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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 23, 2010

Rats and High-Fructose Corn Syrup

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Posted by Derek

OK, enough politics around here for a while. It's time to talk about fat rats. When I last wrote about fructose around here, it was to highlight a paper that suggested that it had effects on satiety signaling in the brain. The hypothesis was that fructose could lead to an abnormal drop in ATP levels in the hypothalamus, leading to an inappropriate hunger signal. This is partially borne out by the results of infusing various sugars directly into the brains of rats: if you do that trick with glucose, the rats stop eating - their cells have detected abundant glucose, which is a signal that they've been fed recently. On the other hand, if you use fructose, the rodents actually eat more.

Some of the big questions, though, have been whether fructose does this under normal conditions in rats (that is, without the power-drill route of administration into the brain), and whether that result carries over to humans. There's a new paper from a group at Princeton that's sure to add fuel to the debate. They studied the effects on rats of access to high-fructose corn syrup (8% in water) versus 10% sucrose, with unlimited access to normal rat chow, and looked at whether it made a difference if you allowed access for half the day versus the whole 24 hours.

Over an 8-week period, the groups diverged significantly. The half-day corn syrup rats put on significantly more weight than the half-day sucrose rats did, even though (most interestingly) the corn syrup group turned out to be ingesting fewer calories from the added corn syrup than the sucrose rats were getting from their sugar water. That is, the difference in caloric intake (and thus the excess weight) was all coming from eating more chow.

When the study was extended to six months, it turned out that it didn't matter much if the rats had 12-hour or 24-hour access to the high-fructose corn syrup - by week 3, the weights of both groups had diverged from the controls. (Looking at the graphs, it appears that the 24-hour group may have done somewhat worse, but I don't think they reached statistical significance versus the 12-hours). But that result is in male rats. The females showed what seems to be a much less dramatic effect. Only the 24-hour-HFCS group showed a significant weight difference from the controls.

Looking at the fat deposits the rats had laid down during this time shows another gender difference, although it doesn't help clear things up any. The males show a tendency for more fat pad mass, although the only measurement that reached significance was the abdominal fat for the 12-hour-a-day group. The females, although they didn't show nearly as wide a difference in weight gain, had much more significant differences in their fat mass (but only for the 24-hour-a-day HFCS group). Finally, in blood chemistry, none of the groups showed differences in insulin levels. But the both the male HFCS groups had elevated triglycerides, as did the 24-hour-HFCS females.

Taken together, it appears that rats (especially males) are able to adjust their caloric intake when given access to small amounts of sucrose, but not so much when given equivalent amounts of HFCS. Earlier work has shown that access to higher levels of sucrose or other sugars, though, will indeed cause rats to gain weight. But not everyone, it seems, even sees these effects. A study from last December looked at a variety of sweetened waters, given to rats 12 hours/day for ten weeks, but only three days out of each week. No differences in weight were seen, although it should be noted that in head-to-head tests, the rats preferred HFCS to agave or Stevia sweeteners. (I wish this group had run sucrose in this experiment, too).

So does this effect even apply across the board in rodents? And if it does, is it operating in humans as well? Short term, no one has been able to find any short-term differences in satiety or blood chemistry when comparing HFCS with sucrose in humans. That alone (as mentioned in the earlier post here linked in the first paragraph) makes you wonder if that fructose/brain hypothesis can hold up in people. But what about long-term effects, which may or may not have anything to do with that CNS-based mechanism?

As far as I can tell, we have no controlled data for that, which isn't surprising, considering the sort of experiment you'd have to run. Most people aren't in a position to have their food and liquid intake completely monitored for two or three months. But short of that, I'm not sure how we're ever going to straighten all this out.

Comments (42) + TrackBacks (0) | Category: Diabetes and Obesity


1. mad on March 23, 2010 11:44 AM writes...

Whats the reasoning behing comparnig HFCS which has glucose and fructose to Sucrose?

Would it not make more sense to compare it to 100% glucose and 100% Fructose?

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2. In Vivo Veritas on March 23, 2010 11:50 AM writes...

Well, with luck Bart Hobel & crew can keep their interpretations in check this time. Bart had a way of producing nice science and then souring everyone on it by screaming "This is evidence of sugar addiction - soda companies are making your kids fat!!" or something like that. It's really an impediment - I think it makes his colleagues dismissive of his nice creative research. Yet Bart can't understand why nobody else shares his fist-pounding enthusiasm.
Oh well, scientists have "interesting" personalities. Present company excluded, of course....

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3. Anonymous on March 23, 2010 11:50 AM writes...

because it mimics american diet better

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4. In vivo veritas on March 23, 2010 11:55 AM writes...

Hey Mad - it's because pure fructose is poorly absorbed in the absence of glucose. The right way to compare fructose and glucose is sucrose (glucose-fructose dimer) vs. maltose (glucose-glucose dimer).
Plus HFCS is so abundant in the american diet that it's more interesting to study than pure fructose, which is pretty rare in food.

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5. Ed on March 23, 2010 11:58 AM writes...

If you were to replace "causes obesity" with "causes cancer" in this work there is absolutely no doubt that it would take the FDA all of one zeptosecond to pull HFCS from the market, even if the studies were only in rats and only of marginal statistical significance and only at high doses.

Because it might only cause increased obesity I suspect they will do diddly.

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6. RB Woodweird on March 23, 2010 12:00 PM writes...

"Most people aren't in a position to have their food and liquid intake completely monitored for two or three months."

True that, but when I was a young whelp at a certain technological institute hereabouts, some of us routinely made pocket money by subjecting ourselves to studies run by the Food and Nuts department. I only ever went and ate a rather bland piece of shortbread at teatime for a couple of weeks, followed by bloodletting at the end of the study. On the other hand, some fellows (for in those dark days there were few nonfellows) engaged themselves in projects demanding that they ingest only the foodstuffs prepared for them, and that they collect everything - and I do mean everything - which left their bodies. I recall seeing runners on the river loop clutching plastic containers into which they were obliged to expectorate.

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7. Sigivald on March 23, 2010 12:09 PM writes...

Ed: Which is good, because "keeping people from getting fat" isn't their job, and FDA overreaction is worse than complete inaction.

(I've already seen the "Ban HFCS Now!!!" people pushing this study as Further Proof Corn Syrup Kills Babies, sadly.)

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8. RM on March 23, 2010 12:16 PM writes...

Yes, Ed, and if you replaced "causes dry mouth" with "causes instant death" in any given drug trial, the FDA would also yank the drug.

People consistently forget about the second factors in these issues. "The dose makes the poison." It's not just "chance of effect", it's "chance of effect" *and* "severity of effect". And it's not just "severity of effect", it's really "severity of effect directly attributable to the effect".

"Causes cancer" gets yanked from the market because the effects of cancer are usually dire, and usually outweigh whatever benefit you get. Even a small increase in risk of cancer can be an issue because of the severity.

"May contribute to obesity" is less severe than cancer. (Imagine what you'd prefer to hear your doctor tell you "You're obese" or "You have cancer") While the effects of obesity can be deadly, obesity is a chronic condition caused by a large number of factors - there's no indication that banning HFCS would reduce morbidity due to obesity, as opposed to a "causes cancer" compound, where we can clearly state that removing the compound would directly effect the cancer rate.

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9. Cloud on March 23, 2010 12:19 PM writes...

Thanks for posting this. I hadn't seen the study. It is the first one I've seen that makes me think there might be anything at all different in drinking a Coke sweetened with HFCS vs a Coke sweetened with sugar.

Of course, I don't actually drink either of those things, but still, its an interesting study.

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10. mad on March 23, 2010 1:16 PM writes...


I see the HFCS vs sugar idea but still its comparing monomer to dimer. Or is sucrse quickly broken down to glucose and fructose?

I think also knowing if HFCS is any differnet than glucose alone would be a big question. At lest in perception of how "bad" it really is.

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11. Cloud on March 23, 2010 1:34 PM writes...

mad- sucrose is readily cleaved into fructose and glucose in the body. The glucose and fructose are then broken down to extract energy... if you are curious to know more, get your hands on a basic biochemistry book. Or, I suppose, you could start with the wikipedia entry for "glycolysis" and follow links from there.

Comparisons of pure glucose and pure fructose usually show pure glucose to be "better" (where different groups look at different endpoints as the definition of "better"). But neither is used extensively as added sugar in food.

As an interesting aside- plain old "corn syrup" is mostly glucose. HFCS was invented to make corn syrup sweeter.

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12. CRH on March 23, 2010 1:49 PM writes...

I understand the issue with "causes cancer" vs. "may contribute to obesity" as to why the FDA might not act. However, I don't see this as a obesity vs. cancer argument; more of a trans fat type of scenario and there are several cities (NY - as an example) that have banned trans fats. Therefore, maybe the FDA won't pull HFCS off the market; but rather, it may be banned much like trans fats.

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13. Sili on March 23, 2010 2:15 PM writes...

OK, enough politics around here for a while.
He sez and jumps straight into HFCS ...
It is the first one I've seen that makes me think there might be anything at all different in drinking a Coke sweetened with HFCS vs a Coke sweetened with sugar.
Same here, though I can't claim to have followed the subject closely. But I've been catching up on the old Skeptoid episodes so this was relatively fresh in memory.

Can't say I'm happy that it seems to support the nutters, but if dem's de facts, I have to accept the new reality (in due time).

Thank Mammon that the powers that be pour money into beets over here instead of corn. (Free Market, my Belgium.)

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14. Rachel on March 23, 2010 3:26 PM writes...

It's an insanely easy experiment to do in people. Give half the people sugar Coca-Cola and half corn syrup Coca-Cola. Track in the long-term and look for different outcomes. Unlike most science, the results would actually be relevant and easy to interpret.

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15. Cloud on March 23, 2010 4:06 PM writes...

Rachel, I can't tell if you're joking.

It is not at all an easy experiment to do in humans, because of confounding factors.

You can standardize the other factors in rats (same chow, same activity levels... heck, you can even get the same genetic background to a large extent). Humans, on the other hand, live peskily complicated lives.

Come to think of it, though, Coke in some other countries is made with sucrose, so in effect this experiment has been done. The data are not straight-forwardly interpretable.

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16. Sili on March 23, 2010 4:18 PM writes...

I believe Mexico uses sucrose (since they subsidise cane (I think)). Is Texas prone to jumping the border to be cheap stuff the way Denmark is?

In that case it might be possible to try comparing populations in North and South Texas, say.

But I assume that much work has already been done with demographics.

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17. Dave on March 23, 2010 4:42 PM writes...

Which HFCS was it? I'm guessing HFCS 55, but the abstract doesn't say.

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18. John Thacker on March 23, 2010 5:34 PM writes...

I believe Mexico uses sucrose (since they subsidise cane (I think))

You have it backwards. It's the US that subsidizes sugar production, but through quotas (and a complex "use your sugar as collateral in a loan valued at a certain amount, but then you can forfeit the sugar") and raises the price of sugar to twice or more of the world price.

It's a pretty bipartisan scandal; the only really anti-sugar quota, anti-HFCS presidential candidate in recent years went down hard in 2008.

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19. Eve on March 23, 2010 6:01 PM writes...

Ed: isn't it a legal issue there, insofar that the Delaney clause only applies to things that cause cancer, not to things that cause obesity?

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20. Handles on March 23, 2010 6:13 PM writes...

What about these guys as test subjects? I guess the sample size is too small to be useful...

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21. Tok on March 23, 2010 6:30 PM writes...

I seem to recall a recent study that gave half a prison vitamin supplements and half placebo to see if this affected violence. Can't find a link to it though.

Seems like that would be an ideal situation to test the HFCS vs glucose and sucrose in humans under very controlled conditions and over the long term.

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22. Eric on March 23, 2010 9:38 PM writes...

Has anyone proposed a reasonable mechanism for how an HFCS with roughly 50% fructose and 50% glucose could have a different biochemical effect than sucrose? Is the cleaving of the glycosidic bond slow enough that blood levels of fructose remain lower after ingesting sucrose than after ingesting HFCS?

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23. David Gillespie on March 23, 2010 11:53 PM writes...

"... considering the sort of experiment you'd have to run"

Its a long way from a controlled trial, but at least at the population level, this sort of experiment is being done (sort of). Australia has a demographic and lifestyle profile that would easily allow it to be confused with most American states.

However in Australia HFCS is not used at all (and never has been). The primary sweetener is cane sugar (Australia is a major exporter of cane sugar). Our obesity stats are not quite as bad as the US but we are catching up very fast. It would be interesting to compare ingestion rates over time to see whether it is possible to imply a difference based on HFCS v sucrose.


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24. marvel on March 24, 2010 6:53 AM writes...

Sounds like it's time to do a microbiome study of the gut flora of the HFCS-fed vs glucose-fed rats.

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25. Virgil on March 24, 2010 10:59 AM writes...

There is one very important detail being glossed over in the press...

To quote the study... "fructose intake might not result in the degree of satiety that would normally ensue with a meal of glucose or sucrose, and this could contribute to increased body weight"

They fed rats HFCS vs. sucrose, and gave them free access to standard lab chow. The caloric intake from sugar was less in the HFCS group (21 kcal) vs. the sucrose group (31 kcal). However, the total caloric intake was the same. Where did the HFCS group make up those extra calories? By eating more chow! That's why they gained more weight. Put differently, the sucrose group was more "sated" by their sugar drink, so they ate less chow, and gained less weight.

Furthermore, the authors mixed the HFCS up at a different strength than the sucrose drink. Maybe the calorie intake from HFCS was less because the rats didn't like the taste of it so much?

I'm not a nutritionist, and have no interests whatsoever in the soft drink industry. I'm an academic biochemist with a broad interest in metabolism, and it annoys me to see such studies given a lot of press, when they're so poorly controlled. What they should have done, is to alter the make-up of the chow diets between the groups, in order to ensure that both groups consumed exactly the same amount of antioxidants, proteins, fats, etc., and the ONLY difference would be the carbohydrate source. This could be done by just grinding up the chow and mixing in different carbohydrate sources. As soon as you're relying on the rats themselves to control the amount of sugar water they drink, you introduce all kinds of other variables which invalidate the study. As it stands, this study does not have the source of carbohydrate as a single independent variable.

Bottom line - drinking HFCS interferes with how "full" you feel, and that might cause you to eat more food which makes you fat, but there is no evidence in this study at HFCS itself makes you fat.

(Oh, and its published in an obscure journal with an impact factor of 2.7)

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26. Cloud on March 24, 2010 11:07 AM writes...

Virgil- Excellent critique. I'll go you one further: drinking HFCS interferes without how "full" you feel IF YOU'RE A RAT.

I've yet to see a study that demonstrates the same effect in humans.

Eric- As far as I know, no one has demonstrated a mechanism for how HFCS makes you fat. The current research seems to be around the idea that it interferes with satiety cues.

My personal theory is that its primary effect on our waistlines is that it makes calories cheap, and so we consume too many of them.

However, I think marvel's idea is an intriguing one.

I'm not at all connected with the food industry, either. I got interested in this area of research because I have kids, and am constantly being told how bad HFCS is for them. So I went and did some reading on it, and came away with the opinion that the evidence really only indicates that a lot of processed sugar, be it sucrose or HFCS, is bad for them.

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27. Eric on March 24, 2010 11:41 AM writes...

Thanks Cloud. What I meant to ask, however, is that if HFCS has the same glucose & fructose content as sucrose, how can one affect the body differently than the other? I haven't heard anyone explain how this is the case. To me, it's like saying that drinking water chilled to 32C has a different effect on the body than ingesting crushed ice at 32C.

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28. Cloud on March 24, 2010 12:05 PM writes...

Eric, I have yet to see a credible mechanism for that, which is why I remain so skeptical of the idea.

HFCS is usually 55-45, so there is slightly more fructose in it than in sucrose. Perhaps that slight difference is important?

Perhaps there is some sort of receptor on your tongue that recognizes sucrose and says "yum! calories" but fails to recognize HFCS?

It doesn't seem to me that much research is being done by people thinking mechanistically.

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29. RM on March 24, 2010 12:39 PM writes...

As to why 50-50 glucose-fructose is different from sucrose, it may indeed have to do with how it's metabolized. I know that in yeast experiments, people tend to use raffinose (a fructose-glucose-galactose trisaccharide) as an energy source, as it neither induces the galactose metabolism pathway nor induces the "presence of glucose" metabolism response, despite having both glucose and galactose monomers.

That said, it was my understanding that strong acids readily hydrolize the bond in sucrose, so I don't know how much disaccharide makes it through the stomach, let alone the bottle of pH ~3 Coca Cola.

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30. Tok on March 24, 2010 3:06 PM writes...

Virgil - "Bottom line - drinking HFCS interferes with how "full" you feel, and that might cause you to eat more food which makes you fat, but there is no evidence in this study at HFCS itself makes you fat."

I'd argue that if that's what it does, then HFCS is in fact making you fat. If I fed you a compound in your food that had 0 calories but made you always feel ravenously hungry no matter what you ate, then that compound is making you fat by affecting your behavior.

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31. Sili on March 24, 2010 4:08 PM writes...

I'd argue that if that's what it does, then HFCS is in fact making you fat. If I fed you a compound in your food that had 0 calories but made you always feel ravenously hungry no matter what you ate, then that compound is making you fat by affecting your behavior.

Indeed. This is a sideeffect of some antidepressants, certainly (I should know). To the point that they're sometimes prescribed to the elderly who can have notoriously low appetites.

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32. Neva Cochran on March 24, 2010 4:48 PM writes...

Check out the assessment of this study by NYU nutrition professor, Marion Nestle, PhD, at You cannot necessarily draw conclusions about what would happen in humans based on a study with rats given abnormally high amounts of sucrose and high fructose corn syrup. A previous study in women comparing the metabolic effects of sucrose and HFCS found no abnormal effects of either and no difference between the two. Total calorie intake is the significant factor in weight gain, not the source of the calories. There is no scientific evidence to suggest that high fructose corn syrup is uniquely responsible for obesity. In fact, the American Medical Association concluded that, "high fructose corn syrup does not appear to contribute more to obesity than other caloric sweeteners." As a registered dietitian, I advise that all sweeteners be consumed in moderation as part of a nutritionally adequate diet with plenty of whole grains, fruits and vegetables and moderate amounts of lean meat, low-fat or nonfat dairy and healthy fats. Neva Cochran, MS, RD, LD

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33. Cynthia1770 on March 24, 2010 9:28 PM writes...

My google alert for HFCS picked up your post.
I constantly read from bloggers what the CRA would like you to believe: that HFCS-55 is essentially similar to sucrose. According to the CRA, HFCS-55 is 55% fructose: 45% fructose. This may appear to be 5% different than the 50:50 in sucrose, until you do the math.
55%:45% = 55/45 = 1.22. This means that in every
Coke, there is compared to glucose, 22% more fructose. What does this mean in everyday terms?
5 HFCS-55 Cokes
=4.25 SUCROSE Cokes +0.75 FRUCTOSE Coke.
Considering that the average teen chugs a couple
of caloric sodas a day, that is a lot of extra
fructose assaulting our livers. I am not at all surprised about the results of the long term Princeton study comparing HFCS with sucrose.
Older studies, reviews published by the AJCN only looked at the short term effects of sucrose vs. HFCS in human subjects. The big soda boys, Pepsi and Coke, switched to HFCS-55 in 1985. We did not turn obese and diabetic overnight. The Princeton study has strong implications that the CRA has been brewing an industrial sweetener laced with fructose and our bodies just can't handle it.
Ditch HFCS, especially HFCS-55.
To your health.

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34. Jose on March 24, 2010 10:50 PM writes...

There is quite a body of data that suggests diet (ie, calorie free) soda is just as deleterious to health as the normal stuff, as per the behaviour modification mentioned above.

Our pancreases and brains were never designed for anything sweeter than berries or the occasional bounty of honey. Google "thrifty gene hypothesis" for more info, esp. the cryoprotectant extensions.

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35. sgcox on March 25, 2010 5:03 AM writes...

Second to Jose comment.
Read for example this New Scientist article:

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36. Sili on March 25, 2010 5:54 AM writes...

Ah, the true believers have arrived.

Considering that the average teen chugs a couple of caloric sodas a day
Now, I wonder if this might have something to do with the obesity 'pandemic'. Permalink to Comment

37. David L on March 25, 2010 10:04 AM writes...


Even better experiment...take as many identical twins as you can find...Let one half drink sodas with sucrose and the other one with HFCS then run some statistics and write some papers.

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38. Tok on March 27, 2010 3:37 PM writes...

Sili "This is a sideeffect of some antidepressants, certainly (I should know)."

I've always wondered how in the world an antidepressant gets on the market with this side effect. I had a relative who was underweight when she started on antidepressants, gained an enormous amount of weight in less than a year, and began to have serious health problems because of it. I don't really see how this could prevent depression; if anything it would cause it. Toss 80 lbs on any person and see how their self image improves, especially when they can hardly walk anymore because of stress fractures.
Any antidepressant with this side effect should never have made it on the market.

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39. Sili on March 27, 2010 4:41 PM writes...

I have to disagree with you there, Tok.

If I hadn't had the pills I wouldn't have had the energy to benefit from therapy - I tried, and the first coupla months were essentially wasted since just holding myself took too much of energy. The dope helped with the basic maintenance so that I could get to work on getting better.

I've never been particularly active, but it didn't take me more than regular walks to stay moderately fit even if a bit heavier than 'normal'. And that exercise was good for my mental health as well - a brisk walk, fresh air, sun on the face. Pretty holistic actually.

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40. D. on March 27, 2010 11:54 PM writes...

#34: Our brains weren't "designed" at all, and squeezing a tangerine into your mouth requires no science to deliver a massive blood sugar spike. Monkeys manage it.
There is also no evidence for refined sugar avoidance in super-centenarians. Jeanne Calment, for example, ate a kilo of chocolate every week of her adult life and died at 122.

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41. mallikarjun on April 13, 2010 1:30 PM writes...

how fructose icrese feed intake in normal and high fat fed nSTZ rats.

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42. Magaret Wojnowski on March 1, 2012 2:08 PM writes...

Write more, thats all I have to say. Literally, it seems as though you relied on the video to make your point. You obviously know what youre talking about, why throw away your intelligence on just posting videos to your site when you could be giving us something informative to read?

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