Trends in Endocrinology & Metabolism
ReviewFructose induced lipogenesis: from sugar to fat to insulin resistance
Section snippets
Too much of anything is good for nothing
Perhaps we should have heeded the edict against that apple in the Garden of Eden. Or what of the tale of Persephone and the pomegranate? It is unlikely that these tales intended to portend the perils of the fructose contained in those mystical fruits, though now the very real dangers of fructose overconsumption are increasingly appreciated. In 2004, Bray et al. made the observation that the rising prevalence of obesity was temporally associated with the increased consumption of high-fructose
Fructose: the fat sugar?
The recent increase in total sugar consumption reflects an increase in both glucose and fructose; however, the increase in fructose is of particular concern. Our bodies are well suited to dispose of glucose. Glucose uptake is regulated by a variety of glucose transporters that differ in their tissue distribution, regulation and kinetics [6]. In addition, glucose triggers the release of insulin, which further facilitates glucose uptake by increasing the translocation of glucose transporter
Fructose mediated lipogenesis
The aforementioned studies in humans elegantly exemplify that increased fructose consumption rapidly promotes lipogenesis and worsens insulin resistance. The mechanisms by which fructose promotes lipogenesis are likely to be multiple, but only a few have been proposed to date. For example, fructose metabolism might alter the activity of specific enzymes to promote lipogenesis. One example of this is the ability of fructose to alter the activity of pyruvate dehydrogenase (PDH) by inhibiting PDH
Missing links
The studies discussed so far clearly show that fructose metabolism is associated with activation of lipogenic pathways, through either activation of enzyme activity as in the case for PDH, or activation of a transcriptional program controlling lipogenesis as in the case for PGC1β and XBP1. However, the link between fructose and these downstream effects are still unknown. Specifically, what is the signal from fructose metabolism that directly activates these pathways? Although insulin activates
From fat to insulin resistance
The studies reviewed in this paper demonstrate the lipogenic potential for fructose and the possible mechanisms by which fructose activates the cellular lipogenic program. Moreover, these studies have shown the association between hepatocellular lipid content and hepatic insulin resistance. But how does hepatic steatosis lead to hepatic insulin resistance?
Wild type mice and rats develop hepatic steatosis after a few days of high fat feeding 45, 46. In rats, 3 days of high-fat feeding markedly
Conclusions and future perspectives
Many unanswered questions remain regarding fructose induced lipogenesis. Future studies are likely to uncover new pathways and regulatory steps that will further our understanding of fructose metabolism, possibly identifying novel therapeutic targets and informing the development of new agents.
The far greater challenge will be curbing the steady increase in fructose consumption. In my hospital, we often query new patients referred for diabetes about their juice and soda intake, and encourage
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