TY  - JOUR
A1  - Jordan, Sabine D.
A1  - Krüger, Markus
A1  - Willmes, Diana M.
A1  - Redemann, Nora
A1  - Wunderlich, F. Thomas
A1  - Brönneke, Hella S.
A1  - Merkwirth, Carsten
A1  - Kashkar, Hamid
A1  - Olkkonen, Vesa M.
A1  - Böttger, Thomas
A1  - Braun, Thomas
A1  - Seibler, Jost
A1  - Brüning, Jens C.
T1  - Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism
JF  - Nature Cell Biology
N2  - 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.
Y1  - 2011
U6  - https://doi.org/10.1038/ncb2211
SN  - 1465-7392
VL  - 13
IS  - 4
SP  - 434
EP  - 446
PB  - Nature
CY  - New York
ER  - 
TY  - JOUR
A1  - Inagaki, Akiko
A1  - Sleddens-Linkels, Esther
A1  - Wassenaar, Evelyne
A1  - Ooms, Marja
A1  - Cappellen, Wiggert A. van
A1  - Hoeijmakers, Jan H. J.
A1  - Seibler, Jost
A1  - Vogt, Thomas F.
A1  - Shin, Myung K.
A1  - Grootegoed, J. Anton
A1  - Baarends, Willy M.
T1  - Meiotic functions of RAD18
JF  - Journal of Cell Science
Y1  - 2011
U6  - https://doi.org/10.1242/jcs.081968
SN  - 1477-9137
VL  - 124
IS  - 16
SP  - 2837
EP  - 2850
PB  - Company of Biologists Limited
CY  - Cambridge
ER  -