Dietary inorganic nitrate: From villain to hero in metabolic disease?

Abstract

Historically, inorganic nitrate was believed to be an inert by-product of nitric oxide (NO) metabolism that was readily excreted by the body. Studies utilising doses of nitrate far in excess of dietary and physiological sources reported potentially toxic and carcinogenic effects of the anion. However, nitrate is a significant component of our diets, with the majority of the anion coming from green leafy vegetables, which have been consistently shown to offer protection against obesity, type 2 diabetes and metabolic diseases. The discovery of a metabolic pathway in mammals, in which nitrate is reduced to NO, via nitrite, has warranted a re-examination of the physiological role of this small molecule. Obesity, type 2 diabetes and the metabolic syndrome are associated with a decrease in NO bioavailability. Recent research suggests that the nitrate-nitrite-NO pathway may be harnessed as a therapeutic to supplement circulating NO concentrations, with both anti-obesity and anti-diabetic effects, as well as improving vascular function. In this review, we examine the key studies that have led to the re-evaluation of the physiological function of inorganic nitrate, from toxic and carcinogenic metabolite, to a potentially important and beneficial agent in the treatment of metabolic disease.

Keywords: Adipose Tissue; Diabetes; Dietary inorganic nitrate; Metabolic disease; Metabolism; Nitric oxide; Obesity.

Figure 1

Dietary nitrate is sequentially reduced to nitrite and then NO via the enterosalivary pathway. Once nitrate is ingested, it is absorbed into the bloodstream in the upper gastrointestinal tract. Here it can mix with nitrate produced by the oxidation of NO and nitrite. This nitrate can then continue along the enterosalivary pathway to be reduced to NO by commensal bacteria in the oral cavity. Further, nitrate could enter cells such as adipocytes (where it may be reduced to NO to bring about systemic changes), or it may be excreted by the kidneys.

Figure 2

The effects of dietary inorganic nitrate on white adipose tissue. Dietary nitrate stimulates the browning response in hypoxic white adipose tissue. Nitrate is taken up from the blood by beige adipocytes where it triggers an increase in mitochondrial biogenesis, fatty acid β‐oxidation and brown adipocyte‐specific gene expression. The metabolic activity of the adipocytes is increased, raising the rate of thermogenesis. The mechanism by which nitrate activates browning relies on cGMP‐PKG signalling, followed by increased expression of the transcriptional activator PGC‐1α. PKG, protein kinase G.

Figure 3

The three proposed mechanisms through which inorganic nitrate reduces blood pressure. Nitrate is converted to NO via the enterosalivary pathway or the XOR‐catalysed nitrate‐nitrite‐NO pathway. NO can then activate soluble guanylyl cyclase (sGC), reducing blood pressure in the canonical manner. Further, it can inhibit superoxide production by NADPH oxidase, a vasoconstriction pathway stimulated by angiotensin II. Finally, NO can suppress hepatic erythropoietin (EPO) expression, reducing haemoglobin levels and thus the haematocrit.