Current understanding and dispute on the function of the Wnt signaling pathway effector TCF7L2 in hepatic gluconeogenesis

Abstract

Approximately 10 years ago, the Wnt signaling pathway effector TCF7L2 (=TCF-4) was recognized as a type 2 diabetes (T2D) risk gene through a genome wide association study (GWAS). As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups, great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas, liver and adipose tissues. Although these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis, studies conducted to date have also generated controversial suggestions. Here I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies. I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk, a gain-of-function event versus a loss-of-function event. This will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives.

Keywords: Gluconeogenesis; Insulin; TCF7L2; Transgenic mice; Type 2 diabetes; Wnt; β-Catenin.

Fig. 1

A) A simplified schematic of the Wnt signaling pathway. Without Wnt ligand stimulation, β-cat is sequestered in the cytoplasm and degraded by the proteasome. This process involves four major proteins: Axin, APC, GSK-3 and CK-1α, which form the β-cat destruction complex. TCFs will recruit nuclear co-repressors (HDAC, CtBP1 and Groucho) and inhibit Wnt target gene expression (left panel). Following the binding of Wnt ligand to the Frizzled receptor and LRP5/6 co-receptor, the destruction complex is disrupted by Dvl. β-cat will enter the nucleus and forms the bipartite transcription factor with a TCF member (right panel). In addition, β-cat can be activated by insulin or GLP-1 signaling cascade, involving its S675 or S552 phosphorylation. B) Structure of β-cat. Four S/T residues at the N-terminus can be phosphorylated by GSK-3 and CK-1α, leading to its proteasome degradation. The phosphorylation on the two S residues at the C-terminus leads to its activation. T, transactivation domain; Arm Repeats, the armadillo repeat domain.

Fig. 2

TCF7L2 genetic structure and the positions of the T2D risk SNPs. TCF7L2, located on chromosome 10q25.3, consists of 17 exons. Among them, five can be alternatively spliced, leading to the generation of 13 different sized transcripts. Two T2D risk SNPs in Caucasian population, namely rs7903146 and rs12255372, are located within intron 4 and 5 respectively. Two other risk SNPs, rs11196218 and rs290487 were identified in Asian and Chinese populations. Ex1b-e are promoters identified in the brain during embryonic developmental stage. Their transcription leads to the generation of native dominant negative molecules. Western blot can detect two different sized TCF7L2 proteins, with estimated molecular weights of 58 kDa (short) and 78 kDa (long), respectively. For both forms, relative positions for the β-cat interaction domain, the HMG DNA binding domain and the CtBP interaction domains are indicated.

Fig. 3

Potential mechanisms contributing to the repression of hepatic gluconeogenesis by Wnt signaling activation. The gluconeogenic gene Pck-1 is utilized here for the illustration purpose. The elevation of plasma glucagon level during fasting leads to PKA activation and the stimulation of gluconeogenesis, with the participation of Pck-1 transactivators CREB, FoxO, CRTC2 and β-cat. Postprandial elevation of plasma insulin level leads to repressed hepatic gluconeogenesis, which is achieved by the inactivation of FoxO. In addition, insulin can simultaneously stimulate TCF7L2 expression and β-cat S675 phosphorylation. Thus, more β-cat molecules will team up with TCFs instead of with FoxOs, which finally contributes to the repression of Pck-1 and other gluconeogenic genes.