Abstract 17585: Long-term Dietary Nitrite and Nitrate Deficiency Causes Metabolic Syndrome in Mice

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A17585
• Main Authors: Tsutsui, Masato, Kina-Tanada, Mika, Sakanashi, Mayuko, Matsuzaki, Toshihiro, Noguchi, Katsuhiko, Ishida, Masayoshi, Nakasone, Junko, Shimokawa, Hiroaki, Ohya, Yusuke, Arasaki, Akira
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11-11-2016
• ISSN: 0009-7322; 1524-4539

BackgroundNitric oxide (NO) is formed not only from L-arginine by a family of NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate (NOx). Green leafy vegetables are rich in nitrate. However, little is known about the role of the exogenous NO production system in disease pathogenesis. In this study, we tested our hypothesis that long-term dietary NOx deficiency causes metabolic syndrome in mice.Methods and ResultsTo this end, we prepared a low NOx chow in which the contents of L-arginine, carbohydrate, protein, fat, and calorie were identical with a regular chow, and ultrapure drinking water in which NOx levels were undetectable. The low NOx diet was administered in male wild-type (WT) C57BL/6 mice for 3-20 months (n=6-12). We previously reported that plasma NOx levels were extremely low in mice lacking all three NOS isoforms, suggesting that the exogenous NO production system might play a minor role in the regulation of NO production in vivo. However, unexpectedly, the low NOx diet for 3 months resulted in a marked decrease in plasma NOx levels in the WT mice as compared with a regular diet. The low NOx diet for 3 months markedly reduced endothelial NOS (eNOS) expression levels in the visceral fat, accounting for the markedly lower plasma NOx levels in the low NOx diet-fed mice. Importantly, the low NOx diet for 20 months significantly increased body weight, and caused visceral adiposity, dyslipidemia, glucose intolerance, and insulin resistance as compared with the regular diet, without affecting food or calorie intake. Furthermore, the low NOx diet for 20 months significantly induced an impairment of acetylcholine-induced endothelium-dependent relaxations and down-regulation of eNOS in the aorta. These phenotypes were inhibited by supplementation of sodium nitrate, and were significantly associated with hypoadiponectinemia and dysbiosis of gut microbiota.ConclusionsThese results demonstrate that long-term dietary NOx deficiency causes metabolic syndrome in mice, indicating the novel pathogenetic role of the exogenous NO production system in metabolic syndrome. Our findings also demonstrate identification of the specific dietary ingredients that give rise to metabolic syndrome even in the absence of excess calorie intake.