Glutathione Depletion Prevents Diet-Induced Obesity and Enhances Insulin Sensitivity

stag

Abundant evidence has demonstrated the accumulation of oxidative stress during obesity and suggests a causal participation of pathological ROS concentrations in the development of insulin resistance (1,2). For instance, nutrient excess increases mitochondrial production of H2O2, which attenuates insulin signaling (3). Conversely, antioxidant treatment or over-expression of antioxidant enzymes can prevent diet-induced insulin resistance in mice (11). However, despite these apparent deleterious effects of pathological ROS concentrations on insulin sensitivity, it is well established that physiological levels of ROS enhance cellular signaling (4). Particularly H2O2 has been implicated in the activation of protein phosphorylation-dependent pathways, including insulin signaling and can exert insulin-mimicking effects through the inactivation of oxidation-sensitive protein tyrosine phosphatases (3). In mammalian cells, the primary antioxidant system to scavenge H2O2 is the glutathione system, which converts H2O2 to water through the activity of GPx using reduced glutathione as an electron donor (6). Using a pharmacological approach, our findings demonstrate that glutathione depletion enhances insulin sensitivity and, interestingly, prevents diet-induced obesity by increasing energy expenditure and locomotor activity. These observations complement prior studies using genetic modulation of glutathione peroxidase in mice. GPx1-deficient mice are protected from high-fat diet-induced insulin resistance (6) while mice overexpressing GPx1 are insulin resistant due to altered insulin signaling (12). Moreover, increased ROS levels in GPx1-deficient mice protected against diet-induced obesity and increased energy expenditure (6), which is consistent with our data obtained through pharmacological glutathione depletion. Although the molecular mechanisms underlying increased energy expenditure in glutathione-depleted mice remain unknown, is it possible that the observed increase in the expression of UCP-2 and UCP-3 in BSO-treated mice induced mitochondrial uncoupling, which has previously been described in response to increased levels of ROS (13). Alternatively, the enhanced energy expenditure in BSO-treated mice might be the result of increased locomotor activity. In skeletal muscle, ROS are necessary for optimal contractile function, force production, and exercise-induced adaptations (14). Furthermore, particularly H2O2 is increasingly recognized as a potent neuromodulator (15). It is therefore conceivable, that glutathione depletion may lead to activity-stimulating changes in the redox environment of muscle or brain.

Mauritio

@stag said in Glutathione Depletion Prevents Diet-Induced Obesity and Enhances Insulin Sensitivity:

increase in the expression of UCP-2 and UCP-3 in BSO-treated mice induced mitochondrial uncoupling, w

So is it this compensatory increase in UCPs that's the cause of the benefits ?

LucH

See the reference 3
Glutathione Depletion Prevents Diet-Induced Obesity and Enhances Insulin Sensitivity
Hannes M. Findeisen et al. 2012 https://doi.org/10.1038/oby.2011.298
Abstract
Excessive accumulation of reactive oxygen species (ROS) in adipose tissue has been implicated in the development of insulin resistance and type 2 diabetes. However, emerging evidence suggests a physiologic role of ROS in cellular signaling and insulin sensitivity.
In this study, we demonstrate that pharmacologic depletion of the antioxidant glutathione in mice prevents diet-induced obesity, increases energy expenditure and locomotor activity, and enhances insulin sensitivity. These observations support a beneficial role of ROS in glucose homeostasis and warrant further research to define the regulation of metabolism and energy balance by ROS.
Excerpt
(…) Since glutathione peroxidase (GPx) constitutes the principal antioxidant defense system to scavenge physiological concentrations of H2O2 in mammals (6), we investigated in this study the role of pharmacological glutathione depletion on diet-induced obesity and insulin sensitivity. Surprisingly, depletion of endogenous glutathione protected mice from obesity, preserved insulin sensitivity, and increased energy expenditure, pointing to a more complex role of endogenous ROS in diabetes and energy balance than previously anticipated.

=> There is a contradiction and a bias in the title as well in the abstract.
To be reminded: too much of a good thing is bad. No need for more than 2x/wk 100 mcg. Diet with meat and eggs brings +/ 50 % of the RDA.
Supplement is only bioavailable at +/ 60%.
More info (In French, translator needed)
https://mirzoune-ciboulette.forumactif.org/t1953-selenium-too-much-of-a-good-thing-is-bad#27971
=> Selenium forms, bioavailability, enzymatic functions, synergy with other antioxidants,
Sources and References.