title: Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism.
abstract: The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143-145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143-ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.
authors: Department of Mouse Genetics and Metabolism, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, University Hospital Cologne, Max Planck Institute for Neurological Research, Zülpicher Strasse 47, D-50674 Cologne, Germany.
authors: Sabine D
authors: SD
authors: Jordan
authors: Markus
authors: M
authors: Krüger
authors: Diana M
authors: DM
authors: Willmes
authors: Nora
authors: N
authors: Redemann
authors: F Thomas
authors: FT
authors: Wunderlich
authors: Hella S
authors: HS
authors: Brönneke
authors: Carsten
authors: C
authors: Merkwirth
authors: Hamid
authors: H
authors: Kashkar
authors: Vesa M
authors: VM
authors: Olkkonen
authors: Thomas
authors: T
authors: Böttger
authors: Thomas
authors: T
authors: Braun
authors: Jost
authors: J
authors: Seibler
authors: Jens C
authors: JC
authors: Brüning
mesh_terms: D000818:Animals; D004032:Diet; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose