Biphasic Response of Mitochondrial Biogenesis to Oxidative Stress in Visceral Fat of Diet-Induced Obesity Mice

Wang, Pei‐Wen; Kuo, Hsi-Kung; Huang, Hung‐Tsai; Chang, Alice Y.W.; Weng, Shao‐Wen; Tai, Ming‐Hong; Chuang, Jiin‐Haur; Chen, I-Ya; Huang, Shun‐Chen; Lin, Tsu-Kung; Liou, Chia‐Wei

doi:10.1089/ars.2013.5334

Cited by 30 publications

(29 citation statements)

References 67 publications

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“…21 Mitochondrial biogenesis is orchestrated by a transcriptional cascade involving peroxisome proliferatoractivated receptor g coactivators 1a (PGC-1a), PGC-1b, PGC-1-related coactivator (PRC), estrogen-related receptor a (ERRa), nuclear respiratory factors 1 (NRF1) and 2 (NRF2) and mitochondrial transcription factor A (Tfam). 22 Mitochondrial biogenesis was enhanced in WAT of the AdSod2 KO mice and was associated with increased transcription of PGC-1a, PGC-1b and nuclear and mitochondrial-encoded genes, implying a causal role for ROS in the induction of mitochondrial biogenesis.…”

Section: Adsod2 Ko Increases Energy Expenditure and Protects Against Diomentioning

confidence: 99%

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

2016

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Reactive oxygen species (ROS) production and oxidative stress (OS) in adipose tissue are associated with obesity and insulin resistance (IR). The nature of this relationship i.e., cause and effect or consequence has not been clearly determined. We provide evidence that elevated mitochondrial ROS generated by adipocytes from mice with diet-induced obesity (DIO) represents an adaptive mechanism that precipitates fatty acid oxidation, mitochondrial biogenesis, and mitochondrial uncoupling in an effort to defend against weight gain. Consistent with that, mice with adipocytespecific deletion of manganese superoxide dismutase (MnSOD) exhibit increased adipocyte superoxide generation and are protected from weight gain and insulin resistance which otherwise develops in wild-type (WT) mice that consume an obesogenic diet. The defense mechanism displayed by MnSOD-deficiency in fat cells appears to be mediated by a dual effect of ROS on inefficient substrate oxidation through uncoupling of oxidative phosphorylation and enhanced mitochondrial biogenesis. The aim of this commentary is to summarize and contextualize additional evidence supporting the importance of mitochondrial ROS in the regulation of mitochondrial biogenesis and the modulation of uncoupling protein 1 (UCP1) expression and activation in both white and brown adipocytes. Mitochondria are the major sites of substrate oxidation in mammalian cells and a major source of ROS.1-3 Mitochondria can generate superoxide and hydrogen peroxide (H 2 O 2 ) from at least 11 different oxidoreductases associated with substrate catabolism and the electron transport chain (ETC).4 ROS generation by mitochondria is a tightly controlled process i.e., low levels for cellular signaling are allowed whereas high levels that can damage the cellular milieu are mitigated by endogenous antioxidant enzymes. Importantly, there is substantial uncertainly regarding the different mechanisms controlling increased mitochondrial ROS generation in vivo, as well as the type of ROS species that are relevant for signaling in different aspects of physiology. Superoxide is the short-lived proximal ROS generated by mitochondrial oxidoreductases, and is rapidly converted to H 2 O 2 by manganese superoxide dismutase (MnSOD) in the mitochondrial matrix.5 Superoxide that is generated and released in the mitochondrial intermembrane space by complex III and the enzyme p66Shc is converted to H 2 O 2 by the Cu,ZnSOD enzyme.6-8 Matrix H 2 O 2 is degraded by a glutathione-dependent system catalyzed by glutathione peroxidases and the peroredoxin-thioredoxin system, 9 whereas cytosolic degradation of H 2 O 2 is mainly controlled by catalase, cytosolic peroxidases, and peroxiredoxins. 10Distinct from other antioxidant enzymes, MnSOD is important due to its localization in the mitochondrial matrix, and to its high affinity for superoxide in that compartment. 5 The physiologic relevance of MnSOD was demonstrated by the robust phenotype of mice lacking the in vitro Sod2 gene (encoding MnSOD). In this regard, Sod...

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Section: Adsod2 Ko Increases Energy Expenditure and Protects Against Diomentioning

confidence: 99%

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

2016

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“…Contrary to the limited data on humans, several animal studies using either genetic or dietary models of obesity have clearly showed a reduction in mitochondrial oxidative capacity in WAT (Wilson-Fritch et al 2003;Choo et al 2006); however, it remains unclear whether these changes are causal or secondary to the metabolic alterations associated with obesity, such as insulin resistance and diabetes. Indeed, studies performed on high-fat-fed animals revealed that mitochondrial dysfunction might result from altered systemic insulin sensitivity and glucose tolerance in mice (Sutherland et al 2008;Wang et al 2014). The mechanisms responsible for diminished mitochondrial oxidative capacity in WAT with obesity are not well characterized but may involve enhanced inflammation, higher oxidative damage, ER stress, reduced biogenesis and impaired mitochondrial dynamics (Valerio et al 2006).…”

Section: Mitochondrial Dysfunction In White Adipose Tissuementioning

confidence: 99%

“…The mechanisms responsible for diminished mitochondrial oxidative capacity in WAT with obesity are not well characterized but may involve enhanced inflammation, higher oxidative damage, ER stress, reduced biogenesis and impaired mitochondrial dynamics (Valerio et al 2006). Indeed, increased ROS generation in epididymal fat preceded mitochondrial impairments in high-fat-fed mice (Wang et al 2014).…”

Section: Mitochondrial Dysfunction In White Adipose Tissuementioning

confidence: 99%

“…; Wang et al . ). The mechanisms responsible for diminished mitochondrial oxidative capacity in WAT with obesity are not well characterized but may involve enhanced inflammation, higher oxidative damage, ER stress, reduced biogenesis and impaired mitochondrial dynamics (Valerio et al .…”

Section: Introductionmentioning

confidence: 97%

“…Indeed, increased ROS generation in epididymal fat preceded mitochondrial impairments in high‐fat‐fed mice (Wang et al . ).…”

Section: Introductionmentioning

confidence: 97%

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Mitochondrial function/dysfunction in white adipose tissue

Boudina

Graham

2014

Experimental Physiology

123

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New Findings r What is the topic of this review?The review covers basic knowledge about the role of mitochondria in the homeostatic function of adipose tissue. It also provide a comprehensive analysis of how mitochondrial function is affected during obesity and lipoatrophies and discuss the results of recent studies that targeted mitochondrial function specifically in adipose tissue or in fat cells and how these interventions affected whole body adiposity and peripheral insulin sensitivity. r What advances does it highlight?The review provides specific highlights of the major roles of mitochondria in key metabolic processes that occur in adipose tissue including its role in adipogenesis, adipokine secretion, lipogenesis, fatty acid esterification, branched-chain amino acid catabolism and lipolysis. Furthermore, we provide the reader with an update on the specific defects that affect mitochondrial function in adipose tissue during obesity and lipoatrophies. Finally, we discuss the latest mouse studies that specifically targeted mitochondrial function in adipose tissue to assess its contribution to the pathogenesis of obesity and insulin resistance.The role of mitochondria in white adipocytes has long been neglected due in part to their lower abundance in these cells. However, accumulating evidence suggests that mitochondria are vital for maintaining metabolic homeostasis in white adipocytes because of their involvement in adipogenesis, fatty acid synthesis and esterification, branched-chain amino acid catabolism and lipolysis. It is therefore not surprising that white adipose tissue function can be perturbed by altering mitochondrial components or oxidative capacity. Moreover, studies in humans and animals with significantly altered fat mass, such as in obesity or lipoatrophy, indicate that impaired mitochondrial function in adipocytes may be linked directly to the development of metabolic diseases such as diabetes and insulin resistance. However, recent studies that specifically targeted mitochondrial function in adipocytes indicated dissociation between impaired mitochondrial oxidative capacity and systemic insulin sensitivity.

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Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins

et al. 2016

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Biphasic Response of Mitochondrial Biogenesis to Oxidative Stress in Visceral Fat of Diet-Induced Obesity Mice

Cited by 30 publications

References 67 publications

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes

Mitochondrial function/dysfunction in white adipose tissue

Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins

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