title: Adiponectin inhibits Wnt co-receptor, Lrp6, phosphorylation and β-catenin signaling.
abstract: Adiponectin is a pleiotropic adipokine implicated in obesity, metabolic syndrome and cardiovascular disease. Recent studies have identified adiponectin as a negative regulator of tissue fibrosis. Wnt/β-catenin signaling has also been implicated in metabolic syndrome and can promote tissue fibrosis, but the extent to which adiponectin cross-regulates Wnt/β-catenin signaling is unknown. Using primary human dermal fibroblasts and recombinant purified proteins, we show that adiponectin can limit β-catenin accumulation and downstream gene activation by inhibiting Lrp6 phosphorylation, a key activation step in canonical Wnt signaling. Inhibition of Wnt3a-mediated Lrp6 phospho-activation is relatively rapid (e.g., by 30 min), and is not dependent on established adiponectin G-protein coupled receptors, AdipoR1 and R2, suggesting a more direct relationship to Lrp6 signaling. In contrast, the ability of adiponectin to limit Wnt-induced and baseline collagen production in fibroblasts requires AdipoR1/R2. These results suggest the possibility that the pleiotropic effects of adiponectin may be mediated through distinct cell surface receptor complexes. Accordingly, we propose that the anti-fibrotic activity of adiponectin may be mediated through AdipoR1/R2 receptors, while the ability of adiponectin to inhibit Lrp6 phospho-activation may be relevant to other recently established roles for Lrp6 signaling in glucose metabolism and metabolic syndrome.
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA; Department of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Reinke
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA; Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lam
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA; Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA.
authors.forename: Annette S
authors.initials: AS
authors.lastname: Flozak
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA; Department of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA. Electronic address: j-varga@northwestern.edu.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA; Department of Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA; Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago 60611, IL, USA. Electronic address: c-gottardi@northwestern.edu.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
mesh_terms: D052242:Adiponectin / Q000008:administration & dosage*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D010766:Phosphorylation; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D052242:Adiponectin; C495270:CTNNB1 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Adiponectin; Beta catenin signaling; Cardiovascular disease; Fibrosis; Lrp5/6 receptors; Metabolic syndrome; Metabolism; Obesity; Wnt