title: Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes.
abstract: 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.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr Bohrgasse 3, 1030, Vienna, Austria.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
authors.forename: Nicholas
authors.initials: N
authors.lastname: Joza
authors.forename: Paule
authors.initials: P
authors.lastname: Benit
authors.forename: Michael
authors.initials: M
authors.lastname: Orthofer
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Ingo
authors.initials: I
authors.lastname: Ebersberger
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.forename: Renu
authors.initials: R
authors.lastname: Sarao
authors.forename: Gregory
authors.initials: G
authors.lastname: Neely
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Andrey
authors.initials: A
authors.lastname: Kozlov
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Remy
authors.initials: R
authors.lastname: Burcelin
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: 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
chemical_list: D051033:Apoptosis Inducing Factor; D007328:Insulin; D005947:Glucose