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School of Medicine, Centre for Endocrine and Diabetes Sciences, Cardiff University, Heath Park, Cardiff CF14 4XN, UK

(Correspondence should be addressed to M Ludgate; Email: ludgate{at}cf.ac.uk)

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.

Since TSH receptor (TSHR) expression increases during adipogenesis and signals via cAMP/phospho-cAMP-response element binding protein (CREB), reported to be necessary and sufficient for adipogenesis, we hypothesised that TSHR activation would induce preadipocyte differentiation. Retroviral vectors introduced constitutively active TSHR (TSHR*) into 3T3L1 preadipocytes; despite increased cAMP (RIA) and phospho-CREB (western blot) there was no spontaneous adipogenesis (assessed morphologically, using oil red O and QPCR measurement of adipogenesis markers). We speculated that Gβ signalling may be inhibitory but failed to induce adipogenesis using activated Gs (gsp*). Inhibition of phosphodiesterases did not promote adipogenesis in TSHR* or gsp* populations. Furthermore, differentiation induced by adipogenic medium with pioglitazone was reduced in TSHR* and abolished in gsp* expressing 3T3L1 cells. TSHR* and gsp* did not inactivate PPAR (PPARG as listed in the HUGO database) by phosphorylation but expression of PPAR1 was reduced and PPAR2 undetectable in gsp*. FOXO1 phosphorylation (required to inactivate this repressor of adipogenesis) was lowest in gsp* despite the activation of AKT by phosphorylation. PROF is a mediator that facilitates FOXO1 phosphorylation by phospho-Akt. Its transcript levels remained constantly low in the gsp* population. In most measurements, the TSHR* cells were between the gsp* and control 3T3L1 preadipocytes. The enhanced down-regulation of PREF1 (adipogenesis inhibitor) permits retention of some adipogenic potential in the TSHR* population. We conclude that Gs signalling impedes FOXO1 phosphorylation and thus inhibits PPAR transcription and the alternative promoter usage required to generate PPAR2, the fat-specific transcription factor necessary for adipogenesis.

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				A. de Lloyd, J. Bursell, J. W Gregory, D A. Rees, and M. Ludgate TSH receptor activation and body composition J. Endocrinol., January 1, 2010; 204(1): 13 - 20. [Abstract] [Full Text] [PDF]