Fructose bad effects reversed by DHA, an omega-3 fatty acid

Despite alarm signals raised by various groups and organizations regarding the dangers of the presence of sugars – particularly fructose derived from corn syrup – in almost every food in the markets, only in the past decade there has been some serious evidence against high consumption of fructose.

A bitter-sweet (sic!) paper comes from Meng et al. (2016) who, in addition to showing some bad things that fructose does to brain and body, it also shows some rescue from its deleterious effects by DHA (docosahexaenoic acid), an omega-3 fatty acid.

The authors had 3 groups of rodents: one group got fructose in their water for 6 weeks, another group got fructose and DHA, and another group got their normal chow. The amount of fructose was calculated to be ecologically valid, meaning that they fed the animals the equivalent of 1 litre soda bottle per day (130 g of sugar for a 60 Kg human).

The rats that got fructose had worse learning and memory performance at a maze test compared to the other two groups.

The rats that got fructose had altered gene expression in two brain areas: hypothalamus (involved in metabolism) and hippocampus (involved in learning and memory) compared to the other two groups.

The rats that got fructose had bad metabolic changes that are precursors for Type 2 diabetes, obesity and other metabolic disorders (high blood glucose, triglycerides, insulin, and insulin resistance index) compared to the other two groups.

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The genetic analyses that the researchers did (sequencing the RNA and analyzing the DNA methylation) revealed a whole slew of the genes that had been affected by the fructose treatment. So, they did some computer work that involved Bayesian modeling  and gene library searching and they selected two genes (Bgn and Fmod) out of almost a thousand possible candidates who seemed to be the drivers of these changes. Then, they engineered mice that lacked these genes. The resultant mice had the same metabolic changes as the rats that got fructose, but… their learning and memory was even better than that of the normals? I must have missed something here. EDIT: Well… yes and no. Please read the comment below from the Principal Investigator of the study.

It is an ok paper, done by the collaboration of 7 laboratories from 3 countries. But there are a few things that bother me, as a neuroscientist, about it. First is the behavior of the genetic knock-outs. Do they really learn faster? The behavioral results are not addressed in the discussion. Granted, a genetic knockout deletes that gene everywhere in the brain and in the body, whereas the genetic alterations induced by fructose are almost certainly location-specific.

Which brings me to the second bother: nowhere in the paper (including the supplemental materials, yeas, I went through those) are any brain pictures or diagrams or anything that can tell us which nuclei of the hypothalamus the samples came from. Hypothalamus is a relatively small structure with drastically different functional nuclei very close to one another. For example, the medial preoptic nucleus that deals with sexual hormones is just above the suprachiasmatic nucleus that deals with circadian rhythms and near the preoptic is the anterior nucleus that deals mainly with thermoregulation. The nuclei that deal with hunger and satiety (the lateral and the ventromedial nucleus, respectively) are located in different parts of the hypothalamus. In short, it would matter very much where they got their samples from because the transcriptome and methylome would differ substantially from nucleus to nucleus. Hippocampus is not so complicated as that, but it also has areas with specialized functions. So maybe they messed up the identification of the two genes Bgn and Fmod as drivers of the changes; after all, they found almost 1 000 genes altered by fructose. And that mess-up might have been derived by their blind hypothalamic and hippocampal sampling. EDIT: They didn’t mess up,  per se. Turns out there were technical difficulties of extracting enough nucleic acids from specific parts of hypothalamus for analyses. I told you them nuclei are small…

Anyway, the good news comes from the first experiment, where DHA reverses the bad effects of fructose. Yeay! As a side note, the fructose from corn syrup is metabolized differently than the fructose from fruits. So you are far better off consuming the equivalent amount on fructose from a litre of soda in fruits. And DHA comes either manufactured from algae or extracted from cold-water oceanic fish oils (but not farmed fish, apparently).

If anybody that read the paper has some info that can help clarify my “bothers”, please do so in the Comment section below. The other media outlets covering this paper do not mention anything about the knockouts. Thanks! EDIT: The last author of the paper, Dr. Yang, was very kind and clarified a bit of my “bothers” in the Comments section. Thanks again!

Reference: Meng Q, Ying Z, Noble E, Zhao Y, Agrawal R, Mikhail A, Zhuang Y, Tyagi E, Zhang Q, Lee J-H, Morselli M, Orozco L, Guo W, Kilts TM, Zhu J, Zhang B, Pellegrini M, Xiao X, Young MF, Gomez-Pinilla F, Yang X (2016). Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders. EBioMedicine, doi: 10.1016/j.ebiom.2016.04.008. Article | FREE fulltext PDF | Supplementals | Science Daily cover | NeuroscienceNews cover

By Neuronicus, 24 April 2016

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Eating high-fat dairy may lower your risk of being overweight

84 - CopyMany people buy low-fat dairy, like 2% milk, in the hopes that ingesting less fat means that they will be less fattier.

Contrary to this popular belief, a new study found that consumption of high-fat dairy lowers the risk of weight gain by 8% in middle-aged and elderly women.

Rautiainen et al. (2016) studied 18 438 women over 45 years old who did not have cancer, diabetes or cardiovascular diseases. They collected data on the women’s weight, eating habits, smoking, alcohol use, physical activity, medical history, hormone use, and vitamin intake for  8 to 17 years. “Total dairy product intake was calculated by summing intake of low-fat dairy products (skim and low-fat milk, sherbet, yogurt, and cottage and ricotta cheeses) and high-fat dairy products (whole milk, cream, sour cream, ice cream, cream cheese, other cheese, and butter)” (p. 980).

At the beginning of the study, all women included in the analyses were normal weight.

Over the course of the study, all women gained some weight, probably as a result of normal aging.

Women who ate more dairy gained less weight than women who didn’t. This finding is due to the high-fat dairy intake; in other words, women who ate high-fat dairy gained less weight compared to the women who consumed low-fat dairy. Skimmed milk seemed to be the worst for weight gain compared to low-fat yogurt.

I did not notice any speculation as to why this may be the case, so I’ll offer one: maybe the people who eat high-fat dairy get more calories from the same amount of food so maybe they eat less overall.

Reference: Rautiainen S, Wang L, Lee IM, Manson JE, Buring JE, & Sesso HD (Apr 2016, Epub 24 Feb 2016). Dairy consumption in association with weight change and risk of becoming overweight or obese in middle-aged and older women: a prospective cohort study. The American Journal of Clinical Nutrition, 103(4): 979-988. doi: 10.3945/ajcn.115.118406. Article | FREE FULLTEXT PDF | SuppData

By Neuronicus, 7 April 2016

Now, isn’t that sweet?

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When I opened one of my social media pages today, I saw a message from a friend of mine which was urging people to not believe everything they read, particularly when it comes to issues like safety and health. Instead, one should go directly at the original research articles on a particular issue. In case the reader is not familiar with the scientific jargon, the message was accompanied by one of the many very useful links to blogs that teach a non-scientist how to cleverly read a scientific paper without any specific science training.

Needless to say, I had to spread the message, as I believe in it wholeheartedly. All good and well, but what happens when you encounter two research papers with drastically opposite views on the same topic? What do you do then? Who do you believe?

So I thought pertinent to tell you my short experience with one of these issues and see if we can find a way out of this conundrum. A few days ago, the British Chancellor of the Exchequer (the rough equivalent of a Secretary of the Treasury or Minister of Finance in other countries) announced the introduction of a new tax on sugary drinks: the more sugar a company puts in its drinks, the more taxes it would pay. In his speech announcing the law, Mr. George Osborne was saying that the reason for this law is that there is a positive association between sugar consumption and obesity, meaning the more sugar you eat, the fatter you get. Naturally, he did not cite any studies (he would be a really odd politician if he did so).

Therefore, I started looking for these studies. As a scientist, but not a specialist in nutrition, the first thing I did was searching for reviews on the association between sugar consumption and obesity on peer-reviewed databases (like the Nature journals, the US NIH Library of Medicine, and the Stanford Search Engine). My next step would have been skimming a handful of reviews and then look at their references and select some dozens or so of research papers and read those. But I didn’t get that far and here is why.

At first glance (that is, skimming about a hundred abstracts or so), it seems there are overwhelmingly more papers out there that say there is a positive correlation between sugar intake and obesity in both children and adults. But, when looking at reviews, there are plenty of reviews on both sides of the issue! Usually, the reviews tend to reflect the compounded data, that’s what they are for and that’s why is a good idea to start with a review on a subject, if one knows nothing about it. So this dissociation between research data and reviews seemed suspicious. Among the reviews in question, the ones that seemed more systematic than others are this one and this one, with obvious opposite conclusions.

And then, instead of going for the original research and leave the reviews alone, I did something I am trying like hell not to do: I looked the authors and their affiliations up. Those who follow my blog might have noticed that very rarely do I mention where the research has taken place and, except in the Reference section, I almost never mention the name of the journal where the research was published in the main body of the text. And I do this quite intentionally as I am trying – and urge the readers to do the same thing – to not judge the book by the cover. That is, not forming a priori expectations based on the fame/prestige (or lack thereof) of the institution or journal in which the research was conducted and published, respectively. Judge the work by its value, not by its authors; and this paid off many times during my career, as I have seen crappy-crappity-crap papers published in Nature or Science, bloopers of cosmic proportions coming from NASA (see arsenic-DNA incorporation), or really big names screwing up big time. On the other hand, I have seen some quite interesting work, admittedly rare, done in Thailand, Morocco or other countries not known for their expensive research facilities.

But even in research the old dictum “follow the money” is, unfortunately, valid. Because a quick search showed that most of the nay-sayers (i.e. sugar does not cause weight gain) were 1) from USA and 2) had been funded by the food and beverage industry. Luckily for everybody, enter the scene: Canada. Leave it for the Canadians to set things straight. In other words, a true rara avis poked its head amidst this controversy: a meta-review. Lo and behold – a review of reviews! Massougbodji et al. (2014) found all sorts of things, from the lack of consensus on the strength of the evidence on causality to the quality of these reviews. But the one finding that was interesting to me was:

“reviews funded by the industry were less likely to conclude that there was a strong association between sugar-sweetened beverages consumption and obesity/weight gain” (p. 1103).

In conclusion, I would add a morsel of advice to my friend’s message: in addition to looking up the original research on a topic, also look where the money funding that research is coming from. Money with no strings attached usually comes only from governments. Usually is the word, there may be exceptions, I am sure I am not well-versed in the behind-the-scenes money politics. But if you see Marlboro paying for “research” that says smoking is not causing lung cancer or the American Beverage Association funding studies to establish daily intake limits for high-fructose corn syrup, for sure you should cock an eyebrow before reading further.

Reference: Massougbodji J, Le Bodo Y, Fratu R, & De Wals P (2014). Reviews examining sugar-sweetened beverages and body weight: correlates of their quality and conclusions. The American Journal of Clinical Nutrition, 99:1096–1104. doi: 10.3945/ajcn.113.063776. Article | FREE PDF

By Neuronicus, 20 March 2016

Fat and afraid or slim and courageous (Leptin and anxiety in ventral tegmental area)

A comparison of a mouse unable to produce leptin thus resulting in obesity (left) and a normal mouse (right). Courtesy of Wikipedia. License: PD
A comparison of a mouse unable to produce leptin thus resulting in obesity (left) and a normal mouse (right). Courtesy of Wikipedia. License: PD

Leptin is a small molecule produced mostly by the adipose tissue, whose absence is the cause of morbid obesity in the genetically engineered ob/ob mice. Here is a paper that gives us another reason to love this hormone.

Liu, Guo, & Lu (2015) build upon their previous work of investigating the leptin action(s) in the ventral tegmental area of the brain (VTA), a region that houses dopamine neurons and widely implicated in pleasure and drug addiction (among other things). They did a series of very straightforward experiments in which the either infused leptin directly into the mouse VTA or deleted the leptin receptors in this region (by using a virus in genetically engineered mice). Then they tested the mice on three different anxiety tests.

The results: leptin decreases anxiety; absence of leptin receptors increases anxiety. Simple and to the point. And also makes sense, give that leptin receptors are mostly located on the VTA neurons that project to the central amygdala, a region involved in fear and anxiety (curiously, the authors cite the amygdala papers, but do no comment on the leptin-VTA-dopamine-amygdala connection). For the specialists, I would say that they are a little liberal with their VTA hit assessment (they are mostly targeting the posterior VTA) and their GFP (green fluorescent protein) is sparsely expressed.

Reference: Liu J, Guo M, & Lu XY (Epub ahead of print 5 Oct 2015). Leptin/LepRb in the Ventral Tegmental Area Mediates Anxiety-Related Behaviors. International Journal of Neuropsychopharmacology, 1–11. doi:10.1093/ijnp/pyv115. Article | FREE PDF

By Neuronicus, 28 October 2015