Fructose and metabolic health: governed by hepatic glycogen status?

J Physiol 597.14 (2019) pp 3573–3585

Hengist A, Koumanov F and Gonzalez JT.

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  • To present the hypothesis that hepatic glycogen stores may regulate metabolic responses to fructose ingestion and could therefore be a target to prevent or mitigate the negative metabolic effects of fructose intake.


  • Fructose is a commonly ingested dietary sugar, which has been implicated in playing a particularly harmful role in the development of metabolic disease.
  • Fructose is primarily metabolized by the liver in humans, and increases rates of hepatic de novo lipogenesis via numerous mechanisms: 1) by altering transcriptional and allosteric regulation; 2) interfering with cellular energy sensing, and 3) disrupting the balance between lipid synthesis and lipid oxidation.
  • Considering that fructose has the capacity to upregulate hepatic glycogen storage, and replenish these stores more readily following glycogen depleting exercise, the idea that hepatic glycogen storage and hepatic de novo lipogenesis are linked is a considerable prospect.


  • No methodology was reported in this review.


  • In current evidence, insulin response appears to be the main factor dictating acute responses to fructose ingestion, but longer-term detriments are characterized by increased hepatic lipogenesis. This suggests that dietary fructose ingestion may be particularly harmful for health in certain contexts, for example when humans are in a positive energy balance and/or low energy turnover.
  • Evidence also suggests that the mechanisms of hepatic lipid uptake, synthesis, and oxidation are likely the most important targets to regulate metabolic health in relation to hepatic lipid metabolism, as the downstream partitioning to VLDL secretion or hepatic TAG storage are both detrimental to metabolic health when excessively stimulated.
  • Assuming the authors’ hepatic glycogen hypothesis is correct, the ingestion of fructose when hepatic glycogen stores are already saturated would stimulate lipogenesis to a greater extent than when hepatic glycogen stores are low. If glycogen is being utilized at a rate high enough to overcome net glycogen synthesis, despite fructose intake, then theoretically this should reduce hepatic DNL and VLDL output.
  • An inability to further synthesise glycogen upregulates hepatic DNL and, considering that fructose ingestion increases both DNL and hepatic glycogen synthesis, glycogen stores may play a key role in determining the metabolic responses to fructose ingestion. The corollary is that negative metabolic effects of fructose intake are most likely to manifest when hepatic glycogen stores are saturated.


  • This hypothesis provides a rationale for striving to consider nutrient–physical activity interactions in physiology research, and to target turnover and/or utilization of hepatic glycogen stores to improve metabolic health.
  • Future research should strive to take an integrated approach towards understanding physiological responses to nutrients.  Where possible, researchers should strive to understand the effects of fructose ingestion (or any other nutrient) in the context of mediating factors. Measuring physical activity energy expenditure, type, timing and intensity are all useful towards understanding the physiological effects of nutrient ingestion.