OP-24 - Novel Dysregulation of Mitochondria Impacts Brain Insulin Signaling

Abstract

Obesity-related disorders, such as type 2 diabetes, are characterized by insulin resistance not only in peripheral organs but also in the brain. Dysregulation of brain insulin signaling causes obesity and neurological alterations, such as depressive-like behavior. Causal factors of neuronal insulin resistance are multifactorial including exposure to elevated glucose and fatty acid levels, activation of cellular stress responses as well as neuroinflammation. While the effect of the endoplasmatic unfolded protein response (ER stress response) on insulin signaling has been described in detail, the effect of mitochondrial stress is less well understood. We observed that type 2 diabetic mice exhibit hypothalamic insulin resistance and mitochondrial dysfunction due to decreased expression of mitochondrial proteins involved in the mitochondrial unfolded protein response. Reduction of mitochondrial chaperones in neurons is sufficient to cause severe mitochondrial dysfunction with aberrant mitochondrial protein homeostasis leading to oxidative stress and insulin resistance. We further observe that mitochondrial dysfunction is both a causal factor of brain insulin resistance and a consequence of altered brain insulin signaling causing neurological abnormalities.