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Metabolism of Fructose Versus Glucose

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Fructose and glucose are metabolized differently by the body, with some individuals including Dr. Robert Lustig hypothesizing that fructose may be the cause of the rising obesity epidemic in America. There are many differences between the two monosaccharides (another word for single-ringed sugars, as opposed to disaccharides like sucrose — see image below), but they have the same molecular formula (i.e. the same number of carbon, hydrogen, and oxygen atoms). However, glucose has a six-member ring, and fructose a five-member one. Keep in mind that fructose is an intermediate in glucose metabolism (i.e. glucose is converted into fructose at one stage in glycolysis), but that does not mean they have identical effects on the body. For instance, fructose stimulates the secretion of insulin more weakly than does glucose, as well as other peptides involved in appetite regulation.


The hypothalamus is the region of the brain generally considered to control feeding behavior. The thalamus is considered the sensory “relay center” of the brain, filtering all stimuli, and the hypothalamus sits just beneath it (it’s about the size of an almond). It has projections to the pituitary gland, so it controls the fight or flight instinct. For instance, its cells produce many hormones, including thyrotropin-releasing hormone, growth-hormone releasing hormone  (sounds repetitive, right?! It’s just another complex and highly regulated function of our endocrine system!), and vasopressin and oxytocin (the “bonding” hormones, among other things).

Regional cerebral blood flow (CBF) is considered a valid but imperfect marker of neural activation. Think of the occipital lobe of the brain (which sits in the back, above the cerebellum) lighting up when a subject sits in an MRI machine while engaging vision-based tasks. Interestingly in one study, glucose administration reduced hypothalamic CBF within 15 minutes, while fructose did not. ( As the picture above shows, blue regions indicate areas with decreased CBF after fructose or glucose ingestion. You can see that the hypothalamus lit up in the glucose condition (indicating decreased flow); this is a rough approximation, and it’s interesting that fructose led to decreased activation of the hippocampus, a region of the brain involved in memory. I will not speculate on why this result might have occurred, because there is simply too little evidence to draw a conclusion.

Other evidence to support the differential processing of glucose and fructose is a study in 2009 that showed fructose-sweetened, but not glucose-sweetened, beverages increased visceral adiposity (fat) in overweight/obese humans. ( Also in this study, fasting small dense LDL (the bad kind of cholesterol) decreased at 2 weeks in subjects consuming glucose, but increased in subjects consuming fructose.

So here’s a big piece of the equation: fructose metabolism occurs independently of phosphofructokinase (, so that there is no negative feedback loop limiting its metabolism by the liver (as occurs with glucose consumption).  When glucose is absorbed by liver cells, it goes through an extensive process involving, at one point, a phosphorylation step. Phosphorylation is a key regulatory process in the cell, whereby a phosphate group (the same kind in the backbone of our DNA) is attached to a molecule, usually for the purpose of “signaling” another protein/molecule. “Kinases” are enzymes (a type of protein) that typically attach phosphate groups to other molecules.

The liver initially takes up about 50% of the fructose we ingest (considered a high rate of extraction). This fructose is phosphorylated in the liver by fructokinase, and is then split into two smaller molecules (glyceraldehyde and dihydroxyacetone phosphate). After glyceraldehyde is phosphorylated, the glucose and fructose pathways “coverge” (i.e. have same end-products, and by end-products I mean intermediate molecules).

However, the rate-controlling step of glycolysis is catalyzed by phosphofructokinase. Notably, phosphofructokinase is inhibited by ATP and citrate, which are end-products of glycolysis (this is one way in which glucose metabolism is regulated). As a result, fructose is rapidly phosphorylated when it is presented to the liver. Basically there is increased “traffic,” so to speak, through glycolysis. Usually, a negative feedback loop regulates this system, and the accumulation of fructose-1,6-biphosphate inhibits glycolysis. However, fructose ingestion does not lead to fructose-1,6-biphosphate accumulation (I know it’s counter-intuitive given that there is a “fructose” in the name, but it just happens to be a product in glucose metabolism).  Remember that glucose is first converted to fructose when it enters the cell.

Now, consumption of fructose has spiked over the last 4 decades. I won’t bother you with the number of grams per person, but here’s a graph just to give you an idea: (

This post has quickly become much longer than I intended it to be, but it turns out this is a complicated subject (who knew! Not like the thousands of research papers on obesity should be a hint…literally 171645 papers in Pubmed come up if you search the word!). Anyway — I won’t pretend to have covered the entirety of existing literature on fructose and glucose, but this tidbit should give you an idea of some of the key differences, and why fructose is such a topic of interest lately. For a fascinating talk by Robert Lustig, watch this video. In the interest of not boring you to tears right now, I’ll discuss how this metabolic pathway leads to fat storage in a later post!

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