Current Understanding on Role of the Wnt Signaling Pathway Effector TCF7L2 in Glucose Homeostasis

The role of the Wnt signaling pathway in metabolic homeostasis has drawn our intensive attention, especially after the genome-wide association study discovery that certain polymorphisms of its key effector TCF7L2 are strongly associated with the susceptibility to type 2 diabetes. For a decade, great efforts have been made in determining the function of TCF7L2 in various metabolic organs, which have generated both considerable achievements and disputes. In this review, I will briefly introduce the canonical Wnt signaling pathway, focusing on its effector -catenin/TCF, including emphasizing the bidirectional feature of TCFs and -catenin posttranslational modifications. I will then summarize the observations on the association between TCF7L2 polymorphisms and type 2 diabetes risk. The main content, however, is on the intensive functional exploration of the metabolic role of TCF7L2, including the disputes generated on determining its role in the pancreas and liver with various transgenic mouse lines. Finally, I will discuss those achievements and disputes and present my future perspectives. (Endocrine Reviews 37: 254 -277, 2016) I. Introduction II. Canonical Wnt Signaling Pathway and Its Metabolic Implications A. Wnt ligands, receptors, coreceptors, secreted agonists and antagonists, and the major effector -cat/TCF B. Bidirectional feature and metabolic regulation of TCFs C. Post-translational modifications of -cat D. Wnt pathway in the genesis of pancreatic -cells, bone formation, and adipogenesis III. The Recognition of the Wnt Signaling Pathway Effector TCF7L2 as a Diabetic Risk Gene A. The discovery made by the deCODE group B. The follow-up TCF7L2 GWAS in Caucasian populations C. The TCF7L2 GWAS in non-Caucasian populations D. T2D susceptibility SNPs, T2D complications, and other metabolic-related disorders IV. From Association to Functional Exploration A. TCF7L2/Tcf7l2 gene and protein structures B. Functional association study in human subjects C. Functional exploration of TCF7L2 in metabolic organs V. Overall Discussion and Perspectives A. TCF7L2 variants in T2D risk, gain of function, or loss of function B. Technical limitations on TCF7L2 study C. Proposed overviews