Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Ro, Seung Hyun; Nam, Myeong Jin; Jang, Insook; Park, Hwan‐Woo; Park, Haeli; Semple, Ian A.; Kim, Myung-Jin; Kim, Jeong Sig; Park, Haewon; Einat, Paz; Damari, Golda; Golikov, Maya; Feinstein, Elena; Lee, Jun Hee

doi:10.1073/pnas.1401787111

Cited by 82 publications

(87 citation statements)

References 48 publications

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“…Tissues for assessing mitochondrial DNA (mtDNA) content were prepared as described previously (10,41). Briefly, total DNA was isolated by proteinase K digestion followed by phenol/chloroform extraction and ethanol precipitation.…”

Section: Methodsmentioning

confidence: 99%

Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice

Labbé

Caron

Chechi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g., inguinal WAT (iWAT)] following adrenergic stimulation, and they have been referred to as “beige” adipocytes. Whether the presence of these adipocytes, which gives iWAT a beige appearance, can confer a white depot with some thermogenic activity remains to be seen. In consequence, we designed the present study to investigate the metabolic activity of iBAT, iWAT, and epididymal white depots in mice. Mice were either 1) kept at thermoneutrality (30°C), 2) kept at 30°C and treated daily for 14 days with an adrenergic agonist [CL-316,243 (CL)], or 3) housed at 10°C for 14 days. Metabolic activity was assessed using positron emission tomography imaging with fluoro-[18F]deoxyglucose (glucose uptake), fluoro-[18F]thiaheptadecanoic acid (fatty acid uptake), and [11C]acetate (oxidative activity). In each group, substrate uptakes and oxidative activity were measured in anesthetized mice in response to acute CL. Our results revealed iBAT as a major site of metabolic activity, which exhibited enhanced glucose and nonesterified fatty acid uptakes and oxidative activity in response to chronic cold and CL. On the other hand, beige adipose tissue failed to exhibit appreciable increase in oxidative activity in response to chronic cold and CL. Altogether, our results suggest that the contribution of beige fat to acute-CL-induced metabolic activity is low compared with that of iBAT, even after sustained adrenergic stimulation.

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Section: Methodsmentioning

confidence: 99%

Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice

Labbé

Caron

Chechi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Mice deficient in glutathione due to ablation of the glutamate-cysteine ligase modifier subunit exhibit highly oxidized cellular thiol pools systemically, chronically elevated energy expenditure, and resistance to obesity (37). Also, modulation of the thiol antioxidant function of Sestrin2 is sufficient for controlling UCP1 expression in iWAT and BAT, activation of leak respiration, and thermogenic function in vivo (38).…”

Section: Modification Of Thiol Redox Statusmentioning

confidence: 99%

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Chouchani

Kazak

Spiegelman

2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeBrown and beige adipose tissues can catabolize stored energy to generate heat, relying on the principal effector of thermogenesis: uncoupling protein 1 (UCP1). This unique capability could be leveraged as a therapy for metabolic disease. Numerous animal and cellular models have now demonstrated that mitochondrial reactive oxygen species (ROS) signal to support adipocyte thermogenic identity and function. Herein, we contextualize these findings within the established principles of redox signaling and mechanistic studies of UCP1 function. We provide a framework for understanding the role of mitochondrial ROS signaling in thermogenesis together with testable hypotheses for understanding mechanisms and developing therapies. Brown adipose tissue (BAT)2 has long been recognized as a critical thermogenic organ, exemplified by its importance in maintenance of thermal homeostasis in cold environments (1). More recently, clusters of distinct adipocytes with thermogenic capacity have been characterized in white adipose tissue-beige adipocytes-arising in response to various physiological stimuli (2, 3). The thermogenic endowment of these tissues has prompted the reasonable hypothesis that they might be leveraged to catabolize lipid and glucose as an anti-obesity and antidiabetic therapy. As such, recent decades have seen vigorous research into the mechanisms controlling brown and beige adipose tissue identity and function. Thermogenesis in BAT and beige adipose tissue relies on the key effector protein uncoupling protein 1 (UCP1), which can dissipate the electrochemical H ϩ gradient across the inner mitochondrial membrane (4). This UCP1-mediated inducible proton "leak" uncouples protonmotive force from ATP synthesis leading to an increased rate of mitochondrial respiration and heat generation. Additionally, UCP1-independent effectors of thermogenesis have been uncovered in recent years, including utilization of creatine-dependent substrate cycling in beige adipose tissue (5). Of course, expression of UCP1 (or other effectors) per se is not sufficient to drive thermogenesis; these are gas pedals that need a foot, fuel, and an engine. Indeed, thermogenic adipocytes require exceptionally high mitochondrial content and oxidative capacity to support elevated respiration. Moreover, thermogenic respiration is regulated acutely by upstream physiological signals that are required to activate UCP1-mediated uncoupling. So, elucidating the mechanisms that activate thermogenically-poised adipocytes is critical from a therapeutic standpoint.The purpose of this review is to contextualize recent findings that provide evidence for an important signaling role by reactive oxygen species (ROS) in adipose tissue thermogenesis. Remarkably, the importance of ROS signaling in this context has been demonstrated primarily through investigation of redox metabolism using in vivo mouse and intact adipocyte models of thermogenesis. In contrast, studies of ROS and thermogenesis using in vitro and reconstituted systems have provided...

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“…1C). To test if the toxicity of VgrG3 results in increased ROS levels, we used a general ROS fluorescence sensor CM-H2DCFDA (30,31) to compare ROS levels in VgrG3-expressing cells. We found ROS levels were about sevenfold higher in E. coli expressing WT VgrG3 than in cells expressing VgrG3 D842A (Fig.…”

Section: Significancementioning

confidence: 99%

Generation of reactive oxygen species by lethal attacks from competing microbes

Dong

Catalano

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

144

125

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Whether antibiotics induce the production of reactive oxygen species (ROS) that contribute to cell death is an important yet controversial topic. Here, we report that lethal attacks from bacterial and viral species also result in ROS production in target cells. Using soxS as an ROS reporter, we found soxS was highly induced in Escherichia coli exposed to various forms of attacks mediated by the type VI secretion system (T6SS), P1vir phage, and polymyxin B. Using a fluorescence ROS probe, we found enhanced ROS levels correlate with induced soxS in E. coli expressing a toxic T6SS antibacterial effector and in E. coli treated with P1vir phage or polymyxin B. We conclude that both contact-dependent and contact-independent interactions with aggressive competing bacterial species and viruses can induce production of ROS in E. coli target cells.T6SS | reactive oxygen species | interspecies competition | antibiotics |

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Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Cited by 82 publications

References 48 publications

Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice

Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Generation of reactive oxygen species by lethal attacks from competing microbes

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