Conclusions/interpretation
These results provide a novel mechanism whereby peroxisome proliferator-activated receptor-gamma activation can terminate WNT signalling and promote adipogenesis. Furthermore, they provide an explanation for why TZD treatment can lead to reduced bone formation and increased risk of fractures, since inhibited WNT signalling in progenitor cells promotes adipogenesis while osteogenesis is reduced.
Methods
We examined the effect of TZDs on secretion and DKK1 levels in pre-adipocytes and mature adipose cells and also measured circulating DKK1 levels in 11 patients with type 2 diabetes before and after treatment with the TZD rosiglitazone for 90 days.
Results
TZDs added in vitro rapidly increased DKK1 protein levels and secretion in both fully differentiated adipose cells and pre-adipocytes undergoing differentiation. In parallel, beta-catenin levels, a marker of canonical WNT signalling, were reduced. Serum levels of DKK1 were also increased in several of the patients with type 2 diabetes after treatment with rosiglitazone for 90 days. Conclusions/interpretation: These results provide a novel mechanism whereby peroxisome proliferator-activated receptor-gamma activation can terminate WNT signalling and promote adipogenesis. Furthermore, they provide an explanation for why TZD treatment can lead to reduced bone formation and increased risk of fractures, since inhibited WNT signalling in progenitor cells promotes adipogenesis while osteogenesis is reduced.