Ruegsegger 2019 JCI Insight

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Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, Lucchinetti CF, Nair KS (2019) Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI Insight 4:130681.

» PMID: 31534057 Open Access

Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, Lucchinetti CF, Nair KS (2019) JCI Insight

Abstract: 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.

Keywords: Diabetes, Endocrinology, Metabolism Bioblast editor: Plangger M O2k-Network Lab: US MN Rochester Nair KS


Labels: MiParea: Respiration, Exercise physiology;nutrition;life style  Pathology: Diabetes 

Organism: Mouse  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 


Coupling state: LEAK, OXPHOS, ET  Pathway: ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

Labels, 2019-10, Amplex UltraRed