Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes.
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.
Pospisilik
J Andrew
JA
Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr Bohrgasse 3, 1030, Vienna, Austria.
Knauf
Claude
C
Joza
Nicholas
N
Benit
Paule
P
Orthofer
Michael
M
Cani
Patrice D
PD
Ebersberger
Ingo
I
Nakashima
Tomoki
T
Sarao
Renu
R
Neely
Gregory
G
Esterbauer
Harald
H
Kozlov
Andrey
A
Kahn
C Ronald
CR
Kroemer
Guido
G
Rustin
Pierre
P
Burcelin
Remy
R
Penninger
Josef M
JM
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000172:deficiency* / Q000235:genetics; D019069:Cell Respiration / Q000187:drug effects; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004032:Diet / Q000009:adverse effects; D017353:Gene Deletion; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009030:Mosaicism / Q000187:drug effects; D009132:Muscles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009928:Organ Specificity / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010641:Phenotype; D013379:Substrate Specificity / Q000187:drug effects
D051033:Apoptosis Inducing Factor; D007328:Insulin; D005947:Glucose