Niacinamide Lowers Fatty Acid Oxidation By Inhibiting SIRT1

Discussion in 'Scientific Studies' started by haidut, Mar 19, 2014.

  1. haidut

    haidut Member

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    Many of you have probably heard of the resveratrol "miracle pill", which works by activating the SIRT1 "longevity gene". Well, the whole story is a classic example of medical fraud, and resveratrol was a miserable failure in clinical trials. This is not surprising to me as resveratrol has similar structure to estrogen and is estrogenic in vivo as well. Ray has written about his suspicion that the SIRT1 gene is nothing special and activating it will probably have detrimental effects such as causing cancer. It looks like some of the bad effects of that gene are caused by the fact that activating it turns on fatty acid oxidation by the mitochondria. Niacinamide is a known SIRT1 inhibitor and fatty acid oxidation inhibitor, but to the best of my knowledge Ray has not written about how niacinamide achieves its latter effects. This study claims that the two effects mentioned above go hand in hand. Namely, anything that inhibits SIRT1 will inhibit fatty acid oxidation, and niacinamide is one such compound.
    The only downside to this study is that the concentration of niacinamide / nicotinamide used
    was in the range of 5mM - 10mM. Taking a massive dose of 6g niacinamide orally achieves only 1mM concentration in humans. However, niacinamide does build up in tissues and hopefully lower doses taken over longer period can also achieve this effect.

    Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. - PubMed - NCBI
    "...We have recently identified GCN5 as the main PGC-1α acetyltransferase and a negative regulator of PGC-1α biological functions (Lerin et al, 2006). We therefore investigated whether GCN5, by opposing SIRT1-positive effects, would negatively regulate PGC-1α function on mitochondrial and fatty acid utilization genes. Indeed, in C2C12 myotubes, GCN5 largely abolished PGC-1α-induced mitochondrial, fatty acid utilization and mitochondrial transcriptional regulator gene expression (Figure 5A). As C2C12 muscle cells express low levels of endogenous PGC-1α, we again used primary skeletal myotubes to analyze the effects of GCN5 expression. The same pattern of gene expression was observed in these cells, but without ectopically expressing PGC-1α (Supplementary Figure S1). To support that these effects of GCN5 were mediated through acetylation of PGC-1α, we used the SIRT1 inhibitor, nicotinamide. Consistent with the effects of GCN5, treatment of C2C12 or primary skeletal muscle cells with nicotinamide caused a decrease in expression of PGC-1α targeted mitochondrial and fatty acid utilization genes (Figure 5B and Supplementary Figure S2). To demonstrate that these effects were dependent on SIRT1, we again used SIRT1−/− MEFs. As shown in Figure 5C, nicotinamide decreased expression of cyt-c and MCAD by approximately three-fold in SIRT1+/+ MEFs; however cells that lack SIRT1 did not decrease these genes in response to nicotinamide. Moreover, and consistent with the effects of transcription on these genes, PGC-1α potently induced fatty acid oxidation that was blocked by expression of GCN5 or nicotinamide treatment (Figure 5D). Together, these results suggest that acetylation of PGC-1α is a regulatory chemical modification that controls the oxidative function of this transcriptional coactivator."

    Given that fatty acid oxidation is a hallmark of stress and cancer, inhibiting it (by inhibiting SIRT1) explains some of niacinamide anti-cancer effects. So, it looks like Ray is right again in his statement linking SIRT1 to cancer.
     
  2. Vinero

    Vinero Member

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    Sources of resveratrol seem to be: Red grapes, red wine, peanut butter, dark chocolate, blueberries and soy.

    I don't include any of these things in my diet anyway except for the dark chocolate, which is my primary source of magnesium.
    Almost all foods are pathetically low in magnesium except dark chocolate/cacao
    That's why I eat some everyday.
     
  3. charlie

    charlie The Law & Order Admin

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    Obligatory.

    [glow=red]Ray Peat right again!
    [/glow]


    :mrgreen:
     
  4. himsahimsa

    himsahimsa Member

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    If the body is cranking along well and metabolism is good (health), running glucose low in the absence of nicotinamide might not be such a bad thing once in a while in order to deplete stored PUFAs. (Making hay while the sun shines.) Because, in the event of sickness, when stress is already elevated, and added burdens are not easily born, a fever can rapidly deplete glucose leading to the generation of stress hormones and the use of fatty acids for energy. PUFAs then enter the blood and mitochondrial metabolism exactly when the system is weakest, further increasing stress. A downward spiral.
     
  5. jyb

    jyb Member

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    Wouldn't use of FFA for energy occur during late sleep every night anyway?
     
  6. Elephanto

    Elephanto Member

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    Aspirin may promote mitochondrial biogenesis via the production of hydrogen peroxide and the induction of Sirtuin1/PGC-1α genes
    http://www.ncbi.nlm.nih.gov/pubmed/23228932

    "We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1"

    SIRT1 activation by methylene blue
    http://www.ncbi.nlm.nih.gov/pubmed/24486702

    Pretty interesting that you and Ray picture sirt1 as a cancer promoter, yet you claim the many benefits of methylene blue and aspirin, when both promote sirt1. So what's the verdict?
     
  7. OP
    haidut

    haidut Member

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    The first study says that aspirin increases H2O2 like you said and the second study says MB increases NAD/NADH ratio. While both studies claim that this results in induction of SIRT1, I'd stay away from substances that directly activate SIRT1 (resveratrol). Here are two studies that discuss the dual nature of SIRT1 - i.e. it is a tumor promoter as well.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631220/
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764469/
     
  8. Such_Saturation

    Such_Saturation Member

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    I think, and you can also see this with caffeine, the cells simply become more hungry and you get the autophagy response which may or may not cause sick mitochondria to be digested. Now that you would choose to induce this through, or even compare caffeine to, caloric restriction, is your choice. But I think "SIRT1" is just a piece of code that gets caught in the crossfire.
     
  9. OP
    haidut

    haidut Member

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    Didn't you post something on lithium working through this mechanism - i.e. causing sick mitochondria to die off?
     
  10. Such_Saturation

    Such_Saturation Member

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    Yes, it likewise messes with autophagy, fat and SIRT. viewtopic.php?f=36&t=6498

    http://www.ncbi.nlm.nih.gov/pubmed/24464007
     
  11. Mito

    Mito Member

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    The answer is yes according to tyw, "First, no matter what you do, fatty acids will have to be used at some stage through each person's circadian cycle. In terms of fuel availability, fatty acids are always in much larger amounts in the body, and will constantly be mobilised to some degree. Circadian cycling of fuel use should always be the norm, and proper entrainment to the cycles of the sun will also come with relative changes in fuel use through the day. A simplified stance will be:
    - During wakeful (daylight) hours, more fuel use, and more carbohydrate use
    - During sleeping (night time) hours, less fuel use, and proportionately more fatty acid use"
    https://raypeatforum.com/community/posts/210229/
     
  12. Nikki

    Nikki Member

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    Not that niacinamide isn't a great supplement for overall health, but I was researching blood pressure recently and found that increase in blood pressure does not necessarily correlate to heart attack. Some of the studies and articles I were reading or suggesting that higher than the Baseline normal BP is actually beneficial in many cases. I don't have sources to site because I don't feel well enough to do so now. I just hope somebody else might look into that and add some comments here.
     
  13. MrThyroid

    MrThyroid Member

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    so aspirin and niacinamide blocks fat oxidation, espiacially β-Oxidation. So if i want loose stubborn fat should i avoid aspirin and niacinmide and instead take niacin, caffeine and nicotine.
    Or whats the conclusion pls i need to know
     
  14. Vinero

    Vinero Member

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    Stubborn bodyfat is caused by Low DHT. I suggest eating more zinc. Low dose aspirin and niacinamide will not stand in the way of getting a lean body in my experience.
     
  15. MrThyroid

    MrThyroid Member

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    i had actually extremely high DHT until i lost extremely fast fat (pufa) due it and fucke.d up my whole system now its almost 2 years since this happened.
    Im recovering extremely slowly but steadily.
    I noticied that liposomal glutathion, coffe , selenium (brazil nuts), vitamin c ( citrus fruits) and cruciferous ( garlic, onion) are the only things which help me.
    Its so dumb those pufas in stubborn keep releasing FFA in my bloodstream which leads to permanent inflamation, my balls are permanently imflammed sucks so hard. But i guess its the only way too loose this timebomb(pufas) before it explode.

    Now you say take niacimide and aspirin. Yes aspirin so awesome i get urgently leaner in stomach everything gets leaner hormon production goes in one day up . But the problem is i wont loose this stubborn pufa with aspirin niacinamide combo its never ever happen.
    In my opinion its obvious how to loose pufa by burning it, but like haidut said aspirin and niacinamide blocks beta oxidation in first place. Or im wrong did i miss sth ?
    Pls guys i need help i also thought about aspirin and caffeine combo. Maybe due the coffe i still get enough beta oxidation to burn pufa also if im on aspirin.
    I could also stack some nicotine gums for the higher DHT. My stack would be aspirin( or maybe ginseng lesser ASS), caffeine, nicotine.

    Any suggestion ?
     
  16. Curiousman

    Curiousman Member

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    Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization

    Abstract
    Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N1-methylnicotinamide (MNAM). Nnmt is an emerging metabolic regulator in adipocytes but its role in the liver, a tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and in humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect, which is required for their metabolic benefits. In summary, we describe a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.
     
  17. Curiousman

    Curiousman Member

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  18. Kyle Bigman

    Kyle Bigman Member

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    Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in ...https://www.ncbi.nlm.nih.gov/pubmed/28417163

    Haidut, can you help me interpret this study? Would this mean that niacinamide only inhibits Sirt1 short term and then acts much like reservatrol?
     
  19. OP
    haidut

    haidut Member

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    It would depend on how much of it converts into NAD. Lower doses niacinamide, up to maybe 500mg daily, probably end up mostly as NAD and thus may activate SIRT even though they would inhibit it in the first 4-6 hours after taking. However, higher doses of 750mg+ daily would have predominanly an effect on SIRT as niacinamide instead of NAD and thus likely inhibit it. This is what the study below found - inhibition of SIRT in vivo with HED of about 7.5mg/kg daily.
    Long-term Treatment With Nicotinamide Induces Glucose Intolerance And Skeletal Muscle Lipotoxicity
     
  20. Kyle Bigman

    Kyle Bigman Member

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    So,I know Ray Peat says to take low dosages throughout the day. Would you recommend against this in light of SIRT activation?
     
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