Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society?

Abstract

Uric acid has historically been viewed as a purine metabolic waste product excreted by the kidney and gut that is relatively unimportant other than its penchant to crystallize in joints to cause the disease gout. In recent years, however, there has been the realization that uric acid is not biologically inert but may have a wide range of actions, including being both a pro- and anti-oxidant, a neurostimulant, and an inducer of inflammation and activator of the innate immune response. In this paper, we present the hypothesis that uric acid has a key role in the foraging response associated with starvation and fasting. We further suggest that there is a complex interplay between fructose, uric acid and vitamin C, with fructose and uric acid stimulating the foraging response and vitamin C countering this response. Finally, we suggest that the mutations in ascorbate synthesis and uricase that characterized early primate evolution were likely in response to the need to stimulate the foraging "survival" response and might have inadvertently had a role in accelerating the development of bipedal locomotion and intellectual development. Unfortunately, due to marked changes in the diet, resulting in dramatic increases in fructose- and purine-rich foods, these identical genotypic changes may be largely responsible for the epidemic of obesity, diabetes and cardiovascular disease in today's society.

Fig. 1

Purine metabolism. Purines can be synthesized from amino acids (the primary mechanism in reptiles and birds) or from purines liberated during nucleic acid metabolism or from ATP degradation (the primary mechanism in humans). Purines are metabolized by a series of enzymes, ultimately leading to urea and ammonia generation. However, the genes controlling purine metabolism have been mutated in many species such that this pathway cannot be completed. For example, humans have no functional uricase, so the final enzymatic end-product of purine metabolism is uric acid

Fig. 2

The Fattening fasting cycle: potential role of uric acid. During the preparation before a fast, an animal will ingest foods that will increase total body fat stores. We propose fructose is especially desirable due to its specific ability to increase serum lipids, hepatic fat stores, and serum uric acid. Vitamin C may have negative effects on this pathway (shown by dashed lines). Once fasting, the fat is preferentially broken down as an energy source, but once depleted there is the breakdown of protein with the release of uric acid and cortisol that stimulate a foraging response for food with additional survival benefits including effects on blood pressure and insulin resistance. In the event that foraging is not successful, wasting occurs with hypotension and death. In contrast, excessive stimulation of uric acid (primarily by diet) or of cortisol (primarily by endocrine overproduction) may lead to a condition resembling the metabolic syndrome with obesity, hypertension, dyslipidemia and insulin resistance