Hey My Dudes [PUFA, Ketosis, Insulin Resistance]

[BigYellowLemon]

That's very interesting, @BigYellowLemon

I started the Hyperlipid article. I will need to keep Wikipedia handy for this, lol. Thank you for the details.

Read, read, and keep reading. Try to get as many viewpoints and perspectives as you can, so that you can grow intellectually.

From what I've been reading, I honestly don't know why Ray Peat doesn't recommend a HFLC/ketogenic diet. I really have to read more about why he likes carbs so much. I understand the CO2 part, but the rest is a mystery to me.

Sorry I didn't respond earlier. My browser wasn't letting me access this website, said it was unsafe.

 

[BigYellowLemon]

Unsaturated fatty acids induce cytotoxic aggregate formation of amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutants. - PubMed - NCBI

Formation of misfolded protein aggregates is a remarkable hallmark of various neurodegenerative diseases including Alzheimer disease, Parkinson disease, Huntington disease, prion encephalopathies, and amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) immunoreactive inclusions have been found in the spinal cord of ALS animal models and patients, implicating the close involvement of SOD1 aggregates in ALS pathogenesis. Here we examined the molecular mechanism of aggregate formation of ALS-related SOD1 mutants in vitro. We found that long-chain unsaturated fatty acids (FAs) promoted aggregate formation of SOD1 mutants in both dose- and time-dependent manners. Metal-deficient SOD1s, wild-type, and mutants were highly oligomerized compared with holo-SOD1s by incubation in the presence of unsaturated FAs. Oligomerization of SOD1 is closely associated with its structural instability. Heat-treated holo-SOD1 mutants were readily oligomerized by the addition of unsaturated FAs, whereas wild-type SOD1 was not. The monounsaturated FA, oleic acid, directly bound to SOD1 and was characterized by a solid-phase FA binding assay using oleate-Sepharose. The FA binding characteristics were closely correlated with the oligomerization propensity of SOD1 proteins, which indicates that FA binding may change SOD1 conformation in a way that favors the formation of aggregates. High molecular mass aggregates of SOD1 induced by FAs have a granular morphology and show significant cytotoxicity. These findings suggest that SOD1 mutants gain FA binding abilities based on their structural instability and form cytotoxic granular aggregates.

Explain your thinking to me Dave, if you would.

 

[BigYellowLemon]

Pretty interesting article. Peter scared me off a bit awhile back when he talked about raising FFA to induce uncoupling, so I have not been an avid reader of his.

In the comment section Peter and some others talked about how the hi fat diet was a way to side step the metabolic dysfunction at complex 1, but not necessarily cure it. In other words it was a bit like a band aide. This really rang true in my head and I started thinking what that dysfunction could be. Could it be the presence of CO2? It would fit the details very well.

It would explain how a high fat diet, overtime would make that complex dysfunction even worse as fats do not generate CO2 nearly as well as sugar does. If you are really metabolically damaged as they say, and you go live up at 15k feet for awhile...well it doesn't really matter how fat or damaged you are, you are going to need to eat and you will get skinny.

Why would you be scared of raising FFA's to induce uncoupling? Uncoupling is (generally) great! Especially when the uncoupler is an energetic substrate itself.

Yes, Peter mentions that a lot. His reasoning is probably this: in someone with a broken complex 1, it would be better to obtain their energy from saturated fat via FADH2, vs carbohydrate, which favors NADH. If you feed someone with a broken complex 1 carbohydrates, then they will suffer from extreme amounts of reverse electron flow (making them insulin resistant). Saturated fat driven metabolism side-steps this and allows the mitochondria to prosper.

Does CO2 increase complex 1? Does it help carbohydrate metabolism?

 

[BigYellowLemon]

[ moderator edit: post moved from Dairy Fat Successfully Replaced My Thyroid Medication ]

PRT: 4 cal/g
CHO: 4 cal/g
FAT: 9 cal/g

By calories:

PRT: 4/(4+4+9) = 23.5%
CHO: 4/(4+4+9) = 23.5 %
FAT: 9/(4+4+9) = 53.0%

Macronutrient Ratios Per Capita

• 
  
  
  • World: 2780 kcal/person/day (Carbohydrates: 63%, Proteins: 11%, Fats: 26%)
  • Developed countries: 3420 kcal/person/day Carbohydrates: 53%, Proteins: 12%, Fats: 34%
  • Developing World: 2630 kcal/person/day Carbohydrates: 67%, Proteins: 11%, Fats: 23%
  • Sub-Saharan Africa: 2240 kcal/person/day Carbohydrates: 72%, Proteins: 10%, Fats: 19%
  • Central Africa: 1820 kcal/person/day Carbohydrates: 75%, Proteins: 11%, Fats: 26%

The more industrialized the nation, the greater proportion of calories from fat.[/

The fat being consumed by "developed" countries is almost all PUFA, probably.

 

[ATP]

Why would you be scared of raising FFA's to induce uncoupling? Uncoupling is (generally) great! Especially when the uncoupler is an energetic substrate itself.

Yes, Peter mentions that a lot. His reasoning is probably this: in someone with a broken complex 1, it would be better to obtain their energy from saturated fat via FADH2, vs carbohydrate, which favors NADH. If you feed someone with a broken complex 1 carbohydrates, then they will suffer from extreme amounts of reverse electron flow (making them insulin resistant). Saturated fat driven metabolism side-steps this and allows the mitochondria to prosper.

Does CO2 increase complex 1? Does it help carbohydrate metabolism?

Isn't getting energy from fat mean nutritional ketosis? That only comes from metabolic stress, which is the complete opposite of what Ray believes to be optimal.

 

[BigYellowLemon]

Isn't getting energy from fat mean nutritional ketosis? That only comes from metabolic stress, which is the complete opposite of what Ray believes to be optimal.

Well, it can come from "stress", like starvation. When you stop eating, your glycogen runs out and your body starts burning fat, and converting fat to sugar, with ketones as a byproduct.

"Nutritional ketosis" doesn't necessarily have to be stressful. It can happen by withholding carb intake.

Eating MCT's also creates ketones. Would that be stressful?

So you can either starve/fast, eat primarily fat, or consume MCT's. None of these is inherently stressful (though fasting would probably be stressful for the majority of people).

 

[ATP]

Well, it can come from "stress", like starvation. When you stop eating, your glycogen runs out and your body starts burning fat, and converting fat to sugar, with ketones as a byproduct.

"Nutritional ketosis" doesn't necessarily have to be stressful. It can happen by withholding carb intake.

Eating MCT's also creates ketones. Would that be stressful?

So you can either starve/fast, eat primarily fat, or consume MCT's. None of these is inherently stressful (though fasting would probably be stressful for the majority of people).

Regardless of calorie intake, without ingesting sugar your glycogen stores deplete. I was under the impression when that happens even in the presence of ketones which would increase stress hormones and lower thyroid function, which the liver needs sugar to be able to convert t4.

 

[charlie]

Sorry I didn't respond earlier. My browser wasn't letting me access this website, said it was unsafe.

I'm Getting A Message From All Browsers About Forum's Security Certificate

 

[BigYellowLemon]

Regardless of calorie intake, without ingesting sugar your glycogen stores deplete. I was under the impression when that happens even in the presence of ketones which would increase stress hormones and lower thyroid function, which the liver needs sugar to be able to convert t4.

Yeah, in deep ketosis with very little carbs, cortisol rises, and I'm pretty sure adrenaline too.

I think that's why so many people have bad results with HFLC diets, they either cut carbs too much or use PUFA's instead of SFA's.

I would suggest getting more than 50g of carbs if you're doing HFLC.

I might try a HCLF diet soon. It's all very confusing.

 

[BigYellowLemon]

I'm Getting A Message From All Browsers About Forum's Security Certificate

I'm glad we're safe Charlie!

Thanks.

 

[ATP]

Yeah, in deep ketosis with very little carbs, cortisol rises, and I'm pretty sure adrenaline too.

I think that's why so many people have bad results with HFLC diets, they either cut carbs too much or use PUFA's instead of SFA's.

I would suggest getting more than 50g of carbs if you're doing HFLC.

I might try a HCLF diet soon. It's all very confusing.

I've tried HFLC at around 50 grams of carbs and I couldn't produce any ketones even with MCT oil. I have a blood ketone meter.

 

[BigYellowLemon]

I've tried HFLC at around 50 grams of carbs and I couldn't produce any ketones even with MCT oil. I have a blood ketone meter.

Damn. I wonder why.

How did you feel on HFLC? What were you eating?

I assume you came here after HFLC didn't work?

As I said, it's all very confusing. It seems regardless of the diet, there will always be people who get better and people who get worse.

 

[ATP]

Damn. I wonder why.

How did you feel on HFLC? What were you eating?

I assume you came here after HFLC didn't work?

As I said, it's all very confusing. It seems regardless of the diet, there will always be people who get better and people who get worse.

It is very confusing!

I've tried every diet. From vegan to paleo.

Every time I go low carb I feel fatigued and light headed. I have some friends who have gone low carb long enough to produce ketones and they feel fantastic. So I'm definitely confused.

 

[BigYellowLemon]

It is very confusing!

I've tried every diet. From vegan to paleo.

Every time I go low carb I feel fatigued and light headed. I have some friends who have gone low carb long enough to produce ketones and they feel fantastic. So I'm definitely confused.

Damn.

We should really consider other factors besides diet. I've noticed that a lot of my health issues stem not from diet, but from being OCD about things, and about my perspective on life, or EMF, ect. Diet is important but not the key.

If the "Ray Peat Diet" isn't working, maybe try HFLC, try to get all of your fat in saturated form, keep protein lowish, keep carbs low, and let your body adapt. Apparently it takes a bit for your body to adapt, like a month or longer. I'll let you know if it works for me.

 

[ATP]

Damn.

We should really consider other factors besides diet. I've noticed that a lot of my health issues stem not from diet, but from being OCD about things, and about my perspective on life, or EMF, ect. Diet is important but not the key.

If the "Ray Peat Diet" isn't working, maybe try HFLC, try to get all of your fat in saturated form, keep protein lowish, keep carbs low, and let your body adapt. Apparently it takes a bit for your body to adapt, like a month or longer. I'll let you know if it works for me.

Yeah if you try it let me know how you go :)

 

[BigYellowLemon]

It is very confusing!

I've tried every diet. From vegan to paleo.

Every time I go low carb I feel fatigued and light headed. I have some friends who have gone low carb long enough to produce ketones and they feel fantastic. So I'm definitely confused.

I just had a thought.

I think the reason many people feel like ***t on a ketogenic diet is because either their fat stores are comprised primarily of PUFA, or they are eating too much PUFA.

PUFA is insulin sensitizing, and on a high fat diet with little glucose, you don't want that. You want saturated fat, which will create insulin resistance in the body, which will leave glucose in the blood for the brain.

Perhaps the PUFA-FFA's in their blood sensitize's their insulin, and allow glucose to be up-taken into the cells in their body (leaving little for the brain), and this would lower blood glucose, which would basically starve the brain, and create an episode of hypoglycemia, which would result in tiredness, lethargy, nausea, ect.

The reason I like the idea of a high saturated fat diet, is because I remember Ray Peat mentioned that it's not about the absolute quantity of PUFA, but the PUFA/SFA ratio. On a HFLC diet with minimal PUFA, you would be (ostensibly) saturating your cardiolipin with goodies like palmitic acid or stearic acid. On a HCLF diet, it's usually inevitable you'll get around 1g of PUFA a day, and this will only have a gram of SFA to balance it out.

idk. Sadly aspirin seems unusable on a HFLC diet.

 

[DaveFoster]

Explain your thinking to me Dave, if you would.

"We found that long-chain unsaturated fatty acids (FAs) promoted aggregate formation of SOD1 mutants in both dose- and time-dependent manners."

The study shows that oleic acid, the most abundant MUFA in food sources, promotes the development of certain neurological disorders.

 

[tyw]

"Insulin Resistance" needs to be treated accurately ..... Chris Masterjohn's explanation is accurate -- Insulin Resistance Isn’t All About Carbs and Insulin

The right approach is the energetic one, and whereby you are looking to systemically match Energetic substrate inputs, to actual cellular energy requirements.

More energetic substrate is only good if there isn't enough energy in a cell to begin with, AND the cell is capable of using that substrate.

What Peter @ Hyperlipid is talking about is cell-level failure in responding to insulin. He tries to go as low-level as possible, and bases his conclusions on cell membrane charge (termed "delta psi", or by the greek symbols "ΔΨ"). His argument is that:

• when delta psi is low, Insulin fails to function.
  
  
• Reactive Oxygen Species (ROS) reliably reduces delta psi
  
  
• Reverse Electron Transport (RET) through Complex 1 produces the most amount of ROS. That said, too much flow through to Complex 3 and 4 also produces a lot of ROS.
  
  For details, search for paper "How Mitochondria produce Reactive Oxygen Species"
  
  NOTE: as Chris Masterjohn rightly points out, ROS is not the only mediator of this sort of behaviour. The canonical case is exercise, where you get high ROS, but also an increased need for energy, and subsequent upregulation of all the machinery used to bring more energy into the cell (everything from more GLUT1 transporter activity, to greater insulin sensitivity).
  
  
• RET is most likely when the CoQ couple is already in the reduced state -- reduction implies a gaining of an electron, "reduced state" means that no more electrons can be gained, and thus no further electrons from Complex 1 are accepted .
  
  
• While full oxidation of any substrate yields both NADH (complex 1 entry) and FADH2 (complex 2 entry), fatty acid beta oxidation directly yields much more FADH2. The amount of FADH2 is directly proportional to the saturation and chain length of the fatty acid.
  
  
• Therefore, saturated fats produce the most FADH2, and the most propensity to result in RET through Complex 1. PUFAs do not produce as much FADH2, and therefore "allow the cell to remain insulin sensitive / receptive to more energetic substrate input"

All of this assumes full oxidation of substrate.
All tests used to come to these conclusions are in-vitro tests (ie: not in a living body).
Some tests account for the cyclic behaviour of NADH and FADH2 entry, some do not.
Some tests account for saturation quantities of substrate, some do not.

Whether or not low level mechanics are a reflection of high level dietary inputs is uncertain. There is no way to predict what an individual can process at a particular time of the day, given their state of enzymatic function, given other stressful compounds in food, etc .....

-----

Regarding the study referenced by the first poster, it is plausible that in the context of a high fat and high carbohydrate diet (see note below), that Saturated Fat surpresses the ability for non-adipose cells to take in energy ("Insulin Resistance"), and thereby divert excess energy to adipose stores.

NOTE: "a 50% fat, 50% carb, 50% calorie restricted diet is a ketogenic diet " (credit to ItsTheWoooo!). Caloric insufficiency by definition means that there will be net mobilisation of lipids from adipose tissue (unless there is something seriously wrong). Have enough caloric insufficiency (hence the "50% calorie restricted"), and FFAs will be high enough to induce ketogenesis.

Similarly, when in caloric excess, a 100g carb "low carb diet" is by definition a "state of excess carbs" from an energetic perspective.

The key point is that in energetic surplus, there is a systemic need for cells to create a signal to "reject excess incoming energy". Insulin Resistance needs to be viewed based upon energetic need.​

Keep in mind that the participants of this study were "very lean young men and women". We assume that "insulin sensitivity" is going to be high, both in adipose and non-adipose tissue. In the context of a caloric surplus, that encourages deposition of fat into adipose tissue.

A couple more points:

(a) The fat that you store is the fat that you eat.
(a1) De novo lipogenesis is insignificant on a mixed diet, even at the surplus that the participants were given

(b) If Peter @ Hyperlipid is correct, metabolically active tissues receive the brunt of the effect of Saturated fat induced Insulin resistance -- his explanation relies on the actual beta oxidation of fatty acids, and subsequent passage through mitochondrial complexes. PUFAs exert a much lesser effect on this.

Therefore, higher energy flux tissues like the liver and skeletal muscles are the ones that become "insulin resistant", whereas adipose tissue is relatively more primed to uptake energy. More fat gain could then happen after eating Saturated fat in caloric surplus, compared to PUFA in caloric surplus.

There is still excess energy on the PUFA laden arm of the study though, and that energy has to go somewhere. Part of it will be oxidised in tissues to ATP, part of it will be oxidised in tissue and subsequently uncoupled from ATP production, part of it will be stored in those tissues, etc .... but there would probably be a "larger sink" in the metabolic active tissues to deal with this surplus energy on the high PUFA protocol vs the high Saturated fat protocol.

With regard to uncoupling of respiration, this depends on many factors, and is highly dependent on the individual and the context they are exposed to. It is not a simple "saturated fat induces uncoupling" effect when dealing with live subjects. Too much energy encourages uncoupling, cold stress encourages uncoupling, etc .....

----

In any case, the study needs to be interpreted in terms of the exact context it was performed in. The overriding factor in that study is definitely going to be the caloric surplus. In that case, it seems like Saturated Fat produces more fat gain on a mixed diet.

This doesn't say anything for truly ketogenic diets (even if in surplus), nor does it say anything for a high saturated fat eucaloric diet.

Experiment accordingly

....

 

[BigYellowLemon]

"Insulin Resistance" needs to be treated accurately ..... Chris Masterjohn's explanation is accurate -- Insulin Resistance Isn’t All About Carbs and Insulin

The right approach is the energetic one, and whereby you are looking to systemically match Energetic substrate inputs, to actual cellular energy requirements.

More energetic substrate is only good if there isn't enough energy in a cell to begin with, AND the cell is capable of using that substrate.

What Peter @ Hyperlipid is talking about is cell-level failure in responding to insulin. He tries to go as low-level as possible, and bases his conclusions on cell membrane charge (termed "delta psi", or by the greek symbols "ΔΨ"). His argument is that:

• when delta psi is low, Insulin fails to function.
  
  
• Reactive Oxygen Species (ROS) reliably reduces delta psi
  
  
• Reverse Electron Transport (RET) through Complex 1 produces the most amount of ROS. That said, too much flow through to Complex 3 and 4 also produces a lot of ROS.
  
  For details, search for paper "How Mitochondria produce Reactive Oxygen Species"
  
  NOTE: as Chris Masterjohn rightly points out, ROS is not the only mediator of this sort of behaviour. The canonical case is exercise, where you get high ROS, but also an increased need for energy, and subsequent upregulation of all the machinery used to bring more energy into the cell (everything from more GLUT1 transporter activity, to greater insulin sensitivity).
  
  
• RET is most likely when the CoQ couple is already in the reduced state -- reduction implies a gaining of an electron, "reduced state" means that no more electrons can be gained, and thus no further electrons from Complex 1 are accepted .
  
  
• While full oxidation of any substrate yields both NADH (complex 1 entry) and FADH2 (complex 2 entry), fatty acid beta oxidation directly yields much more FADH2. The amount of FADH2 is directly proportional to the saturation and chain length of the fatty acid.
  
  
• Therefore, saturated fats produce the most FADH2, and the most propensity to result in RET through Complex 1. PUFAs do not produce as much FADH2, and therefore "allow the cell to remain insulin sensitive / receptive to more energetic substrate input"

All of this assumes full oxidation of substrate.
All tests used to come to these conclusions are in-vitro tests (ie: not in a living body).
Some tests account for the cyclic behaviour of NADH and FADH2 entry, some do not.
Some tests account for saturation quantities of substrate, some do not.

Whether or not low level mechanics are a reflection of high level dietary inputs is uncertain. There is no way to predict what an individual can process at a particular time of the day, given their state of enzymatic function, given other stressful compounds in food, etc .....

-----

Regarding the study referenced by the first poster, it is plausible that in the context of a high fat and high carbohydrate diet (see note below), that Saturated Fat surpresses the ability for non-adipose cells to take in energy ("Insulin Resistance"), and thereby divert excess energy to adipose stores.

NOTE: "a 50% fat, 50% carb, 50% calorie restricted diet is a ketogenic diet " (credit to ItsTheWoooo!). Caloric insufficiency by definition means that there will be net mobilisation of lipids from adipose tissue (unless there is something seriously wrong). Have enough caloric insufficiency (hence the "50% calorie restricted"), and FFAs will be high enough to induce ketogenesis.

Similarly, when in caloric excess, a 100g carb "low carb diet" is by definition a "state of excess carbs" from an energetic perspective.

The key point is that in energetic surplus, there is a systemic need for cells to create a signal to "reject excess incoming energy". Insulin Resistance needs to be viewed based upon energetic need.​

Keep in mind that the participants of this study were "very lean young men and women". We assume that "insulin sensitivity" is going to be high, both in adipose and non-adipose tissue. In the context of a caloric surplus, that encourages deposition of fat into adipose tissue.

A couple more points:

(a) The fat that you store is the fat that you eat.
(a1) De novo lipogenesis is insignificant on a mixed diet, even at the surplus that the participants were given

(b) If Peter @ Hyperlipid is correct, metabolically active tissues receive the brunt of the effect of Saturated fat induced Insulin resistance -- his explanation relies on the actual beta oxidation of fatty acids, and subsequent passage through mitochondrial complexes. PUFAs exert a much lesser effect on this.

Therefore, higher energy flux tissues like the liver and skeletal muscles are the ones that become "insulin resistant", whereas adipose tissue is relatively more primed to uptake energy. More fat gain could then happen after eating Saturated fat in caloric surplus, compared to PUFA in caloric surplus.

There is still excess energy on the PUFA laden arm of the study though, and that energy has to go somewhere. Part of it will be oxidised in tissues to ATP, part of it will be oxidised in tissue and subsequently uncoupled from ATP production, part of it will be stored in those tissues, etc .... but there would probably be a "larger sink" in the metabolic active tissues to deal with this surplus energy on the high PUFA protocol vs the high Saturated fat protocol.

With regard to uncoupling of respiration, this depends on many factors, and is highly dependent on the individual and the context they are exposed to. It is not a simple "saturated fat induces uncoupling" effect when dealing with live subjects. Too much energy encourages uncoupling, cold stress encourages uncoupling, etc .....

----

In any case, the study needs to be interpreted in terms of the exact context it was performed in. The overriding factor in that study is definitely going to be the caloric surplus. In that case, it seems like Saturated Fat produces more fat gain on a mixed diet.

This doesn't say anything for truly ketogenic diets (even if in surplus), nor does it say anything for a high saturated fat eucaloric diet.

Experiment accordingly

....

Amazing, thank you for the clarification!

What are the implications of complex 3/4 ROS? For some reason I feel as though that carbohydrates favor this kind of ROS generation.

Thanks.

 

[DaveFoster]

The fat being consumed by "developed" countries is almost all PUFA, probably.

I would say heavily weighted in PUFA, definitely.

I was more leaning to a human preference for larger amounts of fat in the diet. We gravitate toward ice cream and bacon, for example.