title: The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis.
abstract: The type 2 diabetes risk gene TCF7L2 is the effector of the Wnt signaling pathway. We found previously that in gut endocrine L-cell lines, TCF7L2 controls transcription of the proglucagon gene (gcg), which encodes the incretin hormone glucagon-like peptide-1 (GLP-1). Whereas peripheral GLP-1 stimulates insulin secretion, brain GLP-1 controls energy homeostasis through yet-to-be defined mechanisms. We aim to determine the metabolic effect of a functional knockdown of TCF7L2 by generating transgenic mice that express dominant-negative TCF7L2 (TCF7L2DN) specifically in gcg-expressing cells. The gcg-TCF7L2DN transgenic mice showed reduced gcg expression in their gut and brain, but not in pancreas. Defects in glucose homeostasis were observed in these mice, associated with attenuated plasma insulin levels in response to glucose challenge. The defect in glucose disposal was exacerbated with high-fat diet. Brain Wnt activity and feeding-mediated hypothalamic AMP-activated protein kinase (AMPK) repression in these mice were impaired. Peripheral injection of the cAMP-promoting agent forskolin increased brain β-cat Ser675 phosphorylation and brain gcg expression and restored feeding-mediated hypothalamic AMPK repression. We conclude that TCF7L2 and Wnt signaling control gut and brain gcg expression and glucose homeostasis and speculate that positive cross-talk between Wnt and GLP-1/cAMP signaling is an underlying mechanism for brain GLP-1 in exerting its metabolic functions.
authors.affiliation: Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Shao
authors.forename: Dingyan
authors.initials: D
authors.lastname: Wang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chiang
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ip
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhu
authors.forename: Fenghao
authors.initials: F
authors.lastname: Xu
authors.forename: Joshua
authors.initials: J
authors.lastname: Columbus
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
authors.forename: David M
authors.initials: DM
authors.lastname: Irwin
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wen
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D052336:Proglucagon / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D011993:Recombinant Fusion Proteins; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D005576:Colforsin; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D055372:AMP-Activated Protein Kinases; D005947:Glucose