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The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte
Development and Function.
Chen X, Ayala I, Shannon C, Fourcaudot M, Acharya NK, Jenkinson CP, Heikkinen S,
Submitted Externally on 4/9/2018
Volume : Pages
67 : 554 - 568
The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest
type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2
protein is a key transcriptional effector of the Wnt/ß-catenin signaling
pathway, which is an important developmental pathway that negatively regulates
adipogenesis. However, the precise role that TCF7L2 plays in the development and
function of adipocytes remains largely unknown. Using a combination of in vitro
approaches, we first show that TCF7L2 protein is increased during adipogenesis
in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is
required for the regulation of Wnt signaling during adipogenesis. Inactivation
of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding
domain in mature adipocytes in vivo leads to whole-body glucose intolerance and
hepatic insulin resistance. This phenotype is associated with increased
subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation.
Finally, we demonstrate thatTCF7L2mRNA expression is downregulated in humans
with impaired glucose tolerance and adipocyte insulin resistance, highlighting
the translational potential of these findings. In summary, our data indicate
that TCF7L2 has key roles in adipose tissue development and function that may
reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.
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