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  - http://dx.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  - Koch, Linda
A1  - Wunderlich, F. Thomas
A1  - Seibler, Jost
A1  - Könner, A. Christine
A1  - Hampel, Brigitte
A1  - Irlenbusch, Sigrid
A1  - Brabant, Georg
A1  - Kahn, C. Ronald
A1  - Schwenk, Frieder
A1  - Brüning, Jens C.
T1  - Central insulin action regulates peripheral glucose and fat metabolism in mice
JF  - The Journal of Clinical Investigation (JCI)
Y1  - 2008
U6  - http://dx.doi.org/10.1172/JCI31073
SN  - 1558-8238
VL  - 118
IS  - 6
SP  - 2132
EP  - 2147
ER  -