Monday, September 28, 2020

Fat and Weight Gain (a Note to Peter) and the Essentiality of Linoleic Acid

 Peter has been looking at the effects of various n-3 PUFAs on metabolism and weight gain.

"Protons (64) The miracle of fish oil (6)"

I came across this fascinating snippet while looking at an entirely different topic (serendipity seems to always arrive to distract one):

"The small emaciated animals on the fat-free diet consume as much food daily as their larger, fat-containing controls (Table IV), yet this food is burned and none is used in growth and fat synthesis. On the addition of the unsaturated fatty acids, growth is resumed and a normal amount of subcutaneous and visceral fat is found in the cured animal at autopsy. Therefore, fat synthesis is dependent upon the presence in the tissues or blood stream of a certain minimum quantity of the essential fatty acids. What percentage of the growth observed is due to storage of fat and what percentage is due to increase in other compounds (protein and carbohydrate) is not yet known."

From 1930: "On the Nature and Rôle of the Fatty Acids Essential in Nutrition", the paper which determined that linoleic acid (LA) is "essential"*.

One wonders exactly what is going on in the mitochondria of these poor little fat-starved animals. I suspect Peter will ponder that topic more effectively than I can.

P.S. Indeed. Follow-up to "Fat and Weight Gain (a Note to Peter) and the Essentiality of Linoleic Acid"

This paper finds that LA is not essential, at least in mice maintained over 10 generations:

2019: "A Diet With Docosahexaenoic [DHA] and Arachidonic Acids [ARA or AA] as the Sole Source of Polyunsaturated Fatty Acids Is Sufficient to Support Visual, Cognitive, Motor, and Social Development in Mice"

"Previous studies have shown that DHA and ARA, the downstream metabolites of ALA and LA, are sufficient to support growth and reproduction in mice (Strijbosch et al., 2008; Le et al., 2009; Nehra et al., 2012; Harauma et al., 2017). To our knowledge, this is the first study demonstrating that mice treated over 10 generations with a 20:1 ratio of DHA/ARA as the sole source of polyunsaturated fatty acids demonstrate equivalent visual, motor, cognitive, and social performance when compared to chow-fed controls. This work further supports the recent findings of Harauma et al. (2017), who proved that DHA and ARA are sufficient to allow the proper development of brain structure and function in delta-6-desaturase knockout mice. Altogether, these findings question the notion of the true essentiality of ALA and LA for cognitive development and growth."
So it took 90 years for "Science" to rebut the claim that linoleic acid is essential, a claim that has led to an incalculable mischief in terms of dietary advice and disease prevalence, IMHO.

How many decades will it take for your physician to read this paper and change practice?

I suggest you won't live long enough, and neither will the physician.

tldr: The answer is "Yes".

P.S. This was spurred from the following sentence:
"Alpha-linolenic acid and linoleic acid have long been considered essential fatty acids, and recent studies have demonstrated that their downstream polyunsaturated fatty acid derivatives, arachidonic acid and docosahexaenoic acid, can alone support healthy development in mice69,70."

Footnote 69 is the 1930 paper above, and 70 is the 2019 paper.
* "Essential" is a term of art in nutritional science, meaning it is required for life and must be consumed in the diet.

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Thursday, September 10, 2020

Comment on "Protons (60) 4-hydroxy-2-nonenal [HNE]"

A key post, and I think my comment is important enough to reproduce here.

Nice post. I have nothing to add to my comment on your previous discussion of Speijer's "Q" paper (replying to @Kenneth Strain), where I noted Speijer's observation:
"Here, palmitate (saturated C-16) and an oxidized (!) FA (4-hydroxy-2-nonenal) enhanced UCP proton transport."
I commented:
"4-hydroxy-2-nonenal is 4-HNE, and so the breakdown of TLCL is a fundamental part of mitochrondial function and regulation.

"The problem occurs, based on my reading, when TLCL overwhelms the regulatory/reactive systems. One sees this is occurring when glutathione (GSH) is diminished, and HNE is escaping the mitochondria unbound to GSH to wreak havoc on surrounding structures, like DNA. The presence of HNE bound to various other things is a marker for every part of the MetS, broadly defined, which includes cardiovascular disease and Alzheimer's. It's everywhere, along with the other N-6 peroxides."
I don't have anything to add to that, as I think it's spot on, even after three years of learning.

It's why my post (in response to Peter and Dr. Eades's discussions) explaining the fundamental problem in these processes contains the word "EXCESS":

Peter observes above:
"So UCPs in general appear to respond to an inappropriately high level of ROS generation by activating the safety valve of uncoupling the mitochondrial membrane potential. Linoleic acid derived 4-HNE is key to this process."
And yes, you can certainly figure out ways to tweak the inputs to alter the outputs. But these are generally non-physiological tweaks, and are not without their own hazards. So you can use "F3666 high PUFA ketogenic rodent food", but you will still kill the liver, as I noted in this post:

Where a high PUFA diet produces a better outcome, in some respects: 
"tl;dr: A diet high in omega-6 and omega-3 polyunsaturated fatty acids has some positive effects on the body: lower weight gain, better preservation of lean mass..."
But, as with Maratos-Flier's keto mouse experiments, it still kills the liver via steatosis, even when weight gain is not part of the outcome.

As Peter also notes, excess n-6 is not something you want. HNE does loads of other fun things, too, as it damages ~24% of the proteins in the cell. Just check out what it does to ATP!
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