TY - JOUR
T1 - Targeted Deletion of AIF Decreases Mitochondrial Oxidative Phosphorylation and Protects from Obesity and Diabetes
AU - Pospisilik, J. Andrew
AU - Knauf, Claude
AU - Joza, Nicholas
AU - Benit, Paule
AU - Orthofer, Michael
AU - Cani, Patrice D.
AU - Ebersberger, Ingo
AU - Nakashima, Tomoki
AU - Sarao, Renu
AU - Neely, Gregory
AU - Esterbauer, Harald
AU - Kozlov, Andrey
AU - Kahn, C. Ronald
AU - Kroemer, Guido
AU - Rustin, Pierre
AU - Burcelin, Remy
AU - Penninger, Josef M.
N1 - Funding Information:
The authors would like to thank J.A. Ehses, M. Roden, G. Obernosterer, and S. O'Rahilly for critical discussion. Also we are endebted to G. Resch, M. Brandstetter, M. Rangachari, P. Steinlein, V. Komenovic, M. Radolf, L. Montbrun, L. Klein, T. Behling, S. Haindl, L. Pénicaud, and the Toulouse Genopole for technical help. J.A.P., G.N., and T.N. are funded by IIF fellowships of the Marie Curie Foundation, P.D.C. from the FNRS, Belgium. C.R.K. is supported by NIH grant DK31036. J.M.P. is supported by IMBA, the Austrian Ministry of Science and Education, and the Austrian National Bank. R.B. is the recipient of grants for the ATIP-CNRS program as well as the “Programme national de recherche en alimentation et nutrition humaine 2005 nos. 5–13.” I.E. greatly appreciates financial support by the Wiener Wissenschafts-, Forschungs- und Technologiefonds (WWTF). P.B. and P.R. were supported by the Integrated European Project Eumitocombat and the Association Française contre les Myopathies.
PY - 2007/11/2
Y1 - 2007/11/2
N2 - Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle- and liver-specific AIF ablation in mice initiates a pattern of OxPhos deficiency closely mimicking that of human insulin resistance, and contrary to current expectations, results in increased glucose tolerance, reduced fat mass, and increased insulin sensitivity. These results are maintained upon high-fat feeding and in both genetic mosaic and ubiquitous OxPhos-deficient mutants. Importantly, the effects of AIF on glucose metabolism are acutely inducible and reversible. These findings establish that tissue-specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity.
AB - Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle- and liver-specific AIF ablation in mice initiates a pattern of OxPhos deficiency closely mimicking that of human insulin resistance, and contrary to current expectations, results in increased glucose tolerance, reduced fat mass, and increased insulin sensitivity. These results are maintained upon high-fat feeding and in both genetic mosaic and ubiquitous OxPhos-deficient mutants. Importantly, the effects of AIF on glucose metabolism are acutely inducible and reversible. These findings establish that tissue-specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity.
KW - CELLBIO
KW - HUMDISEASE
UR - http://www.scopus.com/inward/record.url?scp=35548999739&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2007.08.047
DO - 10.1016/j.cell.2007.08.047
M3 - Article
C2 - 17981116
AN - SCOPUS:35548999739
SN - 0092-8674
VL - 131
SP - 476
EP - 491
JO - Cell
JF - Cell
IS - 3
ER -