title: Antioxidant Drug Tempol Promotes Functional Metabolic Changes in the Gut Microbiota.
abstract: Recent studies have identified the important role of the gut microbiota in the pathogenesis and progression of obesity and related metabolic disorders. The antioxidant tempol was shown to prevent or reduce weight gain and modulate the gut microbiota community in mice; however, the mechanism by which tempol modulates weight gain/loss with respect to the host and gut microbiota has not been clearly established. Here we show that tempol (0, 1, 10, and 50 mg/kg p.o. for 5 days) decreased cecal bacterial fermentation and increased fecal energy excretion in a dose-dependent manner. Liver (1)H NMR-based metabolomics identified a dose-dependent decrease in glycogen and glucose, enhanced glucogenic and ketogenic activity (tyrosine and phenylalanine), and increased activation of the glycolysis pathway. Serum (1)H NMR-based metabolomics indicated that tempol promotes enhanced glucose catabolism. Hepatic gene expression was significantly altered as demonstrated by an increase in Pepck and G6pase and a decrease in Hnf4a, ChREBP, Fabp1, and Cd36 mRNAs. No significant change in the liver and serum metabolomic profiles was observed in germ-free mice, thus establishing a significant role for the gut microbiota in mediating the beneficial metabolic effects of tempol. These results demonstrate that tempol modulates the gut microbial community and its function, resulting in reduced host energy availability and a significant shift in liver metabolism toward a more catabolic state.
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Cai
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.|CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences (CAS) , Wuhan 430071, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jones
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.
authors.forename: Jared B
authors.initials: JB
authors.lastname: Correll
authors.affiliation: Department of Chemistry, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hatzakis
authors.affiliation: Metabolomics Facility, Huck Institutes of Life Sciences, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Smith
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, NIH , Bethesda, Maryland 20892, United States.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University , University Park, State College, Pennsylvania 16802, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D008401:Gas Chromatography-Mass Spectrometry; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000502:physiology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D015870:Gene Expression / Q000187:drug effects; D054884:Host-Pathogen Interactions; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects* / Q000235:genetics; D055432:Metabolomics / Q000379:methods*; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013113:Spin Labels
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; C001803:tempol
keywords: GC−MS; NMR; SCFAs; bomb calorimetry; metabolomics; obesity; tempol