Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species.
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.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Seung-Hyun
SH
Ro
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;Department of Biological Sciences, Gachon University, Yeonsugu, Incheon 406-799, Korea;
Myeongjin
M
Nam
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Insook
I
Jang
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Hwan-Woo
HW
Park
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Haeli
H
Park
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Ian A
IA
Semple
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Myungjin
M
Kim
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul 140-743, Korea; and.
Jeong Sig
JS
Kim
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109;
Haewon
H
Park
Quark Pharmaceuticals, Inc., Ness Ziona 70400, Israel.
Paz
P
Einat
Quark Pharmaceuticals, Inc., Ness Ziona 70400, Israel.
Golda
G
Damari
Quark Pharmaceuticals, Inc., Ness Ziona 70400, Israel.
Maya
M
Golikov
Quark Pharmaceuticals, Inc., Ness Ziona 70400, Israel.
Elena
E
Feinstein
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; leeju@umich.edu.
Jun Hee
JH
Lee
D017667:Adipocytes / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001391:Azo Compounds; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D010544:Peroxidases; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000084622:Sestrins
D001391:Azo Compounds; D005230:Fatty Acids, Nonesterified; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D010544:Peroxidases; D017382:Reactive Oxygen Species; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins; C011049:oil red O
aging; homeostasis; mouse; β-adrenergic signaling