Metabolic syndrome

F stands for fructose and fat

Fructose and glucose have the same caloric value, but the two sugars are metabolized differently. It emerges that mice that cannot metabolize fructose are healthier when placed on carbohydrate-rich diets.

A drastic increase in dietary sugar consumption in the western world during the past four decades has been paralleled by epidemics of obesity and metabolic syndrome, suggesting a cause-and-effect relationship. Yet the relative contribution of individual sugars — as opposed to total caloric intake — to this epidemic remains controversial. For instance, increased intake of fructose, which is enriched in soft drinks and processed foods, has been proposed1 to greatly contribute to these disorders. However, this proposal has not been universally embraced2. Two studies by Johnson and colleagues, published in Hepatology (Ishimoto et al.3) and Nature Communications (Lanaspa et al.4), now investigate the role of fructose metabolism in obesity and metabolic syndrome using a mouse model that cannot metabolize this sugar. The results strongly support the theory that fructose over-consumption has toxic effects.

Dietary sugar encompasses several carbohydrates. Most often, however, it describes starch, sucrose and high-fructose corn syrup, each of which is composed of glucose with or without fructose: starch, found in bread and rice, is a glucose polymer; sucrose (table sugar) is a disaccharide made up of glucose and fructose; and high-fructose corn syrup, a common constituent of soft drinks, is a mixture of approximately 40% glucose and 60% fructose5. From an energetic standpoint, a molecule of glucose has the same caloric value as a molecule of fructose. However, the human body treats these carbohydrates quite differently, raising questions about their individual roles in obesity and metabolic syndrome1.

In general, glucose is used directly by tissues such as the muscles and brain as an energy source. Excess glucose is stored in the liver as glycogen (a glucose polymer) but can also be converted into fructose by the polyol biochemical pathway (Fig. 1). By contrast, fructose is almost exclusively metabolized by the liver. In this organ, ketohexokinase (KHK) — a liver-specific fructose-metabolizing enzyme also known as fructokinase — traps fructose in liver cells as fructose 1-phosphate. Unlike fructose 6-phosphate (an isomer of fructose 1-phosphate that participates in the biochemical pathway of glycolysis), fructose 1-phosphate can bypass a major regulatory step in glycolysis that generates fructose 1,6-bisphosphate through the action of the energy-sensitive enzyme phosphofructokinase. Thus, fructose can be converted into fat, unfettered by the cellular controls that prevent unrestrained lipid synthesis from glucose1,6.

Figure 1: Sugar metabolism.
figure1

Glucose and fructose are dietary sugars. Glucose is mainly metabolized by glycolysis and can be regulated through feedback inhibition by ATP or citrate, which redirects glucose towards storage as glycogen. In liver cells expressing the enzyme ketohexokinase (KHK), fructose is metabolized to fatty acids, triglyceride head groups (glycerol, not shown) and triglycerides — a biosynthetic pathway that is not regulated by the ATP- or citrate-feedback mechanisms. Glucose can also be converted into fructose through the polyol pathway, which involves the action of the enzyme aldose reductase (AR). In the absence of feedback inhibition, glucose metabolites can also be used to generate fatty acids and triglycerides. PFK, phosphofructokinase.

By this logic, diets high in fructose could cause excess fat accumulation in the liver, leading to the liver disorders fatty liver disease, steatohepatitis and, ultimately, cirrhosis. Liver fat could also be released into the circulation and taken up by fat cells in other tissues, resulting in obesity. Furthermore, the circulating fat could accelerate the onset of cardiovascular disease, insulin resistance and type 2 diabetes. So fructose over-consumption may be at the heart of metabolic syndrome, which has also been linked to poor outcome of a wide range of cancers7.

Indeed, there are epidemiological links between fructose consumption, obesity and metabolic syndrome8. Moreover, several studies6,9,10 have demonstrated that excess fructose consumption causes features of metabolic syndrome in laboratory animals and humans. For example, in overweight humans, a diet high in fructose (25% of total caloric intake) promoted insulin resistance, elevated levels of the lipid triglyceride and visceral obesity — features not observed in overweight individuals on an otherwise identical glucose-based diet6. Such studies strongly suggest that over-eating fructose (as opposed to glucose) promotes metabolic syndrome. Yet, despite this growing body of circumstantial evidence, and the logic behind the argument, the relative contribution of fructose to this condition has remained unproven.

Ishimoto and colleagues set out to directly assess the role of fructose metabolism on features of metabolic syndrome, using mice lacking KHK and, as such, incapable of processing fructose. Their findings are consistent with those of several previous studies: wild-type mice fed a western diet (one that is high in fat and fructose, in which the fructose comes from sucrose) developed severe fatty liver and liver inflammation (disorders collectively known as non-alcoholic steatohepatitis) along with liver fibrosis. By contrast, KHK-deficient mice fed the same diet were protected from liver inflammation and fibrosis, and developed only mild fatty liver. Because the authors demonstrate that the mutant and wild-type mice had equivalent caloric intake, the protection afforded by the mutant animals' inability to process fructose is direct evidence that this sugar has a role in exacerbating specific features of metabolic syndrome.

Lanaspa et al. take the matter a step further, examining the effect of carbohydrate-rich diets devoid of fructose in KHK-deficient mice. Intriguingly, these animals were also protected from the adverse effects of excess glucose consumption. This makes sense, given that in the liver the polyol pathway converts excess glucose into fructose, which is stored as fat only in the presence of KHK (Fig. 1). In fact, the authors validate the dependence of fructose synthesis on this pathway in mice lacking the polyol-pathway enzyme aldose reductase; these animals were also protected from glucose-induced fatty liver.

Whether fructose biosynthesis from a high-glucose diet is also relevant to metabolic syndrome in humans remains unknown. Regardless of the answer, the current papers make a strong case for the toxic effects of excess carbohydrate intake, placing fructose metabolism in the crosshairs. From an evolutionary perspective, enhanced fructose conversion to fat may have been advantageous. For instance, because fruits ripen at the end of the growth season, starch conversion into fructose and, in turn, storage of the abundant fructose as fat rather than glycogen could have facilitated survival through the ensuing months of low food availability.

In the western world today, however, food is rarely limiting at any time of the year, so the fat stored from the consumption of fructose remains unused. Moreover, many of the foods that are available at low cost year-round are those with the highest fructose content (sugary drinks and processed foods). That only about half of the calories in sucrose and in high-fructose corn syrup are immediately available as glucose for use by the muscles and brain may also contribute to our tendency to over-eat these sugars in order to maintain blood glucose levels. Thus, despite being calorically equivalent, a basic biochemical understanding of sugar metabolism clearly illustrates that fructose and glucose are not equal.

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Correspondence to Costas A. Lyssiotis or Lewis C. Cantley.

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Competing interests

L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing drugs to inhibit such enzymes in order to disrupt tumour-cell growth and survival.

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Lyssiotis, C., Cantley, L. F stands for fructose and fat. Nature 502, 181–182 (2013). https://doi.org/10.1038/502181a

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