Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts

Abstract

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

Keywords: fructose; metabolic syndrome; metabolic water; uric acid; vasopressin.

Fig. 1

A Common Survival Pathway. The simple sugar, fructose, likely had a major role in evolution due to its unique metabolism that activates processes that prepares the animal for pending shortage in food, water or oxygen. Specifically, fructose shifts the energy provided in nutrients towards fuel storage (fat, glycogen) and away from energy (ATP) production by downregulating mitochondrial metabolism and the favouring of glycolysis. The fat and glycogen provide a source for energy and metabolic water when food and water are scarce. The switch towards glycolysis is associated with a reduction in energy demand and results in protection from hypoxic and ischaemic states. Gluconeogenesis and insulin resistance occur to raise serum glucose levels to provide fuel to the brain. Sodium is retained, and vasoconstrictors are stimulated to increase blood pressure, and innate immunity is also stimulated. Foraging develops, and thirst and hunger occur as a mechanism to increase weight, largely from the development of leptin resistance and hyperosmolality-driven thirst. These processes are mediated by endproducts of fructose metabolism that include vasopressin, lactate and uric acid. While providing a key survival advantage in conditions of scarce resources, excessive fructose can stimulate metabolic diseases, dementia and cancer.

Fig. 2

Biochemical Basis of Fructose Metabolism. Fructose can be obtained either from the diet or can be produced from glucose endogenously via the aldose reductase-sorbitol dehydrogenase (polyol) pathway. The unique feature of fructose metabolism is that it reduces the energy (ATP) and intracellular phosphate in the cell during its metabolism that sets off an ‘alarm’ signal that triggers the survival pathway. Specifically, fructose is metabolized by fructokinase C (KHK-C) in various tissues including the intestine, liver, kidney, islets, adipose tissue and brain, where it causes a rapid phosphorylation of fructose to fructose-1-phosphate. Fructose-1-phosphate is then metabolized further by aldolase B and other enzymes to lead to the production of glucose, lactate, glycogen and triglycerides. However, the initial phosphorylation of fructose by KHK-C results in a fall in intracellular phosphate that activates AMP deaminase-2 that triggers the degradation of AMP to IMP and eventually uric acid. Vasopressin is also stimulated by fructose metabolism, although it is not known if it is mediated by the energy depletion pathway. These processes lead to mitochondrial dysfunction and a shift from energy production to energy storage.

Fig. 3

Fructose Stimulates Thirst by Shifting Water into the Cell. The administration of fructose (such as in a soft drink) following heat stress is associated with remarkable stimulation of vasopressin (noted by serum copeptin) compared to intake of water. The increased vasopressin is associated with an amplification in urinary concentration compared to water hydration. However, serum osmolality fails to decrease because the water retained through the action of vasopressin shifts into the cell, resulting in a persistently contracted extracellular volume with increased intracellular volume (measured by bioimpedance). This is likely because glycogen is being rapidly made, and glycogen incorporates water into its lattice structure [33, 95]. The original study excluding the bioimpedance data is from Ref [36].