The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

Abstract

Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and ␤-catenin (␤-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/ TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and ␤-cat Ser 675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated ␤-cat Ser 675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes. transcription factor 7-like 2; ␤-catenin; glucose production; liver; phosphoenolpyruvate carboxykinase; Wnt-3a TRANSCRIPTION FACTOR 7-LIKE 2 (TCF7L2, previously known as TCF-4) belongs to the T cell factor (TCF) family of highmobility group box transcription factors and is a major effector of the canonical Wnt signaling pathway (defined as the Wnt pathway hereafter unless further clarification is necessary) (18,24). Upon stimulation by Wnt ligands, a TCF protein binds to nuclear ␤-catenin (␤-cat) to form a bipartite transcription factor cat/TCF, leading to the stimulation of Wnt target gene expression (14). cat/TCF may also serve as an effector of other signaling molecules, including certain peptide hormones that utilize cAMP as a second messenger, IGF-I, insulin, and the lipid metabolite lysophosphatidic acid (LPA) (2,5,14,15,37).Previous studies have established the fundamental role of TCF7L2 and Wnt in embryogenesis and tumorigenesis. However, the involvement of Wnt signaling and TCF7L2 in hormone gene expression and metabolic homeostasis has been recognized only recently (15,21,25,26,41).During the past few years, extensive genome-wide association studies have revealed that certain single nucleotide polymorph...

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

“…We were unable to determine whether the regulation of TCF7L2 expression in livers of diabetic patients involved different mechanisms related to hyperglycaemia or insulin resistance, or whether the higher TCF7L2 expression levels were a consequence of other confounding factors such as differences in medication of type 2 diabetic individuals. Recent reports have shown that mouse TCF7L2 expression is insulin-responsive [20,22] and that in insulin-resistant mice expression of the short and medium C-terminal transcripts (e.g. including T3 and T5) was reduced [21].…”

“…An initial study of alternatively spliced Mature mRNA transcript Transcript number N-terminal C-terminal TCF4 nomination [13] Major pancreatic and liver TCF7L2 isoforms [12 [19]. TCF7L2 expression is highest in pericentral hepatocytes, where gluconeogenesis is low [20]. As evidence that TCF7L2 affects liver glucose metabolism [20][21][22] is accumulating, we sought to further characterise the expression of alternative human TCF7L2 transcripts in livers of normoglycaemic and type 2 diabetes individuals genotyped for rs7903146.…”

“…TCF7L2 expression is highest in pericentral hepatocytes, where gluconeogenesis is low [20]. As evidence that TCF7L2 affects liver glucose metabolism [20][21][22] is accumulating, we sought to further characterise the expression of alternative human TCF7L2 transcripts in livers of normoglycaemic and type 2 diabetes individuals genotyped for rs7903146. We also analysed expression levels of these transcripts in HepG2 cells incubated with different glucose concentrations in the presence or not of insulin, as well as the mRNA expression of 84 genes related to glucose metabolism, subsequent to downregulation of TCF7L2 by small interfering RNA (siRNA).…”

“…We also analysed expression levels of these transcripts in HepG2 cells incubated with different glucose concentrations in the presence or not of insulin, as well as the mRNA expression of 84 genes related to glucose metabolism, subsequent to downregulation of TCF7L2 by small interfering RNA (siRNA). Hepatic gluconeogenesis is tightly controlled by rate-limiting enzymes, such as glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase, which are both inhibited by a TCF7L2-dependent pathway [20][21][22]. Hepatocyte nuclear factor 4α (HNF4α) and forkhead box O1 (FOXO1) are transcriptional regulators of G6PC, which mediates regulation of gluconeogenesis in response to feeding or fasting [23].…”

Liver-Specific Expression of Dominant-Negative Transcription Factor 7-Like 2 Causes Progressive Impairment in Glucose Homeostasis

“…Following pivotal studies indicating that the transcription factor 7-like 2 (TCF7L2) is an important risk gene for the development of type 2 diabetes (T2D) (1), great efforts have been made to explore its role as a Wnt signaling molecule in pancreatic b-cells and other tissues including liver (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Although several investigations suggested that TCF7L2 negatively regulates hepatic gluconeogenesis (8,10,11,17), one recent study (7) reported that liver-specific knockout of TCF7L2 reduced hepatic glucose production (HGP), while hepatic overexpression of TCF7L2 increased HGP.…”