Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves' orbitopathy

J Clin Endocrinol Metab. 2012 Feb;97(2):653-62. doi: 10.1210/jc.2011-1299. Epub 2011 Dec 7.


Context: Graves' orbitopathy (GO) is associated with Graves' disease, in which anti-TSH receptor (TSHR) autoantibodies (thyroid-stimulating antibodies) increase cAMP causing hyperthyroidism. Excess adipogenesis and hyaluronan (HA) overproduction [HA synthase 2 (HAS2) is the major source] expand the orbital contents causing GO. TSHR activation participates in both processes but an anti-TSHR monoclonal without TSAB activity also increased HA, suggesting the involvement of other cascades. OBJECTIVE AND PATIENTS STUDIED: We investigated using in vitro models in which preadipocytes/fibroblasts from human orbital (n = 12) and sc (n = 10) adipose tissues were treated with IGF-I (to probe the pAkt pathway, recently identified as a positive regulator of HAS2), TSH, and/or various inhibitors. Changes in HA during in vitro-induced adipogenesis were also evaluated.

Main outcome and results: Adipogenesis in orbital preadipocytes was accompanied by significantly increased HAS2 transcripts and HA accumulation in contrast to sc cells in which differentiation significantly decreased HAS2 mRNA and secreted HA. Surprisingly, IGF-I alone did not increase HAS2 levels, despite significantly increasing the ratio of phosphorylated to total Akt; furthermore, an Akt inhibitor increased orbital (but not sc) HAS2 transcripts. A stimulatory effect of IGF-I on HAS2 transcripts was revealed by addition of rapamycin in sc but by a MAPK kinase inhibitor in orbital fibroblasts.

Conclusions: The results have several possible explanations including a phosphorylation-dependent repressor of HAS2 transcript accumulation, exclusively in the orbit. The difference in control of HAS2 expression allows the activation of one of the mechanisms underlying GO, adipogenesis, to be linked biologically with the second, HA overproduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / physiology
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Adipose Tissue / physiology*
  • Cells, Cultured
  • Fibroblasts / metabolism
  • Fibroblasts / physiology
  • Gene Expression Regulation, Enzymologic
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • Graves Ophthalmopathy / genetics
  • Graves Ophthalmopathy / metabolism*
  • Graves Ophthalmopathy / pathology
  • Humans
  • Hyaluronan Synthases
  • Hyaluronic Acid / metabolism*
  • Observer Variation
  • Orbit / metabolism
  • Orbit / pathology
  • Organ Specificity / genetics
  • Subcutaneous Fat / metabolism
  • Subcutaneous Fat / pathology
  • Transcriptional Activation


  • Hyaluronic Acid
  • Glucuronosyltransferase
  • HAS2 protein, human
  • Hyaluronan Synthases