Thursday, May 27, 2021

Random musings on uncoupling (1)

I thought I'd just take a break from trying to find any studies where sucrose-in-chow causes obesity in the absence of greater than 8% of calories as linoleic acid. That's becoming rather frustrating but is turning up some interesting studies on uncoupling and PUFA along the way.

So just for this post I thought I'd get even more speculative than normal about uncoupling.

Thermogenesis. Thermogenesis makes you hungry. That is not a completely intuitive statement.

It's easiest if we start with a food source which generates heat without utilising uncoupling because there are far less variables to think about. So think protein. Deconstructing a protein chain, processing amino acids to their core constituent energetic compounds such as pyruvate, glutamate etc requires energy and this energy shows up as heat.

Let's say 1000kcal of protein generates 300kcal of heat. I've no idea of (or interest in) the exact value, I just know you can warm a hypothermic patient post operatively using an IV amino acid infusion.

So if you are used to eating 2000kcal of fat a day to run your metabolism, you metabolism requires 2000kcal, tightly controlled. Let's also imagine you live in a thermoneutral environment and so are not muddying the water with (usually necessary) thermogenesis to maintain your body temperature.

If you swap your 2000kcal of fat for 1000kcal of fat plus 1000kcal of protein things change. The 1000kcal of protein provides 700kcal of usable energy and 300kcal of waste heat, which you don't need as you are in a thermoneutral environment.

So you get hot and uncomfortable and have a 300kcal deficit. You cannot run your metabolism of 1700kcal, you need 2000kcal. The hypothalamus notices this 300kcal deficit. What would you do? You would feel hungry and eat enough extra food to ensure that you actually get the 2000kcal you need for metabolism, tolerating the excess heat generation as an unwanted side effect. You would stay weight stable, eat a little extra to hunger and be sweaty.

Forced overfeeding is equally straightforward. You eat too much, uncouple, lose heat and hope you don't really live in a theroneutral environment.

Next is what happens under spontaneous eating but including more than 8% of calories as linoleic acid in your diet.

Here my hypothesis is that excess calories are available, the cell fills up and poorly-opposed insulin allows more calories to enter and for those calories to be sequestered out of the way as lipid (and probably glycogen too). From the cellular point of view energy status is fine (not overloaded) so long as the excess calories entering are being sequestered away from metabolism. The hypothalamus might perceive too few calories in the arterial blood in direct proportion to those being lost into storage in the periphery. So you eat more.

The next step in thinking is 2,4-dinotrophenol. This is a classical uncoupler and probably the most effective weight loss drug, particularly for fat loss, ever marketed. Sadly the therapeutic margin is narrow, unpredictable and can change suddenly.

High dose rate, rapid weigh loss DNP administration uncouples respiration to the point of ATP reduction and massive heat generation. AMPK is activated by the consequences of the fall in ATP, ensuring effective fat oxidation. With a marked fall in mitochondrial membrane potential there is going to be a cessation of reverse electron transport and the mitochondrial component of the ROS generation essential to maintain insulin signalling will collapse. At this point calories will be entering the cell through AMPK facilitated GLUT4s (and probably CD36s as well) and will not be diverted to storage but used for a combination of running metabolism plus extra calories equal to those lost as heat.

I understand from reading around a little that DNP does, indeed, make you hungry. The calories pouring though the mitochondria are coming from fat primarily and if the fat supply cannot keep up with the uncoupling-augmented metabolic needs then blood energy content will fall and the hypothalamus will notice. Also interesting is the use of drugs such as caffeine and ephedrine to control that hunger, both of which are reputed to work. They increase basal and sympathomimetic induced lipolysis, supply more fat and so control the hunger. So the loss of fat from adipocytes due to failed insulin signalling cannot quite keep up with the increased metabolic heat production without a little help. Not surprising because the shrinkage of adipocytes is from a failure of insulin signalling to facilitate fatty acid uptake combined with unopposed basal/sympathetic lipolysis. Neither is directly related to the huge loss of calories from unrestrained uncoupling. It surprises me a little that the supply and demand are so closely matched in such a complex system, especially with a major spanner dropped in to the works.

Which just leaves us with PUFA. These appear to facilitate uncoupling in proportion to the amount present in the diet, even on a meal by meal basis. My mental image for this phenomenon is that, intrinsically, PUFA allow too many calories in to a cell if insulin is the facilitating hormone. The more pronounced this effect, the more the need for uncoupling.

Modest excess, say over 8% of the diet by calories, works by the standard ROS/Protons concept of sequestration of excess calories. But you can only sequester so many excess calories and very high percentages of PUFA have the potential to overwhelm the system. We are talking 35% or over for uncoupling to predominate, but I think this might be a linear effect which is over-shaddowed by the ROS effect at lower concentrations but comes to dominate at very high concentrations.

At these very high levels of uncoupling the body is in caloric deficit because it is actually losing the calories as heat. It is metabolically the equivalent of the hunger of a high fat (10-30% PUFA) diet but does not involve the distention of adipocytes to achieve it. The degree of hunger would be in proportion to the deficit between lipolysis and heat loss via uncoupling and would require (not allow) a few extra calories to be eaten.

EDIT: This last section is poor logic. It might be worth a post to clarify or just a an edit to correct. I'm thinking about it.  I'll take it out and put a more considered discussion up as a follow on post. END EDIT.



cavenewt said...

"It's also worth pointing out that this appears to be an ancient system and that high PUFA exposure might uncouple in anticipation of the cellular caloric influx which PUFA signify."

I'm struggling to stay afloat here, so may not be understanding this completely. Does that statement imply that the system evolved to deal with high levels of PUFA? (Even if nowhere near the levels seen today, of course.) If so, what might have been the source of that PUFA? I realize that there's varying amounts in all fat, more so in birds. But in levels approaching pathological?

Peter said...

Hmmm, wooliest part of the post. Trying to make PUFA uncoupling physiological!

It's easy to see how ROS derived products of PUFA could be co-opted as a signal to uncouple as they would easily be a surrogate for excess ROS generation. That makes PUFA very important as the transmitter of a signal of excess calories. For humans a scarce but undoubtedly available molecule looks to have been selected as the marker of excess ROS and also as the best mechanism for relieving that problem. All at low levels of PUFA, physiologically.

So uncoupling induced by supra physiological levels of PUFA might simply be activating a system, designed to work with low levels of PUFA, to a pathologically excessive degree.

After all, unless you need to generate heat, uncoupling is extremely wasteful. If food is plentiful you should make more babies, not more heat!

Which means that high dose linoleic acid might be as physiological as low dose 2,4,-dinitrophenol. The overall effects might be labeled as good in the modern situation but that might not be ideal on an evolutionary basis

Does that make more sense? If so I'll edit it in to the post.

Thanks for the input


The Carcass Hoarder said...

So, if I understand this correctly, high PUFA intake (>8%) could theoretically indicate to the body excess caloric intake (since PUFA are not easily found in high concentrations in nature) and so more uncoupling occurs, more white-to-beige fat, more heat loss as a method to rid oneself of the excess. What of high seafood diets of certain populations? Would they go regularly go over the 8% threshold in natural environmental conditions and suffer for it? Would relying heavily on wild seafood indicate excess calories and potentially require (from hypothalamic signaling) higher caloric consumption due to unnecessary heat loss? This would also be evolutionarily strange, but maybe? Or would one adapt and become PUFA-to-thermogenesis “resistant”?

Peter said...

I think that I got that section wrong. High PUFA will force excess calories in to cells, which will be perceived by the entire organism as a caloric deficit. Individual cells might need to uncouple at very high levels of PUFA by this a) is not physiology and b) would not trigger driven hypothalamic whole body uncoupling. It has to be more of a local system driven to an extreme by an abnormal dietary supply. That local effect can then be both over activated and shifted to specialised tissues such as BAT.


LA_Bob said...

Referencing Carcass Hoarder (whose carcass is he hoarding, by the way), I thought PUFA from seafood was omega 3 and very long chain and converted to a saturated fat in peroxisomes.

My impression of the ginger paradox thread was that it read like kind of whodunnit with a plot twist at the end, and that was the uncoupling effect of large amounts of omega 6 linoleic acid. I remember thinking, how interesting. The body applies an adaptation to a problem it never sees in nature.

So, referencing cavenewt, is this a phenomenon that would only ever occur in a lab experiment or among crazy people who drink corn oil like it's beer?

Or am I misunderstanding all of this? If so, I'll just go sit in the corner.

cavenewt said...


"The body applies an adaptation to a problem it never sees in nature. "

I think that's kind of what I was getting at; in other words, is there any non-industrial way to get too much LA? Peter's post made it sound like the body can deal with a certain amount of industrial LA, which may be a lucky accident, but of course too much will overwhelm the system.

I guess I need to find the ginger paradox thread and read it again because it sounds interesting!

p.s. I also hoard carcasses, in my freezer.

karl said...

I think that because high levels of LA produces inflammatory signals that LA either never was a huge source of calories before or so long ago in evolution that huge consumption effects are not part of the system?

Good thing we know all the reactions that happen - except we don't - we should be humble.

I wonder if there is some unknown messenger that does the same thing as DNP? How does the body respond if core temperature goes down(or up) as in what hormones are produced - anything at the cellular level happen with cold? What receptors are in BAT(brown fat)?

I know (From somewhere?) that long exposure to cold leads to an increase in T3 and T4 levels in the blood. This can happen without an increase in TSH - why and how? Would that make TSH go down? Could the change in production of TSH adjust other signals at the same time?

I once thought I could go down the thyroid rabbit hole and figure out how everything works - what I found is everything effects everything - directly or indirectly. It was after this that I started doubting quite a bit of settled dogma - it became obvious that our ignorance is under estimated.

There is work that says that mitochondria numbers are controlled by thyroid - but I think it is more complex - ROS - other hormones - available calorie inputs..

Just because there is a receptor that has an effect - does not mean it is 'THE' control. There are also receptors for sex steroids and glucocorticoids in the mitochondria.

So it takes a lot more to really understand - is the effect linear or exponential or dependent on 5 or 6 other signals? Do the signals add, multiply or have an exponent effect?

So I expect that we will learn of these things and often go down false roads and only when we get good enough AI (not the code that 'looks like AI', but the real thing that can design ever better AI) will we be able to figure out what is going on. Something like a mitochondria simulator - where we might be able to input different hormones and messengers and run a program that would test every permutation and eventually have a working model of these controls - not that the end result would be humanly understandable - but our AI might be able to tell us what best to eat - at least if the AI doesn't have its own agenda.


So if ginger drives biogenesis of mitochondria, is that a good thing? or might it have unintended consequences?

Similar thoughts about turmeric - which seems to help with arthritis without burning a hole in the digestive track - but at what cost?

Eating concentrated seed oil is a long way from likely diets when we lived in tribes - with regular near starvation times - extreme cold exposure for those that migrated north - no one selling addictive food products at the local store..

But re long-chain O-3 - I think there might be an anti inflammatory effect - at least I think so this week - I've changed my mind on fish oil 5 or 6 times now. Next week could be different. If we are 'sea-side' apes, could be part of what evolved our brains? How can we know for sure if LC-O-3s are good or bad for us?

Of course we might be regressing back to tribalism - everyone is being put in groups - what is 'true' is defined by group membership - not logical reasoned debate. What was obvious to me a year ago - the origins story - is only now becoming mainstream.

It is so strange to see actual government programs implemented that are designed to increase tribal/group identity. This is not the world I grew up in.

I could be quite wrong, but I'm even thinking the recent UFO stories are likely part of another psych-opp - imagine telling the public some advise comes from advanced life forms that have evolved way beyond our science - so put on your masks. All science is settled - the fact checkers are advanced aliens...

karl said...

After I posted - I found this that contradicted what I 'knew' about cold and thyroid hormones.

cavenewt said...

karl, I'm always very interested in discussions about temperature control, having experienced hot flashes for 15 years now. AFAIK they still don't know the cause/mechanism. I had a hot flash while getting a haircut one day, and the technician commented on the waves of heat radiating off my head. It's definitely a real thing.

As for modern science's lack of humility, absolutely. I view biology as a hideously complex, intricately interconnected network of feedback loops. And yet modern medicine has no compunction about throwing monkey wrenches (aka pharmaceuticals) in random portions of the machinery. Hubris, hubris everywhere.

Passthecream said...
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