Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism

• Published in: Nature cell biology Vol. 13; no. 4; pp. 434 - 446
• Main Authors: Wunderlich, F. Thomas, Brönneke, Hella S, Brüning, Jens C, Böttger, Thomas, Seibler, Jost, Braun, Thomas, Krüger, Markus, Kashkar, Hamid, Olkkonen, Vesa M, Jordan, Sabine D, Willmes, Diana M, Merkwirth, Carsten, Redemann, Nora
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2011; Nature Publishing Group
• Subjects: 692/420/2489/144; 692/699/2743/137/773; 692/699/2743/393; Animals; Biomedical and Life Sciences; Body fat; Cancer Research; Care and treatment; Cell Biology; Developmental Biology; Diet; Enzyme Activation; Glucose - metabolism; Health aspects; Insulin; Insulin - metabolism; Insulin Resistance; Life Sciences; Liver; Liver - enzymology; Mice; Mice, Obese; Mice, Transgenic; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Physiological aspects; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Spectrometry; Stem Cells; Type 2 diabetes; Germany
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2211

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. Upregulation of microRNA-143 occurs in livers of obese mice. Transgenic overexpression of miR-143 in mice leads to insulin resistance through downregulation of the oxysterol-binding protein-related protein ORP8, impairing Akt activation in response to insulin.