. This antibody appears to act via the PI3K signaling cascade, suggesting that inhibition of PI3K signaling may represent a potential novel therapeutic approach in GO.

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          Most cited references 28

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          Graves' ophthalmopathy.

           S Bahn (2010)
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            Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation.

            Akt is a serine/threonine kinase that requires a functional phosphatidylinositol 3-kinase to be stimulated by insulin and other growth factors. When directed to membranes by the addition of a src myristoylation sequence, Akt becomes constitutively active. In the present studies, the constitutively active Akt and a nonmyristoylated control mutant were expressed in 3T3-L1 cells that can be induced to differentiate into adipocytes. The constitutively active Akt induced glucose uptake into adipocytes in the absence of insulin by stimulating translocation of the insulin-responsive glucose transporter 4 to the plasma membrane. The constitutively active Akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3T3-L1 adipocytes directed lipid but not glycogen synthesis. These results indicate that Akt can regulate glucose uptake and metabolism.
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              Thyrotropin receptor autoantibodies are independent risk factors for Graves' ophthalmopathy and help to predict severity and outcome of the disease.

              The objective of this study was to examine whether TSH-receptor antibody [TSH binding inhibitory antibodies (TBII)] levels are associated with the severity of Graves' ophthalmopathy (GO) over the entire course of the disease. A total of 159 patients with GO were followed for 12-24 months. One year after the first symptoms of GO, all patients were classified into mild or severe GO according to their clinical manifestations. TBII were measured every 3 months after onset of GO. Receiver operating characteristic plot analysis was performed to assess the power to discriminate both patient groups by TBII (specificity >90%). TBII levels and prevalence at each time point during follow-up were significantly higher in patients with a severe course of GO compared with patients with a mild course of GO. Prognostic statements on the course of the disease were possible for about half of the GO patients at all time points (except the first). If at first presentation and at consecutive time points TBII levels were less than 5.7, 2.6, 1.5, 1.5, 1.5, and 1.5 IU/liter, the patients had a 2.3- to 15.6-fold higher chance of a mild course. If 5-8 months after GO onset and at consecutive time points TBII levels were above 8.8, 5.1, 4.8, 2.8, and 2.8 IU/liter, the patients had a 8.7- to 31.1-fold higher risk of a severe course. This relationship of TBII to the severity was independent from age and smoking. Follow-up measurements of TBII allow, in half of the patients, assessment of the prognosis of GO and, therefore, could be of additional help for the disease management.

                Author and article information

                J Mol Endocrinol
                Journal of Molecular Endocrinology
                Society for Endocrinology (Bristol )
                June 2011
                14 February 2011
                : 46
                : 3
                : 155-163
                [1 ]Division of Pediatric Endocrinology and Metabolism Mayo Clinic 200 First Street SW, Rochester, Minnesota, 55905USA
                [2 ]Division of Endocrinology Diabetes and Metabolism Mayo Clinic 200 First Street SW, Rochester, Minnesota, 55905USA
                Author notes
                (Correspondence should be addressed to R S Bahn; Email: bahn.rebecca@ 123456mayo.edu )
                © 2011 Society for Endocrinology

                This is an Open Access article distributed under the terms of the Society for Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: National Institute of Diabetes, Digestive and Kidney Diseases
                Award ID: DK77814
                Regular Papers

                Endocrinology & Diabetes


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