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Fructose and DHA

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Thanks Mike,


Here is another popular press account of the fructose and DHA study. The researchers fed rats a high fructose diet (the human equivalent of drinking a liter of soda a day) for six weeks, and found it caused changes to the expression of "hundreds of brain genes" and slowed the rats down in running a maze relative to controls who ate a normal diet without plain water rather than fructose-sweetened water.


Before we get to the DHA part, let me first observe that the authors make a big deal out of poorer serum markers of metabolic health in the fructose rats (higher glucose, triglycerides, insulin, insulin resistance) and their poorer (slower) performance on a Barnes Maze.  Given they reported all these other health markers, it seems to me to be a pretty egregious, if not deliberate, oversight, that nowhere in the paper itself or in any of copious supplemental material do the authors report on the rats' body weight, food intake or percent of calories from fructose that the fructose rats were eating. With ad lib access to food and fructose-laden "cool-aid", and a serum profile resembling metabolic syndrome, it seems pretty likely the fructose-fed rats were substantially heavier and likely obese relative to the control rats.


In short, this wasn't a substitution study, but a study where the simply added fructose on top of an ad lib diet. It therefore runs a serious risk of unfairly maligning fructose, when what was really happening was the rats were simply getting fatter due to a heavily-sweetened, hypercaloric diet.


This is particularly troubling for several reasons. First, it's not clear rodents and people metabolize fructose in the same way - in particular rodents appear to convert carbohydrates to fat much more readily than humans when fed a high carb diet [2]:


Whereas de novo lipogenesis (DNL) under conditions of long-term,
high-carbohydrate feeding accounts for 60% to 70% of fatty acids in rodents
(ref), its contribution in humans is considered quantitatively insignificant,
contributing 5% (ref).


Also, moderate fructose intake looks like it may even be beneficial for metabolic health, including improved insulin sensitivity [2]:


There is also emerging evidence that small, “catalytic” amounts of
fructose may have benefit. Fructose at doses of 7.5 g/meal have been
shown to improve long-term glycemic control in humans (ref) by decreasing
the postprandial glycemic responses to high glycemic index carbohydrates
(ref), mediated by an increase in glycogen synthase activity (ref). This
finding has particularly interesting connotations for the benefit of fruit as
a source of fructose in the diabetic diet (ref).

So moderate fructose consumption in humans may not be bad, and in fact appears to potentially be beneficial, a fact that can't help but be amplified if the fructose is in the form of fiber- and micronutrient-rich fruit.


This failure to control for calorie intake, or even report body weight, wouldn't be so egregious if the authors hadn't used a rather athletic behavioral task to assess "brain health" - namely the Barnes Maze task. In this test, the rats are plunked down in the middle of a brightly lit table and are timed to see how long it takes them to scurry to find and escape through a previously-encountered hidden hole in the table to get out of the frightening light. Do you think obese rats might be a bit slower to solve the Barnes Maze than normal-weight rats, independent of their cognitive health & memory, simply because they are fatties? Yeah, me too...


To compound the anomaly, in the first part of the study that I just described, involving wild-type (non-mutant) rats, they report the time it took the rats to solves the Barnes Maze task. But later, when delving into the details of the gene expression changes using rats with genetic mutations, they use mistakes in the Barnes Maze task (i.e. the number of times the rats went to the wrong hole in the table) compared to WT controls, as the performance metric. Why not use a consistent Barnes Maze metric throughout their study? Sounds a bit like cherry picking to me - especially in combination with the fact that they don't report body weight and use the time-based metric for the rats that I'd predict to be obese.


The authors obliquely acknowledge this IMO pretty serious limitation of their study:


[T]he behavioral changes [i.e. maze running time, or mistakes made - DP] observed ... could be influenced by numerous variables that are either not investigated or difficult to tease out. 


Pretty suspicious if you ask me...


Now on to the DHA part of the study. When the researchers adding DHA to the diets of the fructose guzzling rats, it "pushed the entire gene pattern back to normal, which is remarkable" says the author, and reversed the slowdown in maze running induced by either fructose or simply weight gain.


I won't pretend to understand all the gene changes the authors claim to have observed as a result of fructose feeding, and which they say were reversed by adding DHA to the diet of the rats. Instead I'll point to some "fine print" in the study, not mentioned in the popular press coverage. In particularly, DHA composed 10% of the rat's diet by weight. Since fat has over twice as many calories per gram as standard rodent chow, that mean they were getting upwards of 20% of their calories from pure DHA.


That's the human DHA equivalent of about 20 servings of fatty fish per day, and twice as much as the dubious longevity study (PMID 26875793) that Michael used here to support his DHA-accelerated Aging Hypothesis and that I criticized (and Michael defended) in this and subsequent posts. I note that Michael never rebutted my claim that the rodents in his study were fed a "stupid high" (☺) amount of DHA, and the rats in this fructose/DHA study were getting twice as much.


So the important question of whether fructose in moderate amounts is worse for either metabolic health or gene expression than other forms of sugar for humans is left unaddressed by this study. Also left untouched is the question of whether reasonable intake of DHA can mitigate these alleged negative effects of fructose.


I'm not saying isolated fructose in large amounts isn't bad for your metabolism or your brain, and that it isn't worse than other sugars. Nor am I saying that DHA won't help avoid these downsides. I'm just saying this study provides little if any insight into these questions due to it's flawed design and the way the authors chose to report their results.


Overall a pretty disappointing study that seems to me to have garnered far more attention in the popular press than it deserves, given its shortcomings.





[1] EBioMedicine 2016  (in press)

Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders

Qingying Meng, Zhe Ying, Emily Noble, Yuqi Zhao, Rahul Agrawal, Andrew Mikhail, Yumei Zhuang, Ethika Tyagi, Qing Zhang, Jae-Hyung Lee, Marco Morselli, Luz Orozco, Weilong Guo, Tina M. Kilts, Jun Zhu, Bin Zhang, Matteo Pellegrini, Xinshu Xiao, Marian F. Young, Fernando Gomez-Pinillal, Xia Yang
Nutrition plays a significant role in the increasing prevalence of metabolic and brain disorders. Here we employ systems nutrigenomics to scrutinize the genomic bases of nutrient–host interaction underlying disease predisposition or therapeutic potential. We conducted transcriptome and epigenome sequencing of hypothalamus (metabolic control) and hippocampus (cognitive processing) from a rodent model of fructose consumption, and identified significant reprogramming of DNA methylation, transcript abundance, alternative splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signaling. These signals converged with genetic causal risks of metabolic, neurological, and psychiatric disorders revealed in humans. Gene network modeling uncovered the extracellular matrix genes Bgn and Fmod as main orchestrators of the effects of fructose, as validated using two knockout mouse models. We further demonstrate that an omega-3 fatty acid, DHA, reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders. Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine.
Systems nutrigenomics, Fructose, Omega-3 fatty acid, DHA, Epigenome, Transcriptome, Brain networks, Metabolic diseases, Brain disorders, Extracellular matrix
[2] J Am Diet Assoc. 2011 Feb;111(2):219-20; author reply 220-2. doi:
Is fructose a story of mice but not men?
Sievenpiper JL, de Souza RJ, Kendall CW, Jenkins DJ.
PMID: 21272692
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