ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue
Sara C. Sebag,
Zeyuan Zhang,
Qingwen Qian,
Mark Li,
Zhiyong Zhu,
Mikako Harata,
Wenxian Li,
Leonid V. Zingman,
Limin Liu,
Vitor A. Lira,
Matthew J. Potthoff,
Alexander Bartelt,
Ling Yang
Affiliations
Sara C. Sebag
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Zeyuan Zhang
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Qingwen Qian
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Mark Li
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Zhiyong Zhu
Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Mikako Harata
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Wenxian Li
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Leonid V. Zingman
Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Limin Liu
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
Vitor A. Lira
Department of Health and Human Physiology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA; College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA
Matthew J. Potthoff
Department of Neuroscience and Pharmacology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Alexander Bartelt
Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich Pettenkoferstr. 9, 80336 Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Technische Universität München, Biedersteiner Str. 29, 80802 München, Germany; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA
Ling Yang
Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Corresponding author
Summary: Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status, but the underlying molecular mechanisms are incompletely understood. Protein S-nitrosylation, the nitric-oxide-mediated cysteine thiol protein modification, plays important roles in cellular redox regulation. Here we show that diet-induced obesity (DIO) and acute cold exposure elevate BAT protein S-nitrosylation, including UCP1. This thermogenic-induced nitric oxide bioactivity is regulated by S-nitrosoglutathione reductase (GSNOR; alcohol dehydrogenase 5 [ADH5]), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 in BAT impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction. Mechanistically, we demonstrate that Adh5 expression is induced by the transcription factor heat shock factor 1 (HSF1), and administration of an HSF1 activator to BAT of DIO mice increases Adh5 expression and significantly improves UCP1-mediated respiration. Together, these data indicate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis, which may be therapeutically targeted to improve metabolic health.
