Journal
DIABETES
Volume 64, Issue 2, Pages 471-484Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db14-0496
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Funding
- Medical Research Council
- Biotechnology and Biological Sciences Research Council [bb/H013539/2, bb/I000933/1]
- British Heart Foundation
- Medical Research Council [UD99999906]
- Biotechnology and Biological Sciences Research Council [BB/I000933/1, BB/H013539/2] Funding Source: researchfish
- Medical Research Council [MC_UP_A090_1006] Funding Source: researchfish
- BBSRC [BB/I000933/1, BB/H013539/2] Funding Source: UKRI
- MRC [MC_UP_A090_1006] Funding Source: UKRI
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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 beta-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.
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