Obesity and dementia

You may have heard it a few times already by now: obese people are more likely to develop dementia earlier than thin people. 

You could also hear Dr Lustig asking whether sugar causes dementia and seeing him presenting this slide in his lecture at 52:27:

He spent some time referring to the statements you can see on the left side of the slide. Let me just summarize these points: 

We have proven association between obesity and dementia in humans and animals but only for animals there was some data for causative relationship between the consumption of sugar and declined cognitive skills, which were not affected by the obesity of the animals. 

Since you have learned in the previous article, that sugar is not the main cause of obesity (it was fried potato products) and the sugar consumption has been declining over the past 14 years while the dementia cases continue to rise, can we still say that it can be predicted that sugar causes cognitive decline independently of the consumption of other fast food items and possibly other environmental factors? Remember that the consumption of fast-food continued to rise when the sugar consumption started to decline in 2000. You could also hear Dr Lustig saying that the western diet as whole has been associated with dementia in humans and that we do not know which aspect of it can be attributed to the dementia cases. 

It is also a fact that rodents, which the rats are, have much higher de-novo lipogenesis (DNL) capacity in their bodies than humans have. Could we hypothesize that this factor could have contributed to the decline of the cognitive function of rats while it would be less straightforward in humans if we managed to assess it a similar way? The scientists already made this mistake in the past when predicting the same DNL in humans after finding the extend of DNL in rodents. Now we know that in humans it is different. 

What is more, while it was obesity that was correlated with dementia in both animals and humans, regardless of whether it was sugar or fat as a proximate cause, can we hypothesize that obesity is an absolute cause of dementia? That point that it was sugar, not fat, which leads to the declined cognitive function in animals does not dismiss the link between obesity and dementia as such. Dr Lustig also said that the omega-3 fats produced increased cognitive function in rats. How about omega-6 which is prevalent in our diet? How about the fats, if consumed at high amounts, leading to obesity even without the sugar? It is enough to consume fats with processed carbohydrates such as white bread or the chips as such. 

For now, as Dr Lustig said it openly, we do not have the causative data for dementia in humans in relation to sugar or any other dietary component. We only know that omega-3 fatty acids help reduce the risk. And I would like to keep it at this point, instead of drawing suggestive conclusions, until we have the data.

What I remember though is that even brain can be insulin resistant. But can this be due to fructose content in our diet? Fructose concentrations in the blood appears at 10 - 1000 lower amounts than of glucose. People can become obese even at relatively low amount of refined sugar or HFCS, by simply overeating on processed foods, when muscles do not take much energy in and the increased glucose and insulin concentrations in blood can lead to inflammation of the cells sensitive to insulin and finally down-regulation of insulin receptors. I have heard about patients who improved their cognitive function by consuming coconut oil. A portion of this energy source is converted into ketone bodies by the liver and these serve as an alternative fuel for the insulin resistant brain. Interesting, is it not? 

Comparison of the findings between rats and humans when studying the metabolic effect of sugar and HFCS

I have watched a video which summarized the findings in examining the sugar addiction in rats. The presenter talked about how they conditioned the rats to binge on sugar. One slide, however, reported GLUCOSE consumption patterns at 13:25 minute of the video: 

So the principle of attractive sweetness of fructose, which Dr Lustig has repeatedly highlighted, could not be applied here. In fact, rodents such as mice and rats naturally crave starches or sugars such as grains and fruits they find in nature, not the cheese as the cartoons notoriously portray them. Scroll down to point 3 in this article to find out yourself. 

Further in the video you will see how both groups of rats: 1. having short availability of large amounts of sugar and 2. having sugar available over 24-hours have increased their sugar consumption, but the first group had overall much higher sugar intake than those in the second group. Bingeing rats therefore compensated for the periods of no sugar availability and consumed overall more sugar. Interesting to see. But this was not to contrast with humans, it was just an interesting input from the curiosity.

What I found appealing was the slide (22:24) and the presenter mentioned it as well, was that high-fructose corn syrup (HFCS) had different metabolic effect from sucrose. 

That it is different from glucose is obvious. But from sucrose? I wonder where they got this information when my research and also Dr Lustig consistently report that there is no significant difference between the absorption and metabolism of HFCS and sucrose. This was not discussed in the video.

The two possible explanations would be that some people do not have sucrase - an enzyme cleaving sucrose into free glucose and fructose, which the HFCS actually is and in these people/animals the sucrose is not absorbed. But this is unlikely the case here. More probable explanation is the different content of fructose in HFCS than is in sugar. Especially the beverages contain HFCS-55, which has 5% more fructose than sugar, but solid foods tend to contain HFCS-42, which has 8% LESS fructose than sugar. And as such, in the first case there might be less insulin produced than in the second case, due to the proportionally different content of glucose. But is it that much? Again, the experts have reached the consensus that there is no significant difference in metabolism between HFCS and sugar. 

Moreover, going back to another point of the slide above: HFCS releases triglycerides (like a fat), if you have read my previous articles about fructose metabolism, you now might be aware that fructose contributes only little to the formation of new fats. Most of the increased triglycerides in the blood stream were the re-esterified free fatty acids that were already present in the blood stream - as their concentration always decreased after fructose intake challenge. Did they measure the free fatty acids concentration in the rats, or were they only happy to see the triglycerides rise and make the conclusion above? This was not said and I do not see any legible details of the study itself to check these details. 

The further slide suggest possible addiction-like properties of HFCS, but you could see that the rats behaved the same when receiving sucrose or even glucose. 

These results correspond with the previous slide above - adverse metabolic effect of HFCS. But it also informs us about increased body weight after feeding rats with HFCS. The amount of HFCS was 8% supplementation of the standard chow diet: 

However, nothing was said whether these 8% of extra HFCS were within or on top of the balanced energy intake. By balanced energy intake I mean the amount of calories needed to maintain stable body weight. When doing my research the studies on humans also varied in this: some were in isocaloric settings, when fructose or sugar replaced some other calories, others were in hypercaloric setting, providing calories on top of the balanced state. Any wonder why people gained weight? 

But, to be on the neutral side, I should also refer to this: 

The slide and information presented by the speaker suggests that rats which were bingeing on sugar did not increase their body weight, because although they consumed more sugar than any other group of rats, they compensated for the excess energy intake by consuming less of their normal chow. 

HOWEVER: 

1. this latter case was the observation for only 27 days, not 6 months.

2. the whole study design is different between these two cases: the HFCS study was not binge eating, the rats had normal feeding pattern, just consumed probably excess 8% of calories in a form of HFCS. 

It is therefore not wise to compare these two studies as it was a single trial comparing the effect of sugar and HFCS in one. 

Moreover, from the following slide you can see that all rats gained weight, whether having ad libitum access to HFCS over 12 hours (top curve), bingeing on HFCS when having it available for only 12 hours (middle black curve),  and also when consuming a normal chow (bottom curve). Only the two former cases led to a higher weight gain and of these two the first led to even higher than the second one. But the same was reported for SUGAR, do you remember? Check again the third paragraph of this article above. 

What does that actually say? 

Note the title of this slide: it mentions 5 weeks, but the whole x-axis covers 24 weeks. That is fine, but when you look above the point of 5 weeks, the difference in gained weight between the three designs is not that big, is it?

From the physiology point of view: deprivation of favorite substance (HFCS or sugar) causes an individual to overeat on it when it is available, especially after a fasting period. And that is typical for humans and rats. That also means that higher bulk of this substance is consumed in a shorter period of time - leading to increased insulin level and enhanced fat storage. So not only more calories are consumed at once when bingeing, but the physiological response to the excess of glucose mediates fat storage via insulin. Moreover, the excessive amount of fructose leads to increased fat synthesis, especially in rodents which are more effective in de-novo lipogenesis than humans are, do you remember? So these results cannot be directly applied to humans. 

I would like to finally explain the difference between just supplementation of diet with HFCS and bingeing on a substance, separately from consuming the usual and rather boring rat chow. The Summary slide I posted here did not specify, how the HFCS was supplemented: whether it was in a sweetened drink or mixed with the chow. Since rats like sweet taste, if their chow was sweetened, they were likely to consume more of it and finally gain weight, especially if those 8% were on top of their energy needs. In contrast, having sugar to binge on and then consuming the chow which did not taste as appealing in comparison to sugar, might have been a factor in a self-limiting intake of calories, leading to a stable body weight over time in those rats. The Summary slide also did not inform us about bingeing, so the rats probably only had their diet spiked with 8% of HFCS. This amount of sugar would represent extra 200 kcal, if consumed on top of the energy needs in a person requiring 2500 kcal per day. Overeating 200 kcal on daily basis for 6 months would definitely lead to increased body weight and also perhaps altered biochemistry in the body. One tin of sugary soft drink contains about 150 kcal, just for the comparison. 

And the persisting discrepancy between the body weight on sugar and HFCS bingeing rats over 5 weeks? This would require a closer look into the actual designs of the studies. But maybe rats really have different absorption or metabolism of sucrose from HFCS than humans. It would be interesting to find out what was behind these different results. For now I can tell you, if you have not watched the video to the very end, Dr Lustig was in the audience and questioned this discrepancy as well. But the speedy answer of Ms Avene, the presenter, did not sound convincing to me and I can only guess that Dr Lustig was not completely happy with her reasoning either.