Treatment with a SOD mimetic reduces visceral adiposity, adipocyte death, and adipose tissue inflammation in high fat‐fed mice

Pires, Karla Maria Pereira; Ilkun, Olesya; Valente, M; Boudina, Sihem

doi:10.1002/oby.20465

Cited by 34 publications

(38 citation statements)

References 37 publications

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“…Moreover, we showed that insulin signalling within WAT was preserved with 1 week of HFD in MCAT mice while lipid-supported mitochondrial ROS emissions, lipid peroxidation and inflammatory signalling were normalised, suggesting excess ROS is the principal mechanism in adipose tissue dysfunction. These findings are in agreement with those of Pires et al who demonstrated that ROS sequestering through the administration of a SOD mimetic reduced WAT inflammation with 5 weeks of HFD [36]. Therefore, mitochondrial ROS emissions are a potential early causal factor in diet-induced insulin resistance in WAT.…”

Section: Discussionsupporting

confidence: 92%

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

et al. 2015

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Aims/hypothesis Consuming a high-fat diet (HFD) induces insulin resistance in white adipose tissue (WAT) within 1 week. However, little is known about the initiating events. One potential mechanism that has remained largely unexplored is excessive mitochondrial emission of reactive oxygen species (ROS). Methods To determine the role of mitochondrial ROS emissions at the onset of insulin resistance, wild-type (WT) mice were placed on an HFD for 1 week. WAT insulin sensitivity and inflammation were assessed by western blot. In addition, we optimised/validated a method to determine ROS emissions in permeabilised WAT. Results An HFD for 1 week resulted in impaired insulin signalling, increased c-Jun NH 2 -terminal kinase (JNK) phosphorylation and an increase in oxidative stress. These changes were associated with an increase in fatty-acid-mediated mitochondrial ROS emissions without any change in mitochondrial respiration/content. To determine that mitochondrial ROS causes insulin resistance, we used transgenic mice that express human catalase in mitochondria (MCAT) as a model of upregulated mitochondrial antioxidant enzyme capacity. MCAT mice displayed attenuated mitochondrial ROS emission, preserved insulin signalling and no inflammatory response following an HFD. Conclusions/interpretation Findings from this study suggest that elevated mitochondrial ROS emission contributes to HFD-induced WAT insulin resistance.

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Section: Discussionsupporting

confidence: 92%

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

et al. 2015

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“…We also found no effect of MnTBAP on body mass and glucose tolerance in obese and diabetic 9–10 week-old db/db mice after 3–4 weeks of MnTBAP treatment suggesting that the partial restoration of glucose tolerance in ob/ob mice reported by Houstis et al could be due to the much longer duration of MnTBAP treatment in those studies [10]. Although mitochondrial function in skeletal muscle might have been improved by short-term MnTBAP treatment, as we have previously reported in animal models of diet-induced obesity, it is not sufficient to improve systemic glucose homeostasis [34, 35]. Thus, given the higher energetic demand of cardiac mitochondria and potentially greater degrees of oxidative stress, the beneficial impact of MnTBAP on cardiac insulin signaling and glucose transport might be more readily discerned.…”

Section: Discussionmentioning

confidence: 93%

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Ilkun

Wilde

Tuinei

et al. 2015

Journal of Molecular and Cellular Cardiology

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Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.

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“…We and others have shown that SOD1 has a critical role in regulating lipid homeostasis [11, 31]. For example, we previously reported that delivering SOD1 as Nano reduced plasma and liver triglycerides [11].…”

Section: Discussionmentioning

confidence: 99%

Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling

Gopalakrishnan

Perriotte-Olson

Bhinderwala

et al. 2017

Translational Research

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Evidence suggests that superoxide dismutase 1 (SOD1) promotes glucose versus lipid metabolism depending on the diet type. We recently reported that nanoformulated SOD1 (Nano) improved lipid metabolism without altering glucose homeostasis in high fat (HF) diet-fed mice. Here, we sought to determine the effects and potential mechanisms of Nano in modulating glucose and lipid homeostasis in mice fed a normal chow diet (CD) versus HF diet. Mice were fed a CD or a HF diet (45%) for 10 wk and injected with Nano once every two days for fifteen days. The fasting glucose level was lower (P<0.05) in CD+Nano-treated mice compared to control. Conversely, blood glucose was not altered but serum triglycerides were lower in HF+Nano-treated mice. Genes involved in fatty acid synthesis were reduced by Nano in the skeletal muscle of CD but not of HF diet-fed mice. AMPK, which promotes both glucose and lipid metabolism depending on the fuel availability, is activated by Nano in CD-fed mice. Moreover, Nano increased phosphorylation of ACC, a downstream target of AMPK, in both CD and HF diet-fed mice. Nano increased mitochondrial respiration in C2C12 myocytes in the presence of glucose or fatty acid and this effect is inhibited by Compound C, an AMPK inhibitor. Our data suggest that Nano promotes glucose and lipid metabolism in CD and HF diet-fed mice, respectively, and this effect is mediated partly via AMPK signaling.

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Treatment with a SOD mimetic reduces visceral adiposity, adipocyte death, and adipose tissue inflammation in high fat‐fed mice

Cited by 34 publications

References 37 publications

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling

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