Decrement in resting and insulin‐stimulated soleus muscle mitochondrial respiration is an early event in diet‐induced obesity in mice

New Findings

What is the central question of this study? What are the temporal responses on mitochondrial respiration, and insulin mitochondrial responsivity in soleus muscle‐fibres from mice during the development of obesity and insulin resistance? What are the main finding and its importance? Short‐ and long‐term exposition of high‐fat diet (HFD) markedly reduced soleus mitochondrial respiration and mitochondrial insulin responsivity prior any change in glycogen synthesis. Muscle glycogen synthesis and whole‐body insulin resistance were present after 14 and 28 days, respectively. Our findings highlight the plasticity of mitochondria during the development of obesity and insulin resistance.

Abstract

Recently, significant attention has been given to the role of muscle mitochondrial function in the development of insulin resistance associated with obesity. Our aim was to investigate temporal alterations in mitochondrial respiration, H₂O₂ emission, and mitochondrial responsivity to insulin in permeabilized skeletal muscle‐fibres during the development of obesity in mice. Swiss male mice (5‐6 weeks old) were fed with a high‐fat diet (60% calories from fat) or standard diet for 7, 14 and 28 days to induce obesity and insulin resistance. Diet‐induced obese (DIO) mice presented reduced glucose tolerance and hyperinsulinemia after 7 days of HFD. After 14 days, the expected increase in muscle glycogen content after systemic injection of glucose and insulin was not observed in DIO mice. At 28 days, blood glucose decay after insulin injection was significantly impaired. Complex I (pyruvate + malate) and II (succinate) linked respiration, and oxidative phosphorylation (ADP) were decreased after 7 days of HFD and remained low in DIO mice after 14 and 28 days of treatment. Moreover, mitochondria from DIO mice were incapable of increasing respiratory coupling and ADP responsivity after insulin‐stimulation in all observed periods. Mitochondrial content markers were reduced only after 28 days of treatment. Mitochondrial H₂O₂ emission profile varied during the time course of DIO, with a reduction of H₂O₂ emission in the early stages of DIO and an increased emission after 28 days of treatment. Our data demonstrate that DIO promotes transitory alterations in mitochondrial physiology during the early and late stages of insulin‐resistance related to obesity.

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