title: Acute Wnt pathway activation positively regulates leptin gene expression in mature adipocytes.
abstract: Genome-wide association studies (GWAS) have revealed the implication of several Wnt signaling pathway components, including its effector transcription factor 7-like 2 (TCF7L2) in diabetes and other metabolic disorders. As TCF7L2 is expressed in adipocytes, we investigated its expression and function in rodent fat tissue and mature adipocytes. We found that TCF7L2 mRNA expression in C57BL/6 mouse epididymal fat tissue was up-regulated by feeding but down-regulated by intraperitoneal insulin injection. In high-fat diet (HFD) fed mice, db/db mice and Zucker (fa/fa) rats, epididymal fat TCF7L2 mRNA levels were lower than the corresponding controls. Treating rat adipocytes with 100nM insulin repressed TCF7L2 mRNA and protein levels, associated with the repression of leptin mRNA level. The treatment with 1nM insulin, however, stimulated TCF7L2 and leptin mRNA levels. This stimulation could be attenuated by iCRT14, an inhibitor of β-catenin/TCF-responsive transcription. Wnt3a stimulated leptin mRNA level, which was also blocked by iCRT14 co-treatment. Utilizing the leptin-expressing cell line HTR8 as a tool, we defined an evolutionarily conserved CREB binding motif that mediated Wnt3a activation. Although Wnt activation is known to repress the differentiation of 3T3-L1 cells towards mature adipocytes, short-term Wnt3a treatment of differentiated 3T3-L1 cells stimulated leptin mRNA levels. Thus, wnt pathway plays a dual function in adipocytes, including the well-known repressive effect on adipogenesis and the stimulation of leptin production in mature adipocytes in response to nutritional status.
authors.affiliation: Guangdong Provincial Key Laboratory of Diabetology, Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Zong-Lan
authors.initials: ZL
authors.lastname: Chen
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Wei-Juan
authors.initials: WJ
authors.lastname: Shao
authors.affiliation: Guangdong Provincial Key Laboratory of Diabetology, Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Xu
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Diabetology, Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Bei-Si
authors.initials: BS
authors.lastname: Lin
authors.affiliation: Guangdong Provincial Key Laboratory of Diabetology, Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wei
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Zhuo-Lun
authors.initials: ZL
authors.lastname: Song
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Huo-Gen
authors.initials: HG
authors.lastname: Lu
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: I George
authors.initials: IG
authors.lastname: Fantus
authors.affiliation: Guangdong Provincial Key Laboratory of Diabetology, Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: wjianp@mail.sysu.edu.cn.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Weng
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. Electronic address: tianru.jin@utoronot.ca.
authors.forename: Tian-Ru
authors.initials: TR
authors.lastname: Jin
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D059305:Diet, High-Fat; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D058118:Transcription Factor 7-Like 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D011994:Recombinant Proteins; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D005576:Colforsin
keywords: Adipocytes; Insulin; Leptin; TCF7L2; Wnt3a; β-Catenin