title: Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway.
abstract: Inorganic nitrate was once considered an oxidation end product of nitric oxide metabolism with little biological activity. However, recent studies have demonstrated that dietary nitrate can modulate mitochondrial function in man and is effective in reversing features of the metabolic syndrome in mice. Using a combined histological, metabolomics, and transcriptional and protein analysis approach, we mechanistically defined that nitrate not only increases the expression of thermogenic genes in brown adipose tissue but also induces the expression of brown adipocyte-specific genes and proteins in white adipose tissue, substantially increasing oxygen consumption and fatty acid β-oxidation in adipocytes. Nitrate induces these phenotypic changes through a mechanism distinct from known physiological small molecule activators of browning, the recently identified nitrate-nitrite-nitric oxide pathway. The nitrate-induced browning effect was enhanced in hypoxia, a serious comorbidity affecting white adipose tissue in obese individuals, and corrected impaired brown adipocyte-specific gene expression in white adipose tissue in a murine model of obesity. Because resulting beige/brite cells exhibit antiobesity and antidiabetic effects, nitrate may be an effective means of inducing the browning response in adipose tissue to treat the metabolic syndrome.
authors.affiliation: Medical Research Council - Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB2 9NL, UK.|Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge, CB2 1GA, UK.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge, CB2 1GA, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Ashmore
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
authors.forename: Aleksandra O
authors.initials: AO
authors.lastname: Kotwica
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge, CB2 1GA, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Murfitt
authors.affiliation: Faculty of Medicine, Clinical & Experimental Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: Faculty of Medicine, Clinical & Experimental Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murray
authors.affiliation: Medical Research Council - Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB2 9NL, UK.|Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge, CB2 1GA, UK.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D052437:Adipocytes, Brown / Q000502:physiology; D052438:Adipocytes, White / Q000187:drug effects / Q000502:physiology; D002001:Adipose Tissue, Brown; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism* / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP