Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2015-02-01
Date Acceptance
2014-09-11
Citation
Diabetes, 2015, 64 (2), pp.471-484
ISSN
0012-1797
Publisher
American Diabetes Association
Start Page
471
End Page
484
Journal / Book Title
Diabetes
Volume
64
Issue
2
Copyright Statement
© 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.
long as the work is properly cited, the use is educational and not for profit, and
the work is not altered.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/25249574
Subjects
Adipocytes, Brown
Adipocytes, White
Adipose Tissue, Brown
Adipose Tissue, White
Animals
Cells, Cultured
Cyclic GMP
Cyclic GMP-Dependent Protein Kinases
Dose-Response Relationship, Drug
Male
Mice
Mice, Inbred C57BL
Nitrates
Nitric Oxide
Nitrites
Rats
Rats, Wistar
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2015-01-22