Mitochondrial dysfunction is associated with type 2 diabetes, aging and neurodegenerative diseases, showing the importance of proper mitochondrial function for whole body physiology, especially the brain. Notably, these pathologies are also linked with brain insulin and leptin resistance. Thus, improving mitochondrial function in the brain reduces insulin and leptin resistance in diabetic mouse models, to give one example. Conversely, treating animals with insulin sensitizers can reverse insulin resistance and ameliorate mitochondrial dysfunction in the brain, indicating the interplay of insulin signaling and mitochondrial function in the brain. The detailed molecular mechanisms of this interplay and how insulin and leptin resistance precisely affects this organelle are not completely understood. Mitochondrial dysfunction can occur in various forms, e.g. dysregulated mitochondrial dynamics, alterations in the membrane structure, altered calcium homeostasis, and perturbations in the electron transport chain. Common to these alterations is often an association with increased production of reactive oxygen species (ROS), which activates serine/threonine kinases and induces inhibitory phosphorylation of insulin signaling molecules. A by-product of mitochondrial dysfunction is the production of ROS, which is increased in metabolic disorders. Although oxidative stress is believed to be a causal factor for insulin resistance, as antioxidants can attenuate insulin resistance in vitro, they failed to reverse insulin resistance in clinics. One explanation for this is the fact that oxidative stress is just one aspect of mitochondrial dysfunction. Mitochondria are not only producers of ROS, but they are also crucial for other metabolic pathways, e.g. fatty acid metabolism and BCAA catabolism.

This Research Topic therefore welcomes contributions on:

• Mitochondrial dysfunction in metabolic and insulin-resistant associated neurodegenerative diseases
• Oxidative stress-induced inflammation and leptin resistance
• The effects of ROS on brain metabolism and behavior

Keywords: CNS, insulin/leptin, mitochondria, inflammation, diabetes

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