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Diabetes. 2015 Feb;64(2):471-84. doi: 10.2337/db14-0496. Epub 2014 Sep 23.

Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway.

Author information

  • 1Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, U.K. Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K. lee.roberts@mrc-hnr.cam.ac.uk jules.griffin@mrc-hnr.cam.ac.uk.
  • 2Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, U.K.
  • 3Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, U.K.
  • 4Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.
  • 5Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton General Hospital, Southampton, U.K.

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.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PMID:
25249574
[PubMed - indexed for MEDLINE]
PMCID:
PMC4351918
Free PMC Article
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