title: RNA-binding protein PTB and microRNA-221 coregulate AdipoR1 translation and adiponectin signaling.
abstract: Adiponectin receptor 1 (AdipoR1) mediates adiponectin's pleiotropic effects in muscle and liver and plays an important role in the regulation of insulin resistance and diabetes. Here, we demonstrate a pivotal role for microRNA-221 (miR-221) and the RNA-binding protein polypyrimidine tract-binding protein (PTB) in posttranscriptional regulation of AdipoR1 during muscle differentiation and in obesity. RNA-immunoprecipitation and luciferase reporter assays illustrated that both PTB and miR-221 bind AdipoR1-3'UTR and cooperatively inhibit AdipoR1 translation. Depletion of PTB or miR-221 increased, while overexpression of these factors decreased, AdipoR1 protein synthesis in both muscle and liver cells. During myogenesis, downregulation of PTB and miR-221 robustly induced AdipoR1 translation, providing a mechanism for enhanced AdipoR1 protein expression and activation in differentiated muscle cells. In addition, since both PTB and miR-221 are upregulated in liver and muscle of genetic and dietary mouse models of obesity, this novel translational mechanism may be at least partly responsible for the reduction in AdipoR1 protein levels in obesity. These findings highlight the importance of translational control in regulating AdipoR1 protein expression and adiponectin signaling. Given that adiponectin is reduced in obesity, induction of AdipoR1 could potentially enhance adiponectin beneficial effects and ameliorate insulin resistance and diabetes.
authors.affiliation: Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lustig
authors.forename: Ehud
authors.initials: E
authors.lastname: Barhod
authors.forename: Reut
authors.initials: R
authors.lastname: Ashwal-Fluss
authors.forename: Reut
authors.initials: R
authors.lastname: Gordin
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.forename: Kfir
authors.initials: K
authors.lastname: Baruch-Umansky
authors.forename: Rina
authors.initials: R
authors.lastname: Hemi
authors.forename: Avraham
authors.initials: A
authors.lastname: Karasik
authors.forename: Hannah
authors.initials: H
authors.lastname: Kanety
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D054419:Receptors, Adiponectin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D052242:Adiponectin; C546122:MIRN221 microRNA, mouse; D035683:MicroRNAs; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; D038941:Polypyrimidine Tract-Binding Protein