Roberts Lee D, Ashmore Tom, Kotwica Aleksandra O, Murfitt Steven A, Fernandez Bernadette O, Feelisch Martin, Murray Andrew J, Griffin Julian L
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.
Diabetes. 2015 Feb;64(2):471-484. doi: 10.2337/db14-0496. Epub 2014 Sep 23.
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.
无机硝酸盐曾被认为是一氧化氮代谢的氧化终产物，几乎没有生物活性。然而，最近的研究表明，膳食硝酸盐可以调节人体的线粒体功能，并有效逆转小鼠代谢综合征的特征。我们采用组织学、代谢组学以及转录和蛋白质分析相结合的方法，从机制上明确了硝酸盐不仅能增加棕色脂肪组织中产热基因的表达，还能诱导白色脂肪组织中棕色脂肪细胞特异性基因和蛋白质的表达，大幅增加脂肪细胞中的氧气消耗和脂肪酸β-氧化。硝酸盐通过一种不同于已知生理性褐变小分子激活剂（即最近发现的硝酸盐-亚硝酸盐-一氧化氮途径）的机制诱导这些表型变化。在缺氧（肥胖个体白色脂肪组织中一种严重的合并症）条件下，硝酸盐诱导的褐变效应增强，并且在肥胖小鼠模型中纠正了白色脂肪组织中受损的棕色脂肪细胞特异性基因表达。由于产生的米色/明亮细胞具有抗肥胖和抗糖尿病作用，硝酸盐可能是诱导脂肪组织褐变反应以治疗代谢综合征的有效手段。
