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

Seema Kumar, Sarah Nadeem, Marius N. Stan, Michael Coenen, Rebecca S. Bahn

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

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-stimulatedmRNAencoding adiponectin (67±12%; P=0.021), as well as adiponectin and CCAAT/enhancer-binding protein a protein levels. In conclusion,M22 is a pro-adipogenic factor inGOorbital 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.

Original languageEnglish (US)
Pages (from-to)155-163
Number of pages9
JournalJournal of Molecular Endocrinology
Volume46
Issue number3
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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