Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain
| Autor: | Surendra Dasari, K. Sreekumaran Nair, Patrick M. Vanderboom, Claudia F. Lucchinetti, Christina B. McCarthy, Gregory N. Ruegsegger, Katherine A. Klaus, Parijat Kabiraj |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.medical_treatment Primary Cell Culture Administration Oral Mitochondrion Diet High-Fat Mitochondrial Dynamics 03 medical and health sciences Mice 0302 clinical medicine Insulin resistance Diabetes mellitus Internal medicine Physical Conditioning Animal medicine Animals Humans Insulin Cognitive decline Administration Intranasal Cells Cultured Cerebral Cortex Neurons biology Chemistry Skeletal muscle General Medicine medicine.disease Metformin Receptor Insulin Mitochondria Insulin receptor Disease Models Animal Oxidative Stress 030104 developmental biology Endocrinology medicine.anatomical_structure Glucose 030220 oncology & carcinogenesis Astrocytes biology.protein Mitochondrial fission Insulin Resistance Sedentary Behavior Peptides Research Article |
| Popis: | Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondrial function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states. |
| Databáze: | OpenAIRE |
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