title: Liver-specific expression of dominant-negative transcription factor 7-like 2 causes progressive impairment in glucose homeostasis.
abstract: Investigations on the metabolic role of the Wnt signaling pathway and hepatic transcription factor 7-like 2 (TCF7L2) have generated opposing views. While some studies demonstrated a repressive effect of TCF7L2 on hepatic gluconeogenesis, a recent study using liver-specific Tcf7l2(-/-) mice suggested the opposite. As a consequence of redundant and bidirectional actions of transcription factor (TCF) molecules and other complexities of the Wnt pathway, knockout of a single Wnt pathway component may not effectively reveal a complete metabolic picture of this pathway. To address this, we generated the liver-specific dominant-negative (DN) TCF7L2 (TCF7L2DN) transgenic mouse model LTCFDN. These mice exhibited progressive impairment in response to pyruvate challenge. Importantly, LTCFDN hepatocytes displayed elevated gluconeogenic gene expression, gluconeogenesis, and loss of Wnt-3a-mediated repression of gluconeogenesis. In C57BL/6 hepatocytes, adenovirus-mediated expression of TCF7L2DN, but not wild-type TCF7L2, increased gluconeogenesis and gluconeogenic gene expression. Our further mechanistic exploration suggests that TCF7L2DN-mediated inhibition of Wnt signaling causes preferential interaction of β-catenin (β-cat) with FoxO1 and increased binding of β-cat/FoxO1 to the Pck1 FoxO binding site, resulting in the stimulation of Pck1 expression and increased gluconeogenesis. Together, our results using TCF7L2DN as a unique tool revealed that the Wnt signaling pathway and its effector β-cat/TCF serve a beneficial role in suppressing hepatic gluconeogenesis.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ip
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Shao
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Zhuolun
authors.initials: Z
authors.lastname: Song
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Zonglan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada tianru.jin@utoronto.ca.
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
mesh_terms: D000818:Animals; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D005947:Glucose