The consumption of a high fat diet, which contains mainly saturated long chain fatty acids, induces obesity and insulin resistance in the brain. Insulin resistance in the hypothalamus alters mitochondrial stress responses, specifically the integrated stress response and mitochondrial unfolded protein response (mtUPR) and causes mitochondrial dysfunction and excessive autophagy. Interestingly, reduced expression of genes of the mtUPR is sufficient to induce insulin resistance, highlighting the close interplay of insulin signaling and mitochondrial function in the hypothalamus. Metabolic consequences of brain insulin resistance are hyperphagia and obesity, establishing a vicious cycle for weight gain. Insulin action in the brain does not only impact metabolism but also alters cognition and behavior. Mice with a neuronal insulin receptor knockout (NIRKO) exhibit pronounced anxiety and depressive-like behavior while aging, emotional behaviors which also exist in type 2 diabetic patients. The depressive‑like behavior is due to impaired dopaminergic signaling, as insulin receptor deficiency causes elevated monoamine oxidase expression in the mesolimbic system and reduces dopamine half‑life. This behavioral phenotype is also true for mice with a specific knockout of insulin receptor in glia cells, highlighting the importance of proper brain insulin action for mood and emotionality. Overall these data demonstrate the crucial role of brain insulin signaling for mitochondrial function, metabolism, and behavior.
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