title: Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves' orbitopathy.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Centre for Endocrine and Diabetes Sciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Fiona
authors.initials: F
authors.lastname: Grennan-Jones
authors.forename: Carol
authors.initials: C
authors.lastname: Lane
authors.forename: D Aled
authors.initials: DA
authors.lastname: Rees
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.forename: Marian
authors.initials: M
authors.lastname: Ludgate
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D015588:Observer Variation; D009915:Orbit / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D050151:Subcutaneous Fat / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases