Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes

Area of Science:

• Biochemistry
• Metabolic diseases
• Mitochondrial biology

Background:

• Type-2 diabetes is characterized by insulin resistance and impaired insulin secretion.
• Altered mitochondrial oxidative phosphorylation (OxPhos) is implicated in insulin resistance, but its role is debated.
• The causative or compensatory nature of OxPhos alterations in insulin resistance remains unproven.

Purpose of the Study:

• To investigate the role of mitochondrial OxPhos defects in the development of insulin resistance and type-2 diabetes.
• To determine whether OxPhos deficiency is a cause or a consequence of insulin resistance.
• To explore the therapeutic potential of modulating OxPhos in metabolic diseases.

Main Methods:

• Muscle- and liver-specific ablation of the apoptosis-inducing factor (AIF) in mice to create OxPhos deficiency.
• Assessment of glucose tolerance, insulin sensitivity, and body composition.
• Analysis of genetic mosaic and ubiquitous OxPhos-deficient mouse models.
• Inducible and reversible modulation of AIF function.

Main Results:

• AIF ablation induced OxPhos deficiency mimicking human insulin resistance patterns.
• Mice with OxPhos deficiency exhibited improved glucose tolerance, reduced fat mass, and increased insulin sensitivity.
• These beneficial effects were observed in various genetic models and persisted under high-fat diet conditions.
• The metabolic benefits of AIF modulation were acutely inducible and reversible.

Conclusions:

• Tissue-specific and global OxPhos defects in mice can counteract insulin resistance, type-2 diabetes, and obesity.
• OxPhos deficiency, rather than being a cause, may be a compensatory mechanism against metabolic dysfunction.
• Targeting mitochondrial OxPhos presents a potential therapeutic strategy for metabolic diseases.