Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species
| Autor: | Jun Hee Lee, Seung Hyun Ro, Paz Einat, Haeli Park, Elena Feinstein, Maya Golikov, Insook Jang, Hae-Won Park, Golda Damari, Jeong Sig Kim, Hwan-Woo Park, Myeongjin Nam, Ian A. Semple, Myungjin Kim |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Immunoblotting Adipose tissue Mice Transgenic Oxidative phosphorylation Fatty Acids Nonesterified Biology Real-Time Polymerase Chain Reaction p38 Mitogen-Activated Protein Kinases Ion Channels Mitochondrial Proteins Mice Internal medicine Brown adipose tissue Adipocytes medicine Animals Humans Inner mitochondrial membrane Uncoupling Protein 1 chemistry.chemical_classification Regulation of gene expression Reactive oxygen species Multidisciplinary Nuclear Proteins Biological Sciences Thermogenin Endocrinology medicine.anatomical_structure Gene Expression Regulation Peroxidases chemistry Reactive Oxygen Species Azo Compounds Thermogenesis |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:7849-7854 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1401787111 |
| Popis: | Uncoupling protein 1 (Ucp1), which is localized in the mitochondrial inner membrane of mammalian brown adipose tissue (BAT), generates heat by uncoupling oxidative phosphorylation. Upon cold exposure or nutritional abundance, sympathetic neurons stimulate BAT to express Ucp1 to induce energy dissipation and thermogenesis. Accordingly, increased Ucp1 expression reduces obesity in mice and is correlated with leanness in humans. Despite this significance, there is currently a limited understanding of how Ucp1 expression is physiologically regulated at the molecular level. Here, we describe the involvement of Sestrin2 and reactive oxygen species (ROS) in regulation of Ucp1 expression. Transgenic overexpression of Sestrin2 in adipose tissues inhibited both basal and cold-induced Ucp1 expression in interscapular BAT, culminating in decreased thermogenesis and increased fat accumulation. Endogenous Sestrin2 is also important for suppressing Ucp1 expression because BAT from Sestrin2(-/-) mice exhibited a highly elevated level of Ucp1 expression. The redox-inactive mutant of Sestrin2 was incapable of regulating Ucp1 expression, suggesting that Sestrin2 inhibits Ucp1 expression primarily through reducing ROS accumulation. Consistently, ROS-suppressing antioxidant chemicals, such as butylated hydroxyanisole and N-acetylcysteine, inhibited cold- or cAMP-induced Ucp1 expression as well. p38 MAPK, a signaling mediator required for cAMP-induced Ucp1 expression, was inhibited by either Sestrin2 overexpression or antioxidant treatments. Taken together, these results suggest that Sestrin2 and antioxidants inhibit Ucp1 expression through suppressing ROS-mediated p38 MAPK activation, implying a critical role of ROS in proper BAT metabolism. |
| Databáze: | OpenAIRE |
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