The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function

Abstract

The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/β-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 (ASC), and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivating TCF7L2 protein by removing the 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, in humans with impaired glucose tolerance (IGT) and adipocyte insulin resistance we demonstrate that TCF7L2 mRNA expression is downregulated, 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.