Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans
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 H2O2-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 H2O2 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 H2O2 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.
The introduction is chock-full of background information (references) regarding the etiology of IR in skeletal muscle.
The accumulation of lipid in skeletal muscle has long been associated with the development of insulin resistance (1), a maladaptive response that is currently attributed to the generation and intracellular accumulation of proinflammatory lipid metabolites (e.g., fatty acyl-CoAs, diacylglycerols, and/or ceramides) and associated activation of stress-sensitive serine/threonine kinases that antagonize insulin signaling (2–4). Skeletal muscle of obese individuals is also characterized by profound reductions in mitochondrial function, as evidenced by decreased expression of metabolic genes (5, 6), reduced respiratory capacity (7–9), and mitochondria that are smaller and less abundant (9), leading to speculation that a decrease in the capacity to oxidize fat due to acquired or inherited mitochondrial insufficiency may be an underlying cause of the lipid accumulation and insulin resistance that develops in various metabolic states (10, 11).
H2O2 is hydrogen peroxide. Dip your finger into even the dilute OTC prep, and we see what it can do. Obviously we're not talking those concentrations in the cells or we'd all be dead. But H2O2 is chemically unstable (which is why it is sold in brown opaque bottles with directions to store in a cool place). H202 is a reactive species (RS) that can cause damage.
Here is a link to but one summary article on H2O2, and another on RS and antioxidants in general.
Back to the article and some more background:
In addition to providing energy for the cell, mitochondria are now recognized as an important site for the generation, dispensation, and removal of a number of intracellular signaling effectors, including hydrogen peroxide (H2O2), calcium, and nitric oxide. In fact, the emission rate of H2O2 from mitochondria, which reflects the balance between the rate of electron leak/superoxide formation from the respiratory system and scavenging of H2O2 in the matrix, varies over a remarkably consistent range across diverse forms of aerobic life (20). Once in the cytosol, H2O2 can alter the redox state of the cell by either reacting directly with thiol residues within redox-sensitive proteins or shifting the ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), the main redox buffer of the cell. Thus, the rate at which H2O2 is emitted from mitochondria is considered an important barometer of mitochondrial function and modulator of the overall cellular redox environment (21).
End of chemistry lesson ...
What this article is saying is that H2O2 is one such RS/ROS produced in the mitochondria (under perfectly normal conditions), but that in balance we produce natural antioxidants (glutathione, etc.) that serve to "remove" these ROS before they can damage critical molecules.
Here's where obesity and high fat diet figure in. (Summarized from: Obesity/diet alter mitochondrial H2O2 emission in humans.) The comparison was between lean insulin sensitive (I'll call these LIS) males and obese insulin resistant males (OIR) in skeletal muscle.
- H2O2 emission was 4X greater in OIR vs. LIS at basal ("fat burning") rates
- H2O2 emission was 2X greater in OIR vs. LIS in response to stimulation
- The difference in H2O2 emission did not correlate with O2 utilization which was not different between the two groups.
- Maximum stimulated O2 consumption was ~35% less in OIR vs. LIS indicating reduced respiratory capacity in the obese.
Figure 5 from the article: Caption: H2O2 emission elevated in obese men and lean men following a high fat meal.
Part II to follow as a separate post.
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