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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-09-0099v1 202/2/207    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, L. Articles by Ludgate, M. Search for Related Content PubMed PubMed Citation Articles by Zhang, L. Articles by Ludgate, M.

L Zhang, CEDS, Cardiff University,, Cardiff, United Kingdom
C Paddon, CEDS, Cardiff University,, Cardiff, United Kingdom
M Lewis, CEDS, Cardiff University,, Cardiff, United Kingdom
F Grennan-Jones, CEDS, Cardiff University,, Cardiff, United Kingdom
M Ludgate, CEDS, Cardiff University, Cardiff, CF14 4XN, United Kingdom

Correspondence: Marian Ludgate, Email: ludgate{at}cf.ac.uk

Since thyrotropin receptor (TSHR) expression increases during adipogenesis and signals via cAMP/phospho-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 (radioimmunoassay) 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 Gbeta/gamma signalling may be inhibitory but failed to induce adipogenesis using activated Gsalpha (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 PPARgamma by phosphorylation but expression of PPARgamma1 was reduced and PPARgamma2 undetectable in gsp*. FOXO1 phosphorylation (required to inactivate this repressor of adipogenesis) was lowest in gsp* despite 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 all measurements the TSHR* cells were between the gsp* and control 3T3L1 preadipocytes. The enhanced downregulation of Pref1 (adipogenesis inhibitor) permits retention of some adipogenic potential in the TSHR* population.

We conclude that Gsalpha signalling impedes FOXO1 phosphorylation and thus inhibits PPARgamma transcription and the alternative promoter usage required to generate PPARgamma2, the fat-specific transcription factor necessary for adipogenesis.