Protein, Branched Chain Amino Acids (BCAA) and Alpha-Ketoglutarate
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- เผยแพร่เมื่อ 6 พ.ย. 2024
- Obese humans and torpid animals inefficiently break down BCAA, leading to insulin resistance. One of the reasons for this is a lack of sufficient alpha-ketoglutarate, which is used in the transamination step by the enzyme BCAT2. Restoring alpha-ketoglutarate in rats returns BCAA levels to the control levels.
Alpha-ketoglutarate is currently available from fireinabottle....
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Digging more into your work... this might be where we overlap.
You mentioned ALA as a cofactor for the three dehydrogenase enzymes, but you didn't mention thiamine? I have been discussing thiamine for a long time using mega-doses as treatment for just a tonne of different health problems.
Thiamine can be used to pharmacologically activate those enzymes in the context of chronic inhibition (which appears to also be the case in torpor). I think it is the primary mechanism by which high doses work to reverse certain types of chronic illness. It seems to help bring someout out of the hypometabolic state.
This is particularly relevant in central nervous system disorders and neurodegeneration. Pharmacological activation of PDH and KGDH by thiamine produces remarkable results in alzheimers, parkinson's (this is substantiated by a body of data). I think the same mechanism might occur in fibromyalgia/CFS, which could also be perceived as a similar manifestation of a tropor-like state/cell danger response.
Many describe the hyperthermic/pro-metabolic effects of high dose thiamine, and i have had countless testimonials of people being able to tolerate/metabolise carbohydrates after using it.
TPP not only stimulates BCKD, but also inhibits BCKD-kinase. www.sciencedirect.com/science/article/abs/pii/S0006291X18319569?via%3Dihub
The degree of KGDH inhibition is correlated with the severity of symptoms in neurodegeneration, and supplemental thiamine in a large enough dose reverses the metabolic blockade whilst tracking with symptom improvement.
Likewise, organisms of all kinds (bacteria, fungi, plant, and human) will upregulate TPP-dependent enzymes/thiamine synthesis/thiamine cell uptake during most types of stress. In the plant research TPP is literally referred to as an "environmental stress protectant"". I have a video on this here: th-cam.com/video/63-bHtCrL7o/w-d-xo.html
Very interested to get your thoughts on how thiamine might play into this.
New Fireinabottle video=a great Sunday
A protein video! yay! I'm still confused (less so, thanks)
I've been eating high protein/no pufa/low mufa for about 3 months now while doing resistance training. weight hasn't really changed, but body composition/strength/posture has changed positively,
As always awesome analysis.
Food for thought on alpha lipoic acid -- mct 8 octonic acid is a substrate for lipoic acid in the Mitochondria. Would exogenous r-ala supress a feedback loop or would it allow more to stay in the Mitochondria by reducing external needs?
Study: Mitochondrial Fatty Acid Synthesis Type II: More than Just Fatty Acids. Discusses mcts like mct8 and 10, the fas pathway where mct8 is substrate for mitochondrial lipoic acid.
Perhaps the bulletproof coffee can help support internal lipoic acid production?
Next question is Mitochondria nad supporters. Coq10, Boron, k2, and methylene blue. The last one seems to jump all the complexes right to 5 for atp.
MB appears to raise body temp and improve nad+ at each stage. Perhaps this could be a kick starter while employing the calcium pyruvate, disodium succinate, a-ketoglutarate and stearic acid?
I can’t bring myself to consume anymore supplements. You should release a multi. Side note. In the comments of last video you expressed enthusiasm about coconut oil. A video about its benefits would be interesting. It went from being considered this amazing weight loss secret about 12 years ago then eventually dismissed as a scam and empty calories roughly 6 years ago.
I am working on exactly that, in fact :)
@@fireinabottle3410 the multivitamin or the video about coconut oil?
Brad is doing amazing work 👏 thank you ❤
Great video. I recently was reading a long thread on ray peat forum about supplementing with gelatin. What are your thoughts about too many muscle meats versus organ meats, considering the different amino acid profiles?
Brad I love your content and greatly appreciate you! Id be interested in knowing your opinion on Avocados if you ever want to cover that. Id imagine it would be like olive oil, but avocados have more phytocompounds id assume.
BCAA supplementation also lowers monoamine neurotransmitters, perhaps bc of the effect on methylation you outlined.
Great as usual Brad. What about longevity in all this - if you remain thin/lean and in a bit of torpor do you live longer? (Albeit feeling hungry and maybe miserable!). ie calorie restriction associated with longer life etc
Im a fat dummy.
Just tell me what i should do ;)
So is there a conclusion about protein? If leaness is goal - Keep BCAAs lower? (Is this all those thin vegetarians)
I don’t necessarily like to have firm conclusions. I suspect some will do better on high protein- perhaps the majority based on studies. I suspect a significant minority would do much better with low BCAA consumption.
This might explain skinny vegans but also perhaps one of the reasons why starch eating cultures -Thai rice farmers, the Tsimani - have such high metabolic rates.
I'm sorry brad I need some clarification. at 20:08 you have on the screen and mention that BCAA's are catabolic meaning break down of tissue. Shouldn't that be that BCAA's are anabolic meaning building? or should I rewatch?
I had the same thought. Either anabolic or anti-catabolic.
What milligram B6 p5p do you recommend? They all come in 50-100mg which I think is way too high. I can find 25mg from Seeking Health. I do have 2 mthfr mutations.
What are the best saturated fats? Palmitic/Stearic?
i might have missed it but why is AKG low?
That’s actually unclear to me. It’s possibly it gets used up in a competing reaction. I suspect that it’s not known.
@@fireinabottle3410 hmmm
i asked chat gpt for some pointers on what could affect levels of AKG.
Hypoxia-inducible factor (HIF): A transcription factor that regulates the expression of genes involved in oxygen homeostasis. HIF binds to the alpha-ketoglutarate-dependent enzyme prolyl hydroxylase, which regulates HIF stability and activity.
Isocitrate dehydrogenase kinase/phosphatase: These enzymes regulate the activity of isocitrate dehydrogenase, an enzyme that produces alpha-ketoglutarate from isocitrate in the Krebs cycle.
Pyruvate dehydrogenase kinase/phosphatase: These enzymes regulate the activity of pyruvate dehydrogenase, an enzyme that converts pyruvate to acetyl-CoA, which is a substrate for the Krebs cycle.
Sirtuins: A family of proteins that regulate metabolism, stress responses, and aging. Sirtuins require NAD+ as a cofactor and are involved in the regulation of alpha-ketoglutarate levels by modulating the activity of isocitrate dehydrogenase.
AMP-activated protein kinase (AMPK): A protein kinase that regulates energy metabolism and cellular homeostasis. AMPK is activated in response to cellular energy depletion and stimulates the production of alpha-ketoglutarate by activating isocitrate dehydrogenase.
Nuclear factor erythroid 2-related factor 2 (Nrf2): A transcription factor that regulates the expression of genes involved in antioxidant defense and detoxification. Nrf2 stimulates the production of alpha-ketoglutarate by activating the expression of enzymes involved in the Krebs cycle.
Alpha-ketoglutarate activity can also be regulated by post-translational modifications including phosphorylation, acetylation, and sumoylation. These modifications can alter the enzyme's structure or function and affect its activity. For example, acetylation of alpha-ketoglutarate dehydrogenase can inhibit its activity, while phosphorylation can activate it. Sumoylation may also play a role in regulating alpha-ketoglutarate dehydrogenase activity.
gives us some areas to think about.
4 weeks in a low-carb (
Are you OMAD?
@@MPiKMS72 usually 2 meals/day
@@lel-vj4ve you might try playing around with your protein to fat ratio, some people seem to respond differently to higher fat or higher protein. Some people have increased the food they eat for a while to break a stall too so called "priming". Do you eat a lot of dairy? Some people have broken through a stall by limiting dairy in favor of other foods.
These are just a few ideas off the top of my head. There are a lot of levers to pull and everyone might differ in their response.
Stop listening to quacks who resort to fear mongering just to sell supplements on their site.
‘Go Knicks’
Just got back new labs after around 2 years of strict low mufa/pufa (pufa as low as I can get it whilst eating well) and high saturated fat mostly from red meat/dairy eating intuitively including quite a bit of chocolate/bread with butter, veggies, fruit, cheese etc. Things not going as planned - total cholesterol 259 (not worried), HDL 48, TRIGLYCERIDES 225 (not good), LDL 166, risk profile 5.4 (not good). Fasting blood glucose 103 (still prediabetic). And here is the really bad one....FASTING INSULIN 21.4!!! So I am severely insulin resistant. I don't eat any junk food apart from if you call toblerone junk lol.
I think my doc will probably try to get me on statins (I'm 47 y/o female) and recommend a low fat diet (meh). Weight still the same after 2 years around BMI 27. Any ideas why this might be? Or is this not to be worried about? After listening to the videos on olive oil and MUFA I don't really know what to do differently as that would be my first thing to try. Or maybe giving up the sugar in the chocolate?? I also drink a fair bit of wine/beer - maybe that's the reason for the high triglycerides. Temps usually reach 37 after lunch.
Alcohol is definitely associated with high triglycerides.
How has your body temperature changed? Dairy products from a store or from a farmer?
@@fireinabottle3410 that makes me so sad lol.
@@VladlenTerezhe-yd7wb body temp still the same as it ever has been. But I am also a weirdo in that I don't come from a background of seed oils all my life
@@VladlenTerezhe-yd7wb From a store and from local farmers when it is goat cheese. I live in Chile not the US. The dairy is all from grass fed cows and wild roaming goats here.
👏👏👏👏