Palmitic Acid (palmitate) Strongly Increases Oxidative Metabolism

[haidut]

@haidut

What is going on with the increase in Glutamine intake and the preference for oxidation of that substrate over glucose?

From the study;

"The H4IIEC3 rat hepatoma cell line (American Type Culture Collection, Manassas, VA, USA) was cultured in low glucose DMEM* supplemented with 10% FBS and 1% penicillin/streptomycin antibiotic solution. The glutamine concentration of the culture medium was 2 mmol/L. For fluorescence-based assays, cells were seeded in 96-well plates at 2× 104 cells per well two days prior to experiments to achieve 80%–90% confluency at the time of measurement"

*my note* According to what I see listed by manufacturers online this medium contains 1g/L Glucose. So (1g C6H12O6/180.16g {MM of glucose} = 5.55e-3 moles glucose * 1000 = 5.55 mmol of glucose per L). There is a greater concentration of glucose than glutamine, so the preference for glutamine uptake isn't because there is more glutamine available

"
To further investigate the fuel source driving palmitate-induced mitochondrial activation, we relied on 13C MFA to map the flow of carbon entering the CAC from the major non-lipid substrates glucose and glutamine. We found that glutamine provided the primary fuel for elevated mitochondrial metabolism in the presence of palmitate, rather than fatty acid beta-oxidation, and that glutamine consumption could be reduced through co-treatment with
phenformin but not NAC. These "Cells treated with PA, however, were characterized by a negative net glycolytic rate since glutamine entry to the CAC was elevated relative to glucose."

"Detailed flux mapping with [U-13C5]glutamine revealed that palmitate treatment strongly increased CAC fluxes relative to glycolytic fluxes in H4IIEC3 cells. Changes in intracellular metabolic fluxes coincided with the onset of ROS accumulation and preceded the appearance of apoptotic markers such as caspase 3/7 activation and DNA laddering."

"These studies revealed that palmitate increased oxygen consumption and CAC fluxes independently of fatty acid beta-oxidation. Glutamine, rather than lipid, was the preferred substrate used to fuel palmitate-induced increases in mitochondrial metabolism."



In the past you've posted about the negative effects of glutamine uptake and use as a fuel;

"Some key points from the article that support Ray's views are that cancer cells rely on fermentation and especially glutamine. I think Ray wrote in one of his articles or books, that of all the amino acids tryptophan and glutamine are the most dangerous when taken separately or in high quantities. They are the most growth-promoting aminos for cancer cells." - Haidut, Cancer May Finally Start Getting Treated As Metabolic Issue

Ray has discussed the issue also on his site;

Cancer cells show all the signs of being intensely stimulated, and this includes a high
rate of oxygen consumption (deGroof, et al., 2009). The stimulation increases the
energy requirements beyond the ability of the mitochondria's capacity to meet them,
leading to the production of lactate even when a normal amount of oxygen is present.
Even when both glucose and oxygen are supplied (which they usually aren't), the tumor
cells will consume amino acids as fuel, as well as using them as material for growth.
Tumors have been called "nitrogen traps" or "glutamine traps," but this has meaning
beyond the use of the nitrogen for growth; it is involved in the energetic inefficiency of
this process, and the reorganizing effects this wasteful flow of energy has on the tissue
structure (Medina, 2001). When glutamine enters the Krebs cycle to be used as fuel,
this interferes with the ability to oxidize glucose, causing more lactic acid to be formed,
contributing to the excitation and increased energy requirement
- Ray Peat, Cancer: Disorder and Energy

Is it a good idea to increase cancer cells use of Glutamine?

That is a good point, but the palmitic acid incuded apopotosis in the hepatoma cells, not growth. So, despite this increase in glutamine consumption the overall effects were not negative. Cancer cells show deficiency of ROS production and palmitic acid strongly increased ROS. The amino acid NAC acted opposite to palmitate and cancer cells have a great appetite for antioxidants like NAC.

 

[haidut]

@haidut How does methyl palmitate and other methyl esters of saturated fatty acids that are "resistant to metabolism and conversion into energy" compare if the fuel source driving palmitate-induced mitochondrial activation is glutamine in the study. Sounds like a contradiction. What is the difference between palmitate and methyl palmitate? @Meatbag brings up a good question.

As I mentioned in the response to meatbag, the glutamine metabolism increase is worrying but palmitic acid still acted as an oxidant and induced apoptosis, which was reversed by NAC.

 

[Jon]

I don't think I've ever encountered someone with insulin resistance and obesity who wasn't ingesting a whole spectrum of fatty acids, way more than 20% of total caloric intake. Is it really of consequence that SFAs are more insulin desensitizing than UFAs when we are ingesting <10% total caloric intake?

It might make sense that SFA's are more inclined to create insulin resistance EARLIER than their unsaturated counterparts as a protective measure by the body. From what I understand (which is grossly over simplified) SFA's are easily omitted from entering a cell in instances of surplus due to them inducing enzymatic downregulation along the electron transport chain when excessive amounts of both glucose and SFA's are being metabolized. This is a protective measure to save mitochondria from being flooded with energy and subsequently killed. Unsaturated fats are basically metabolized quicker and are able to "skip" certain portions the ETC which would have otherwise signaled to downregulate the enzymes that admit ffa to access the mitochondria. This in turn will make cells temporarily more insulin sensitive but eventually lead to apoptosis and a more permanent form of insulin resistance via peroxidation destroying a cells ability of insulin reception. Basically cells can say no to saturated fat but can't to unsaturated.

 

[Elephanto]

@haidut

What do you think of palmitic acid triggering TLR 4 ?
Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β. - PubMed - NCBI

Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2

Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-κB pathway in adipocytes links nutritional signalling with innate immunity

Linoleic acid actually inhibits TLR4 while Stearic Acid triggers it
Linoleic acid and stearic acid elicit opposite effects on AgRP expression and secretion via TLR4-dependent signaling pathways in immortalized hypot... - PubMed - NCBI

It seems to me as one goes on a quest to find the perfect fatty acid, the inevitable conclusion is that a low fat intake has benefits independently of its composition. As for its composition : predominantly saturated (mct, palmitic, stearic) and pufa-free. Olive Leaf can replace Olive Oil for its oleuropein if truly no amount of Oleic Acid is safe.

 

[Jon]

@haidut

What do you think of palmitic acid triggering TLR 4 ?
Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β. - PubMed - NCBI

Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2

Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-κB pathway in adipocytes links nutritional signalling with innate immunity

Linoleic acid actually inhibits TLR4 while Stearic Acid triggers it
Linoleic acid and stearic acid elicit opposite effects on AgRP expression and secretion via TLR4-dependent signaling pathways in immortalized hypot... - PubMed - NCBI

It seems to me as one goes on a quest to find the perfect fatty acid, the inevitable conclusion is that a low fat intake has benefits independently of its composition. As for its composition : predominantly saturated (mct, palmitic, stearic) and pufa-free. Olive Leaf can replace Olive Oil for its oleuropein if truly no amount of Oleic Acid is safe.

ROS creation are essential in down regulation of enzymes that metabolize ffa's to grant them access to the mitochondria. This is why unsaturated fats overload mitochondria, being that they don't induce the creation of ROS during their electron transport. So really, the creation of ROS via saturated fat is a protective measure that allows your cells to omit saturated fats from cells lest they die from being flooded with excess energy.

 

[Hans]

@haidut

What do you think of palmitic acid triggering TLR 4 ?
Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell secretion of IL-1β. - PubMed - NCBI

Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2

Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-κB pathway in adipocytes links nutritional signalling with innate immunity

Linoleic acid actually inhibits TLR4 while Stearic Acid triggers it
Linoleic acid and stearic acid elicit opposite effects on AgRP expression and secretion via TLR4-dependent signaling pathways in immortalized hypot... - PubMed - NCBI

It seems to me as one goes on a quest to find the perfect fatty acid, the inevitable conclusion is that a low fat intake has benefits independently of its composition. As for its composition : predominantly saturated (mct, palmitic, stearic) and pufa-free. Olive Leaf can replace Olive Oil for its oleuropein if truly no amount of Oleic Acid is safe.

Saturated fat do activate the TLR4, but only when carrying endotoxins and even then it does not cause inflammation. When a caloric surplus is eaten, inflammation specifically in the adipose tissue is necessary for healthy expansion.
But saturated fat doesn't cause inflammation at all. Haidut also made a thread about it: Coconut Oil "completely Abolished Responses To Endotoxin"

 

[Elephanto]

Saturated fat do activate the TLR4, but only when carrying endotoxins and even then it does not cause inflammation. When a caloric surplus is eaten, inflammation specifically in the adipose tissue is necessary for healthy expansion.
But saturated fat doesn't cause inflammation at all. Haidut also made a thread about it: Coconut Oil "completely Abolished Responses To Endotoxin"

Lauric acid is potently anti-microbial, I haven't seen studies showing palmitic acid and stearic acid to have the same potency.

and even then it does not cause inflammation

But that's not what those studies show, it did cause inflammation. And there are many more showing inflammation.

Inflammation being beneficial doesn't support Peat's view on it ("Inflammation leads to excessive uptake of calcium by cells") and the fact that many of his strategies are aimed at minimizing inflammation, or the fact that inflammatory cytokines trigger estradiol and aromatase. The complete absence of inflammation seems utopic though, I don't think you need to adopt strategies to intentionally increase it in a systemic way (I can understand topically for muscle building). He also advices "one teaspoon of coconut oil with meals" and has praised low fat intake, not only minimizing pufa intake. In the event that at some points you have any amount of endotoxins, wouldn't it be beneficial to not have an high intake of fatty acids that potentiate the receptor through which they exert their damage ? I'm not talking about avoiding palmitic/stearic acids but most of the studies posted by haidut show benefits at very low doses.

down regulation of enzymes that metabolize ffa's

Isn't that largely taken care of by minimizing fatty acids intake, stress and taking Niacinamide ? They all tend to reduce ROS too.

 

[Jon]

Isn't that largely taken care of by minimizing fatty acids intake, stress and taking Niacinamide ? They all tend to reduce ROS too.

Yes I believe so, as long as you're not eating a surplus of energy. What I'm talking about pertains to what happens during a surplus.

 

[Hans]

Lauric acid is potently anti-microbial, I haven't seen studies showing palmitic acid and stearic acid to have the same potency.

I wasn't talking about the anti-microbial effect of coconut oil. Coconut oil also increases the absorption of endotoxins, but they don't cause inflammation. That's why the study in the other treat said: "Coconut Oil completely Abolished Responses To Endotoxin". So coconut oil prevented the inflammation and other bad effects induced by endotoxins, in spite of activating TLR4. But yes, if someone has a compromized immune system and an overgrowth of gut bacteria, ingesting saturated fat can cause problems, but saturated fat do help with disposing endotoxins safely.

But that's not what those studies show, it did cause inflammation. And there are many more showing inflammation.

The studies you posted are in vitro. Animal studies where they feed them coconut oil have very little inflammation, are healthier and lean, whereas the rats that are PUFA fed are full of inflammation, are unhealthy and fat even when PUFAs don't transport endotoxins or activate TLR4.

Inflammation being beneficial doesn't support Peat's view on it ("Inflammation leads to excessive uptake of calcium by cells") and the fact that many of his strategies are aimed at minimizing inflammation, or the fact that inflammatory cytokines trigger estradiol and aromatase. The complete absence of inflammation seems utopic though, I don't think you need to adopt strategies to intentionally increase it in a systemic way (I can understand topically for muscle building). He also advices "one teaspoon of coconut oil with meals" and has praised low fat intake, not only minimizing pufa intake. In the event that at some points you have any amount of endotoxins, wouldn't it be beneficial to not have an high intake of fatty acids that potentiate the receptor through which they exert their damage ? I'm not talking about avoiding palmitic/stearic acids but most of the studies posted by haid

I'm not saying inflammation is good, but that a small amount acutely in the adipose tissue specifically are necessary for adipogenesis only when eaten in a surplus. This is acutely local, not chronically systematically (which is what PUFAs do), and only when eaten in excess. Excess nutrients need to go somewhere, and into the adipose tissue is where you want it. Plus you want healthy adipogenesis, which is what saturated fat will give you, and not PUFAs.

 

[Elephanto]

I wasn't talking about the anti-microbial effect of coconut oil. Coconut oil also increases the absorption of endotoxins, but they don't cause inflammation. That's why the study in the other treat said: "Coconut Oil completely Abolished Responses To Endotoxin". So coconut oil prevented the inflammation and other bad effects induced by endotoxins, in spite of activating TLR4. But yes, if someone has a compromized immune system and an overgrowth of gut bacteria, ingesting saturated fat can cause problems, but saturated fat do help with disposing endotoxins safely.

So you believe that the fact that it's highly anti-microbial has nothing to do with it abolishing the response to endotoxins ? I remain sceptical about it because it has never been shown with butter (and the Coconut Oil study was about 62% saturated at 2% CO) and with the known involvement of the Dairy Industry in scientific research, it should have been proven by now. The only fat where this is proven happens to be highly antiseptic. I also remain unconvinced that only in the case of pathogenic overgrowth would a high intake of palmitic/stearic acid matter. Even when endotoxins amount is small, there is still potentiation of its effects through TLR4 and it seems like a good strategy to get the benefits of palmitic/stearic at low doses while minimizing the potentiation.

I've never questioned pufas being vastly unhealthier btw, simply the existence of a fatty acid type where net positive effects on health remain and/or increase with unlimited intake.

I'd like your opinion though, do you believe that an high intake of palmitic or stearic acid (so an high total fat intake) is healthier in every possible way (not only endotoxin related but also lipolysis, lipogenesis, glucose tolerance, colon health etc) than a lower intake of those fatty acids in doses that achieve important benefits (3g here, 4g of stearic acid as a pufa antagonist/anti-cancer effect) ? Let's say that the person doesn't have a compromised immune system or overgrowth of gut bacteria. Or in other words, when dietary fat is strictly composed of saturated fatty acids, do you think there is no drawback to increasing it ? (let's say up to 300 grams a day to keep it realistic)

 

[Hans]

So you believe that the fact that it's highly anti-microbial has nothing to do with it abolishing the response to endotoxins

No that's not what I said. I was specifically focusing on inflammation and TLR4.
I think the anti-microbial effect is very good and helpful, which could explain a lot of its health promoting effect.
I have not seen studies where they used butter or cocoa butter, which strange. We sure do need those.

I've never questioned pufas being vastly unhealthier btw

Don't worry I wasn't saying you were. I only used PUFAs to help explain my point.

I'd like your opinion though, do you believe that an high intake of palmitic or stearic acid (so an high total fat intake) is healthier in every possible way (not only endotoxin related but also lipolysis, lipogenesis, glucose tolerance, colon health etc) than a lower intake of those fatty acids in doses that achieve important benefits (3g here, 4g of stearic acid as a pufa antagonist/anti-cancer effect) ? Let's say that the person doesn't have a compromised immune system or overgrowth of gut bacteria. Or in other words, when dietary fat is strictly composed of saturated fatty acids, do you think there is no drawback to increasing it ? (let's say up to 300 grams a day to keep it realistic)

Fatty acids are one of those cases where, just because it's good, doesn't mean more is better. And everyones' response and tolerance to fats differ. I do think fats should be kept low so that it doesn't interfere with glucose oxidation, but some people need less than other because of a compromised metabolism, whereas others need more, to slow transit time, bile secretion, better sleep, calmness, etc. So it will definitely have drawbacks in some people to eat high fat as well as for those that eat low fat. It all comes down to the individual.
I think very high fat is definitely not optimal and that doing a keto diet is just temporarily masking symptoms, rather than fixing them.
But bottom line is, I think it would be a good idea to start low and then increase fat intake to where it best fits the individual.

 

[Elephanto]

@Salmonamb

Alright. I just found it weird that Peat never mentioned sat fats affecting TLR4 (bringing a contextually-based counter-argument would have been helpful) or even discussed at all on this forum, and usually it is supposed that anything that raises TLR4 should be limited and anything that inhibits TLR4 is beneficial (linoleic acid is the first exception I've found). I feel really good on low fat (25g or so) and it does have proven mechanisms supporting it regardless of types but I thought that TLR4 was also one of them.

 

[Hans]

@Salmonamb

Alright. I just found it weird that Peat never mentioned sat fats affecting TLR4 (bringing a contextually-based counter-argument would have been helpful) or even discussed at all on this forum, and usually it is supposed that anything that raises TLR4 should be limited and anything that inhibits TLR4 is beneficial (linoleic acid is the first exception I've found). I feel really good on low fat (25g or so) and it does have proven mechanisms supporting it regardless of types but I thought that TLR4 was also one of them.

Yes TLR4 agonists are bad, but saturated fats only activate them when they are carrying endotoxins. Plus, other natural compounds are TLR4 antagonists, and no one is ingesting just saturated fat on its own, but most likely together with these antagonists.

 

[Elephanto]

@Salmonamb I don't think that needing less fat or feeling good with it is necessarily a sign of compromised metabolism though. Not that you implied that but still want to point it out. Like my temps are always high, digestion is good and I never accumulated body fat even with high calories intake. A factor that I think is very underestimated is the impact of your mental state on energy expenditure, your ability to control stress through your mindset that is. I think that a largely underestimated portion of eating is emotionally-based in most people. Even something like taking off my blue-blocking glasses for a while when starring at screens will prompt appetite as it is mildly stressing. Coconut oil increases metabolism but caffeine prompts my appetite much more by also being mildly stressing on top of pro-metabolic. Things that are dopaminergic but don't increase cortisol won't nearly as much. Plus taking supps that are calming like Magnesium facilitate the kind of mindset that reduces stress.

 

[Hans]

I don't think that needing less fat or feeling good with it is necessarily a sign of compromised metabolism though. Not that you implied that but still want to point it out. Like my temps are always high, digestion is good and I never accumulated body fat even with high calories intake.

Yes you're right. I meant that some people might initially do go on a very low fat diet and then start to crave more fat and then do better with more fat. Some people will just keep on being at their best with a low fat diet as yourself.

A factor that I think is very underestimated is the impact of your mental state on energy expenditure, your ability to control stress through your mindset that is. I think that a largely underestimated portion of eating is emotionally-based in most people. Even something like taking off my blue-blocking glasses for a while when starring at screens will prompt appetite as it is mildly stressing. Coconut oil increases metabolism but caffeine prompts my appetite much more by also being mildly stressing on top of pro-metabolic. Things that are dopaminergic but don't increase cortisol won't nearly as much. Plus taking supps that are calming like Magnesium facilitate the kind of mindset that reduces stress.

Yes I agree. The mind definitely plays a big role on digestion, appetite, ability to relax or not, and health in general.

 

[Capt Nirvana]

This is yet another thread as a follow up on the recent posts about plamitic acid inhibiting fatty acid oxidation and having therapeutic roles in cancer, diabetes and all other disease characterized by elevated/abnormal fatty acid metabolism.
Palmitic Acid (palmitate) Is A Fatty Acid Oxidation Inhibitor More Powerful Than Mildronate
Palmitic Acid (palmitate) Dramatically Inhibits Liver Cancer Progression

The study below shows that a physiological concentration (HED: ~3g) of palmitate basically doubled oxygen consumption/metabolism. The increase in respiration was NOT due to palmitate serving as the fuel, and fatty acid oxidation was not increased by palmitate either (something also suggested by the other threads on FAO inhibition).

Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes. - PubMed - NCBI
http://vanderbilt.edu/younglab/pdf/egnatchik14.pdf

"...ROS can be produced due to accelerated flux of electrons through the ETC as a result of increased mitochondrial activity. We measured the oxygen consumption of H4IIEC3 cells treated with 400 μmol/L PA to determine if ROS accumulation was associated with elevated mitochondrial metabolism. PA-treated cells were characterized by increased oxygen consumption (Fig. 2). Cells treated with 400 μmol/L OA had similar oxygen consumption rates as vehicle-treated cells. This result confirms that the elevated oxidative phenotype is unique to cells treated with SFA and that an equal load of MUFA is not sufficient to alter mitochondrial function."

"...Therefore, we analyzed ion fragments of citrate and malate for enrichment of M + 2 mass isotopomers (Fig. 6A). However, we found little to no incorporation of 13C, suggesting that a negligible flux of palmitate carbon was directed into the CAC for complete oxidation."

"...For example, ROS accumulation is a critical event leading to apoptosis of palmitate-treated CHO cells [30], while palmitate-treated neonatal cardiomyocytes undergo apoptosis independently of oxidative stress [31]. In our experiments, we measured a burst of ROS at approximately 6 h following palmitate administration, which was 25%–50% higher than cells treated with vehicle (BSA) alone."

"...Since mitochondria require oxygen to carry out oxidative phosphorylation, increased oxygen consumption is a direct measure of increased mitochondrial metabolism. Palmitate-treated cells exhibited a 2-fold increase in oxygen consumption rate and in most mitochondrial fluxes prior to ROS accumulation. However, NAC co-treatment did not affect palmitate-induced metabolic alterations, indicating that neither elevated ROS nor downstream apoptotic events contributed to mitochondrial activation. Instead, elevated mitochondrial metabolism appears to be an inherent consequence of palmitate overload that is independent of subsequent ROS accumulation and apoptosis initiation."

"...

What about palmitic acid's role in fat necrosis in cattle? Dr. Emanuel Revici warned about palmitic acid's high adrenal defense response, double that of highly unsaturated omega 3 fatty acids. (Cattle seem to be relatively immune to Yellow Fat Disease caused by DHA, EPA, and ALA). —> Overview of Abdominal Fat Necrosis - Digestive System - Merck Veterinary Manual

 

[Rafael Lao Wai]

What about palmitic acid's role in fat necrosis in cattle? Dr. Emanuel Revici warned about palmitic acid's high adrenal defense response, double that of highly unsaturated omega 3 fatty acids. (Cattle seem to be relatively immune to Yellow Fat Disease caused by DHA, EPA, and ALA). —> Overview of Abdominal Fat Necrosis - Digestive System - Merck Veterinary Manual

I think the reason why cattle are less affected by PUFAs is because they are ruminant animals, which means they naturally hydrogenate PUFAs into saturated and trans fatty acids. Also, in the link, they say palmitic acid is a proposed cause, not really a cause for sure.

 

[Fractality]

Palmitic Acid Reduces the Autophagic Flux and Insulin Sensitivity Through the Activation of the Free Fatty Acid Receptor 1 (FFAR1) in the Hypothalamic Neuronal Cell Line N43/5

 

[Green Dot]

Thanks for sharing. Does this also apply to calcium palmitate?

 

[Rinse & rePeat]

Peat has said up to 50 percent of the diet can be from fat sources and has spoken about eating pints of ice cream at a time. If your mum is improving health wise on a ratio of macros, I wouldn't change them simply from a single post on the forum.

Ray Peat says a low-fat diet is good for weight control, warding off diseases and for longevity. He gave up ice cream, because it had too much fat and makes his own. He says ice cream is for people who need to gain weight.