Ketone bodies as signaling metabolites

*non sequiter*

One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.”  It responds to a glucose metabolite and activates transcription of lipogenic genes.  Insulin helps.  Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:




More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation.  Benefits of fasting sans fasting?  Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.

Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate.  Anti-aging (mostly worm studies, but still).




“Fat burns in the flame of carbohydrate” is a misnomer.  In the absence of dietary carbohydrate, some fat turns into ketones in the liver (here’s the why and how) , which are subsequently burned in the periphery.  Different tissues.  Thus, they’re not burned in the liver but are burned after conversion to ketones.  1) I never really liked that phrase; 2) it’s kind-of-wrong (or at least misguided); and 3) ketones are much more interesting than a source of energy (eg, HDAC inhibition).


Fat burns in the flame of carbohydrate


Ketone production is regulated in part by FOXA2, which activates HMG-CoA synthase, an enzyme inhibited by insulin.  FOXA2 works better when it’s acetylated, which is enhanced by ketones (ketones enhance ketone production in this regard).

However, ketogenic diets aren’t super-ketogenic (eg, >10 mM), in part, because ketones inhibit lipolysis via directly interacting with the nicotinic acid receptor on adipocytes.  This is one reason why ketogenic diets don’t produce ketoacidosis.

The higher level of free fatty acids seen in ketogenic diets are obviously important for their pleiotropic effects on metabolism (eg, see Hyperlipid), but ketones are pretty cool, too.



Autophagy and longevity?  Neuro- and cyto-protection?  I’ll take it.

–> Histone acetylation (or inhibition of deacetylation): ketones & butyrate.


HDAC inhibition


Disclaimer: this system is incredibly complicated.  The balance between histone acetylation (ketones & butyrate) and deacetylation (SIRT1) is important.  Different aspects of both pathways are activated with a ketogenic diet: this is confirmed by the overlapping effects of ketogenic diets (ketones) and calorie restriction (SIRT1).  For those intolerant to prolonged periods without food, no worries, intermittent fasting is not necessary!  Low carbohydrate dieting accomplishes many of the same things.  And anyway, three 700 kcal meals cause less metabolic disruption than one 2100 kcal meal, assuming low net carb.

or better yet: big breakfast, modest lunch, and small dinner to take advantage of the tissue-specific circadian regulation of insulin sensitivity and propensity for fat storage.


calories proper


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  • Tuck

    So Dr. Bill, what is the relationship between butyrate (the short-chained fatty acid) and beta-Hydroxybutyric acid (the ketone)?

    Are butyrates a precursor to BHB?

    • Bill Lagakos

      Yes – a lot of butyrate is oxidized in intestinal cells, but some also ends up in acetoacetate.

      • rs711

        Good stuff Bill.

        Thomas Seyfried readjusted his ideas on the need for caloric restriction when it came to ketogenic diets and cancer. I’m probably somewhere between his and your perspective on that. Something tells me that the absence of calories in itself must have some sort of distinct action (whether relevant or not to the purposes of ketosis in cancer). After all, eating (anything) revs up your microbiome (the little buggers start farting), immune system, parts of the ANS/CNS and general ‘metabolism’ so…what does that add up to? Dunno.


        See here for more on butyrate doing some sweet HDAi stuff in colonocytes: It’s interesting how butyrate from RS for e.g. & ketosis share overlapping mechanism of (+) action in this case.

        ” ‘butyrate modulates canonical Wnt signaling (Lazarova et al., 2004) and has been shown in some studies to promote CRC (Freeman, 1986; Lupton, 2004)’…Canonical Wnt signaling = regulates gene transcription, cell size and calcium levels inside the cell; all majorly important factors determining if cells live or die…so yes, of prime interest in cancer ”
        “Details about 2 histone-base mechanism butyrate uses in its **seeming** flip-flops:
        …Colonocytes near the base of crypts receive tiny amounts (uMs) of availablebutyrate and so makes us of the acetyl-CoA/HAT mechanism for histone acetylation (inhibiting aberrant proliferation). The “acetyl-CoA/HAT mechanism involves metabolism of butyrate in the mitochondria followed by the subsequent ACL-catalyzed production of acetyl-CoA.”
        …Luminal colonocytes however receive more available butyrate (maybe in mM quantities) and thus uses another histone-based mechanism (for inhibiting aberrant proliferation), HDAC-inhibition, where higher levels of butyrate surpass the oxidative capacity of the cell, causing it to accumulate butyrate within.”

        • Gemma G


          “Something tells me that the absence of calories in itself must have some
          sort of distinct action (whether relevant or not to the purposes of
          ketosis in cancer).”

          Sure. What about tRNA, namely 5? tRNA halves?

          5? tRNA halves are present as abundant
          complexes in serum, concentrated in blood cells, and modulated by aging
          and calorie restriction

  • Jack Kruse

    Bill I am happy to see you link this to HDAC SIRT 1 and NAD+. In fact, I love it.

    • Bill Lagakos

      SIRT1 is an HDAC, ketones & butyrate are HDAC inhibitors, and CLOCK is a histone acetyltransferase. Too many links to overlook!

  • John Pierce

    “Fat burns in the flame of carbohydrate” is what is told to students to disqualify carb absent diets, atleast in my experience in academia. I never believed it to be true but had yet to research the reasoning behind it.
    Nice post Bill.

    • Bill Lagakos

      Thanks, John.

      “…is what is told to students to disqualify carb absent diets”

      this is a phenomenally complicated attempt to debunk low carb diets! Need a very good understanding of intermediary metabolism to understand it!

  • Chris

    Ketogenic diets also activate AMPk, regardless if the diet is low-calorie or eucaloric. That contributes to mitochondrial biogenesis, decreased Akt and mTor signaling as well as other implications that could contribute to prolonged life-span.

    Champ brilliantly put it in this study:

    Klement, R. J., & Champ, C. E. (2014). Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation. Cancer and Metastasis Reviews, 33(1), 217-229.

  • Bill Lagakos

    Class IIa histone deacetylases are conserved regulators of circadian function.

  • Zach

    Can you elaborate on this sentence: “three 700 kcal meals cause less metabolic disruption than one 2100 kcal meal, assuming low net carb.”


    • Bill Lagakos

      The first half:2100 kilocalories is a lot of calories & nutrients all hitting the bloodstream at once, and it’s going to cause big effects on hormones.
      Three smaller meals will be less disruptive to the relatively “fasting-like” phenotype.

      The second half:
      Low net carb meals are also less disruptive to the fasting-like phenotype.

      • Pat D

        I am sure you have a paper or two that have looked at this, but “hitting the bloodstream at once” would refer to primarily the CHO? as the fat and protein in that large of a meal could take many, many, many hours to reach peak excursion in the blood. My thought behind an intermittent faster who eats once a day is that the meal is so large they end up digesting and assimilating those nutrients (macro) for the equivalent hours (or potentially very close) to that of someone who would eat 2-3 meals in that same time period…thoughts??

        • Bill Lagakos

          Not “many, many, many hours” … the larger the dose (of any nutrient, fat protein or carb), the higher the peak levels in blood. It will take longer to clear as well.
          2100 kcal = super-high peak of nutrients in blood.

  • Jack Kruse

    Couple of things for you to think about. Sirt 1 and 6 are the big STACS in humans. Guys like Rosedale have made lots of bad guesses using Sirtuin data using Sirt2-5. Kenyon alert. But there is something interesting cooking about Sirt 3. It needs oxidative damage to be present to manifest its effects. This maybe why biology is missing its significance. This is why I tell people some XRT and photo-damage should go and and hand with their chocolate and Malbec. So here are some thoughts: systematic exercise upregulates PGC-1alpha and increases SIRT3 expression as well as associated CREB phosphorylation. You just mentioned CREB and this is why I am mentioning it. CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing thetranscription of the downstream genes. I think it uses kinetic isotope effects to work. It appears cellular stress causes SIRT3 to translocate from the nucleus to the mitochondria and to be highly expressed in brown adipose tissue only during uncoupling and when ATP can’t be made. This also happens during REM sleep. It is also why REM sleep is tied to longevity and health in my humble opinion. SIRT3 is a mitochondrial sirtuin protein that serves to deacetylate acetyllysine-modified proteins in mitochondria. It’s another HDAC.

    (PGC-1alpha) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. Art DeVany loves this topic. PGC-1alpha induces several key reactive oxygen species (ROS)-detoxifying enzymes. It has been shown in mice (hate mice studies) that PGC-1alpha strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Sirt3 was found essential for PGC-1alpha-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Big deal here is that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. So SIRT3 integrates cellular energy metabolism and ROS generation using the redox potential of the cell as its guide. It is not a CRON story. Now where it gets interesting is your and mine favorite topic…….circadian biology……

    • Jack Kruse

      Extended wakefulness of modern society affect the redox state of Locus ceruleus cells in the brain. This is a nucleus neurosurgeons pay lots of attn too.

      • Jack Kruse

        Bad sleep cause massive oxidation and a loss of reduction = low NAD+ levels in the mitochondria. The Locus ceruleus nerves are among the most metabolically active neurons that fire at increased rates across sustained wakefulness. Blue light really french fries these cells causing them to lose DHA in their cell membranes. If this is sustained chronically, mitochondria swell, release less IR light to water micelles, and this lack of heat release allows mitochondrial swelling and a loss of the adaptive mitochondrial metabolic responses. Redox injury results screwing sleep, learning, and longevity. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) seems to coordinate how electrons and protons are handled by mitochondria along with the redox homeostasis. Normal circadian signaling of daily light oxidation during wakefulness upregulates SirT3 and antioxidants in these critical neurons. Darkness is how nature protects metabolic homeostasis. Where the mice crap interests me is that in data where mice are lacking SirT3 by experimental design, these mice lose the adaptive antioxidant response and get big time oxidative injury in the locus ceruleus across brief light times and wakefulness. I think this has massive implications for humans in cities. I just think the STACS are different but I would imagine the game plan is the same. Mice are nocturnal and we are not so this is why I hate mice food or sleep studies as you know. It is also why obesity researchers are clueless in my opinion. The more light becomes the key environmental driver the worse ECT does. First cytochrome 1 is taken out and we can’t make superoxide. This is T2D , but as time goes on it demolishes all the cytochromes because mtDNA is adjacent to cytochrome 1 and this mechanism destroys those 13 genes that make the cytochromes. This is when we see other more complex diseases like OSA, PD, ALS, AD etc………..We need researchers looking at Sirt 1 and 6 in humans to tease this stuff out.

        • Jack Kruse

          We also should remember that mitochondria are subject to evolutionary selection pressures due to altered circadian signaling within the brain and body clocks. This simple fact is why most researchers’ have been surprised that mitochondrial defects do not accumulate at high rates in tissues instead defective mitochondria are removed by the mitochondrial recycling programs that respond only to size and shape changed mediated by IR light and the the ability of water to constrict and condense water as it is heated.

  • Marcos Taquechel

    Great article. I love the common assumption by so many “Fat burns in the flame of carbohydrate” It becomes very evident as people try to lose weight by running a lot. I wonder if you have a diet rich in fats, say 60% cal from fat the body becomes more able to burn fat? I guess my question is. Is there such a thing as a metabolism that is more “prone” to burn carbs or fat? Since glucose is a readily available form of energy; could it be a certain preference for this energy production system?
    Don’t know if you are aware: I was having some problems with your site, some bug possibly with the encoding. Some pages lose their formating

    • Bill Lagakos

      Thanks, Marcos!

      “Since glucose is a readily available form of energy; could it be a certain preference for this energy production system?”

      Sure, and it is for many cell types… but that doesn’t mean you need to eat a lot of it 😛

  • Jack Kruse

    Bill saw this today and it makes the points about the need for small amounts of inflammation to stimulate SIRT action.