Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice

Recent studies showed a link between a high fat diet (HFD)-induced obesity and lipid accumulation in non-adipose tissues, such as skeletal muscle and liver, and insulin resistance (IR). Although the mechanisms responsible for IR in those tissues are different, oxidative stress and mitochondrial dysf...

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Bibliographic Details
Published in:PloS one 2013-01, Vol.8 (1), p.e54059-e54059
Main Authors: Yuzefovych, Larysa V, Musiyenko, Sergiy I, Wilson, Glenn L, Rachek, Lyudmila I
Format: Article
Language:English
Subjects:
Adipose tissue
AKT protein
Analysis
Animal tissues
Animals
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Bioaccumulation
Biodegradation
Biology
Damage
Degradation
Deoxyribonucleic acid
Diet
Diet, High-Fat - adverse effects
DNA
DNA damage
DNA repair
DNA, Mitochondrial - genetics
Endoplasmic reticulum
Endoplasmic Reticulum Stress - drug effects
Endoplasmic Reticulum Stress - genetics
Gene expression
Glucose
High fat diet
Insulin
Insulin receptor substrate 1
Insulin resistance
Insulin Resistance - genetics
Insulin Resistance - physiology
Kinases
Liver
Male
Markers
Medicine
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondrial DNA
Muscles
Nuclei
Obesity
Oxidative stress
Oxidative Stress - drug effects
Oxidative Stress - genetics
Proteins
Proteolysis
Rodents
Signaling
Skeletal muscle
Type 2 diabetes
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Summary:Recent studies showed a link between a high fat diet (HFD)-induced obesity and lipid accumulation in non-adipose tissues, such as skeletal muscle and liver, and insulin resistance (IR). Although the mechanisms responsible for IR in those tissues are different, oxidative stress and mitochondrial dysfunction have been implicated in the disease process. We tested the hypothesis that HFD induced mitochondrial DNA (mtDNA) damage and that this damage is associated with mitochondrial dysfunction, oxidative stress, and induction of markers of endoplasmic reticulum (ER) stress, protein degradation and apoptosis in skeletal muscle and liver in a mouse model of obesity-induced IR. C57BL/6J male mice were fed either a HFD (60% fat) or normal chow (NC) (10% fat) for 16 weeks. We found that HFD-induced IR correlated with increased mtDNA damage, mitochondrial dysfunction and markers of oxidative stress in skeletal muscle and liver. Also, a HFD causes a change in the expression level of DNA repair enzymes in both nuclei and mitochondria in skeletal muscle and liver. Furthermore, a HFD leads to activation of ER stress, protein degradation and apoptosis in skeletal muscle and liver, and significantly reduced the content of two major proteins involved in insulin signaling, Akt and IRS-1 in skeletal muscle, and Akt in liver. Basal p-Akt level was not significantly influenced by HFD feeding in skeletal muscle and liver. This study provides new evidence that HFD-induced mtDNA damage correlates with mitochondrial dysfunction and increased oxidative stress in skeletal muscle and liver, which is associated with the induction of markers of ER stress, protein degradation and apoptosis.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0054059