Palmitic Acid (palmitate) Strongly Increases Oxidative Metabolism

haidut

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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."

"...
 

haidut

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Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents
JCI - Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

When looking at the hypothalamus, these researchers arrived at opposite conclusions about palmitic acid and oleic acid.

What do you mean by opposite conclusions? Did they find oleic acid to stimulate metabolism and palmitic to suppress it? The studies I posted also claim that decreased FAO may contribute to insulin resistance. I don't think that is true, so the study you posted actually confirms the one I posted. Most studies consider increased FAO to be a good thing, a concept that Peta has challenged for decades and is now finally being acknowledged in the clinics.
 

Peat Tong

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"We recently demonstrated that saturated fatty acids and, more specifically, palmitic acid cause brain insulin resistance (10). CNS resistance to leptin and insulin compromises the ability of both hormones to regulate food intake and body weight in the presence of diets high in saturated fat/palmitic acid, subsequently resulting in obesity. Additionally, we found that palmitic acid impairs the ability of insulin to activate its intracellular signaling pathways (10). Importantly, these effects of palmitic acid are unique for this the type of fatty acid. Oleic acid, for example, has been demonstrated to act as a central insulin mimetic and to have beneficial effects on hepatic glucose homeostasis and body weight regulation (11). Consistently, it has been demonstrated that diets high in monounsaturated fatty acids (oleic acid) prevent dietary fat–induced insulin resistance (11, 12), whereas diets high in palmitic acid accelerate obesity (10). Potential mechanisms by which these fatty acids differentially influence insulin signaling as well as body weight regulation have been posited. Here, we focus on the CNS and provide data suggesting what we believe to be a novel mechanism by which specific fatty acids impair central insulin (and leptin) signaling by activating a novel family member of PKC."

"The fatty acid composition of the HFS [ high fat, saturated ] diet was 10% myristate/27% palmitate/12% stearate/25% oleate. The composition of the oleic acid diet was 11% palmitate/ 70% oleate/13% linoleate. "
 

haidut

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"We recently demonstrated that saturated fatty acids and, more specifically, palmitic acid cause brain insulin resistance (10). CNS resistance to leptin and insulin compromises the ability of both hormones to regulate food intake and body weight in the presence of diets high in saturated fat/palmitic acid, subsequently resulting in obesity. Additionally, we found that palmitic acid impairs the ability of insulin to activate its intracellular signaling pathways (10). Importantly, these effects of palmitic acid are unique for this the type of fatty acid. Oleic acid, for example, has been demonstrated to act as a central insulin mimetic and to have beneficial effects on hepatic glucose homeostasis and body weight regulation (11). Consistently, it has been demonstrated that diets high in monounsaturated fatty acids (oleic acid) prevent dietary fat–induced insulin resistance (11, 12), whereas diets high in palmitic acid accelerate obesity (10). Potential mechanisms by which these fatty acids differentially influence insulin signaling as well as body weight regulation have been posited. Here, we focus on the CNS and provide data suggesting what we believe to be a novel mechanism by which specific fatty acids impair central insulin (and leptin) signaling by activating a novel family member of PKC."

"The fatty acid composition of the HFS [ high fat, saturated ] diet was 10% myristate/27% palmitate/12% stearate/25% oleate. The composition of the oleic acid diet was 11% palmitate/ 70% oleate/13% linoleate. "

In that reference [10] they simply state that palmitate is "known to induce insulin resistance" and cite 2 studies.
"...Because palmitate readily induces insulin resistance in peripheral tissues (15, 35) and because HF feeding increases hypothalamic palmitoyl-CoA levels (Fig. 3A), we asked whether intracerebroventricular infusion of palmitate in rats maintained on a standard chow diet mimics the effect of HF feeding on hypothalamic insulin signaling, palmitoyl-CoA accumulation, and IKKβ activity. "

However, if you look at those studies (ref 15, 35 above) you will see that one of them does not even mention palmitate, while the other one used a mixture of palmitate and oleate to induce insulin resistance. So, the evidence against palmitate is non-existent or at least based on what the study has cited. In most cases I have seen the narrative is the same as for EFA - i.e. "it is well-known that palmitate causes insulin resistance because it is a saturated fat and SFA are bad". But when you look at the reference cited they usually point to each other in a circular fashion and at the end there is no evidence against palmitate.
 
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yerrag

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But when you look at the reference cited they usually point to each other in a circular fashion and at the end there is no evidence against palmitate.
Can these studies do that? Great for you Haidut to catch it. Another set of fake studies exposed!
 

mujuro

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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?
 

yerrag

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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?
Is 20% the upper limit for fats as far as caloric intake goes? I've been making a formula for my mom where coconut oil is 40% of caloric intake (carbs at 40, protein at 20). Seems to be doing well. My blend is very arbitrary though.
 

Mufasa

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Is 20% the upper limit for fats as far as caloric intake goes? I've been making a formula for my mom where coconut oil is 40% of caloric intake (carbs at 40, protein at 20). Seems to be doing well. My blend is very arbitrary though.

40% is way too much, thats like 9 tablespoons of coconut oil
 

yerrag

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Mufasa

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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.

He had lowered his fat intake though. And his later suggestions are too limit fat much more.

Also he doesnt recommand much more than a couple of teaspoons of coconut oil a day IIRC. He eats more fat from dairy I think.
 

raypeatclips

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He had lowered his fat intake though. And his later suggestions are too limit fat much more.

Also he doesnt recommand much more than a couple of teaspoons of coconut oil a day IIRC. He eats more fat from dairy I think.

Oh yeah don't think I've ever seen him suggest having coconut oil as the sole source of fat he's mentioned 1tsp per day as having beneficial effects.
 

mujuro

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Is 20% the upper limit for fats as far as caloric intake goes? I've been making a formula for my mom where coconut oil is 40% of caloric intake (carbs at 40, protein at 20). Seems to be doing well. My blend is very arbitrary though.

I should have prefaced this with an "IME". This is just my experience. I do best on minimal fats. I was eating lots of ice cream in recent months, but since replacing it with sorbet I feel so much better and my hair and skin are better too. Of the people in my personal life who are overweight and insulin resistant, they tend to eat a lot of fat, misled by the entire "carbs are the problem" myth.
 

yerrag

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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.
I haven't heard this said from Peat, but I'm still going through many interviews of his, and if he has said this I would think it is a matter of context on how much fat one could use. I couldn't tell at all if my mom is doing well on that blend, but I could be overdoing it given that I understand coconut oil to be good for old people, as it prevents the onset of Alzheimer, from what I've been reading. Also, Ray has said many good things about coconut oil, such as it having sterols (or steroid, not sure) that could be used for steroids and hormones, has vitamin E (although it was not expounded upon), and is one of the protective substances he mentions of often enough. It also has shorter chain fatty acids that bypass the liver and is used directly for energy.

Also he doesnt recommand much more than a couple of teaspoons of coconut oil a day IIRC. He eats more fat from dairy I think.
I heard him recommend such amounts, but I didn't get the impression he was using that figure as an upper limit for daily consumption. I felt he was saying that amount would be enough. I find it hard to swallow any oil, and I would not tell anyone to take more than the minimum because it might turn them away from it. Taking in oil has the yukky feel, and just thinking of taking it straight up just makes me put it off until I don't do it. In my mom's case, I would always give her a milk blend of different ingredients, coconut oil being one, so she doesn't feel like it's torture each time.

Of the people in my personal life who are overweight and insulin resistant, they tend to eat a lot of fat, misled by the entire "carbs are the problem" myth.
I understand coconut oil to be a different kind of fat, and it's been recommended by many people for weight loss, given that its quickly metabolized and not stored as fat in the body.

Also, fats contains many calories and it helps because I can't give my mom much volume but I want her to meet her calorie needs. Using sugar instead of rice, for example, is one way. It becomes a toss-up between using sugar and coconut oil, and I could adjust it one way favoring more coconut oil, or the other way favoring sugar. Knowing sugar isn't bad, and knowing my mom has no blood sugar problem, adding more sugar wouldn't be a bad idea. Moreover, sugar also gets converted to saturated fats or mead acid also.

So, I may play around my ratio of macronutrients and will try to observe the effects of different blends.
 

paymanz

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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.
Maybe he just meant that's OK to have half your calorie from good fat, but he probably prefers sugar, for more co2 for example...
 

haidut

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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?

Well, I think the real message is "if you eat too much fat you will inhibit sugar metabolism". But not all fats are equal, so I would like to see a study with glucose/sucrose and pure palmitic acid. Until then nothing really can be concluded from these biased studies.
 

meatbag

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@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?
 
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Obi-wan

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@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.
 
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