Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans

Abstract

High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…Overactivation of stress pathways such as oxidative and endoplasmic reticulum stress have been linked with insulin resistance [36][37][38], though there is also evidence that reactive oxygen species production and the unfolded protein response can positively influence insulin action [39,40]. Obese, insulin-resistant individuals also exhibit a state of chronic low-grade inflammation, and as such activation of inflammatory pathways have also been proposed as a major driver of insulin resistance [1,2].…”

Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes

“…In cultured cells there is experimental evidence that ROS have an inhibitory effect on insulin signalling [16,17]. Human studies have shown that obesity and high-fat diet increase mitochondrial hydrogen peroxide release [18]. Furthermore, a recent study showed that mitochondrial ROS release was higher in muscle of patients with type 2 diabetes than in obese controls, but similar to that observed in lean control participants [19].…”

Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial

“…H 2 O 2 production An aliquot of 0.1 mg isolated mitochondria was used to measure rates of H 2 O 2 production fluorimetrically by the Amplex Red method as described elsewhere [23]. Briefly, the emitted H 2 O 2 was selectively trapped by horseradish peroxidase, which uses Amplex Red as an electron donor during the reduction of H 2 O 2 to H 2 O.…”