Ketones inhibit lipolysis

Petro just posted a brief article about acipimox & the insulin hypothesis.  Similar to insulin’s forte, acipimox inhibits lipolysis.  This leads to expansion of adipose tissue, and eventually, weight gain.

Acipimox acts on the same receptor as niacin and ketones, GPR109a.  That is, all three of those agents inhibit lipolysis.  We’ve discussed some of the implications of this on fuel partitioning HERE.




In brief, plasma lactate reflects muscle glycogen use.  During activity, you usually burn a mix of glycogen and fatty acids; more of the former with higher intensity activity (unless theoretically if you’re ketoadapted).  By inhibiting lipolysis with niacin, acipimox, or beta-hydroxybutyrate, the body is forced to rely more heavily on glycogen and this is reflected in higher plasma lactate.



Theoretically, by forcing the body into this higher intensity fuel usage, this could be a mild performance booster and might even explain the 2% advantage seen in the Cox study on ketone supps.  Probably won’t work with acipimox because it’s not a fuel; at least ketone supps are providing kcals.  Niacin: maybe, but for different reasons.


However, caution is warranted when taking ketone supps out of the #context of exercise.  Similar to mice given acipimox literally in the drinking water, ketone supps may promote an environment supporting expansion of adipose tissue by inhibiting lipolysis via GPR109a.

Also, ketone supps are sort-of-like empty calories; when you could be burning body fat (or glycogen), you’re displacing it with an exogenous fuel source.



So basically my advice remains unchanged: if that 2% performance advantage will benefit you, go for it.  Also potentially useful for mild cognitive impairment.  Not sure if Regular Joe’s should make ketone supps an everyday thing, though.




More on ketone supps HERE.


I think the whole “ketones inhibit lipolysis” mechanism may have evolved *specifically* to prevent ketones from getting too high during starvation.  You’d be losing a lot of energy in the form of ketones via urinary excretion, ramping up renal gluconeogenesis, and wasting a lot of glutamine.

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  • Martin

    Peter wrote about ketones inhibiting lipolysis many times. I wonder what happens in a starvation or fasting mode: ketones increase dramatically but so does lipolysis. What am I missing??

    • I think the whole “ketones inhibit lipolysis” mechanism may have evolved *specifically* to prevent ketones from getting too high during starvation. You’d be losing a lot of energy in the form of ketones via urinary excretion, ramping up renal gluconeogenesis, and wasting a lot of glutamine.

      • valerie

        “…ramping up renal gluconeogenesis”

        You got me curious. What controls renal gluconeogenesis?

        • acidity

          glutamine provides the NH3 to secrete ketones as ammonium salts and the carbons go to glucose

      • People think insulin’s primary function is to lower glucose.
        It’s primary function is to store nutrition *OR* spare nutrition. Insulin spares protein, spares minerals/electrolytes, and it limits FFA waste in starvation. That’s what it does here with FFA and ketones .

    • You arent missing anything. The dance between starvation/insulin deficiency, FFA elevation -> liver ->AcAc -> BOHB -> insulin release -> REGULATION.
      The body regulates its FFA/ketogenesis using insulin during starvation or high fat diets, just as it ordinarily does glucose and insulin on a typical diet.

  • Martin

    Also, it’s interesting that dr Richard Veech, who has done research on ketones for many decades now, does openly advocate ketone esters supplementation alongside regular (higher carb) diets. It does sound like a recipe for disaster.

    • maybe once in a while for competition, but if using more frequently (like for MCI or some other reason), a low carb diet seems prudent

  • TechnoTriticale

    At least one of the current (BHB salt) exogenous ketone products is surreptitiously pitching their product as a weight loss aide, despite D’Agostino telling them “probably not”. This looks like one of the metabolic reasons why.

    Exogenous ketones might be indirectly helpful via appetite control and possibly mitigation of any craving due to hypoglycemia (for those remaining on, or weaning off, a full-time glycemic diet).

    • Yeah I don’t think ketone supps will work particularly well for weight loss, but as NY said, “ketones do many other things”

      that’s what I’m currently more interested in, like their role in MCI, HDACi, circadian biology, etc

    • In my experience, ketone supps actually induce “hypoglycemia”, which is actually FFA suppression and beta oxidation failure from insulin release. They are worse than useless, at least for anyone who is fragile enough to require assistance with appetite/weight control.

  • NY

    Are we saying ketosis is fattening? How their anti lypolytic effect compares to the anti lypolytic effect of carbs is an interesting question. It’s not easy to gain weight while being in ketosis although it is possible, some people do get hungry a lot even when in ketosis and can’t lose weight. However, ketones do many other things; check out hyperlipid.

    • thanks, I’m familiar with Petro’s work. Brilliant.

      also, ketosis isn’t fattening!

      • Amy B

        Re: Ketosis isn’t fattening. Yeah…something inhibiting lipolysis or being “insulinogenic” doesn’t equate to its being fattening. (Ex: Protein is insulinogenic, but so what? Many people do well *increasing* protein intake to lose body fat [at least in a reduced calorie diet]). I think people who write about this stuff (myself included) should emphasize that things are not really black and white, binary on/off type things. Lots of regulation and feedback loops, like Woo says. None of these things happen in isolation; they all affect each other, like zillions (to be precise) of biochemical seesaws constantly modulating up or down, with the bonus that many of the individual seesaws are connected to each other in a big web. I think you do a good job of conveying this, Bill, but its up to us readers to appreciate the significance of it.

      • Holly Holzer

        thanks for that as like Emmie said the title ketones inhibits lipolysis had me confused.

  • rs711

    You say “plasma lactate reflects muscle glycogen use” ==> sort of. yes but not quite linearly. details details….

    From <>

    – humans at rest 3 mM muscle L-lactate, 1.4 mM blood L-lactate
    – “Although net L-lactate production is increased by muscle contraction and the amount of L-lactate released by active muscle increases from rest to exercise, only high-intensity exercise raises plasma L-lactate concentration while plasma L-lactate level remains similar to the value at rest after mild- and moderate-intensity exercise”

  • Antonio

    If niacin inhibits lipolysis (and induces weight gain), where do all those FFa’s come from after 2 hours?

  • Emmie

    OK, I’m confused. Shouldn’t your title be “Exogenous ketones inhibit lipolysis”? I don’t take supplemental ketones, but I lose best when I’m in ketosis.

    • it happens w/ endogenous ketones, too, but I doubt many people on a LC/ketogenic diet get high enough ketones to make an appreciable impact

      • by definition if one has endogenously produced ketones high enough this requires very low insulin levels to augment lipolysis and FFA levels enough to produce them in the liver. All these ketones might do in this context is regulate metabolism to prevent acidosis and a type 1 diabetic like situation.

    • No, all ketones inhibit lipolysis, but if they are produced naturally, you are getting them by avoiding food and lipolysis itself. It’s merely that ketones produced from diet induced lipolysis, are a regulatory break for the same lipolysis that produces the ketones.

      Bill is not suggesting endogenous ketones induce insulin/fat gain, only that taking extra is NOT a weight loss hack. It may be an energy hack, but so is sugar.

      • Emmie

        Which is why I suggested he focus his title and discussion on ‘taking extra.’ It’s too confusing to conflate endogenous and exogenous ketones in the same discussion.

      • Sally Oh

        It’s a weight loss hack because it suppresses appetite. At least that’s what exo ketones do for me.

    • Amy B

      Someone correct me if I’m wrong here, but you’ve observed that you lose best when you’re in ketosis because the ketones are an indicator of lipolysis. Elevated ketones are the result, not the cause, of lipolysis. Meaning, you’re breaking down fat, and the results of that are fat loss and elevated ketones. The ketones don’t come first and don’t steer the ship. *Very high* amounts of ketones inhibit lipolysis because if you have a large amount of fuel (ketones) coming in from the outside, then there is no need to break down your own adipose stores to get some, and insulin is the anti-catabolic signal. (This is part of what is compromised in type 1 diabetes, right? Their ketones go up and up and up, but because there is no insulin (or barely any) to suppress the lipolysis, they waste away because of nonstop breakdown of their fat stores. You *want* ketones (maybe especially endogenous ones) to be at least mildly insulinogenic. Like Woo has said, it’s all just regulatory feedback and it works very well when… well, when it works well. 😉

      • Exactly.

      • Emmie

        Yes, you’re wrong–or at least misread my post. I only said that I lose best when in ketosis (i.e., eating very low carb). I never claimed that the ‘ketones are an indicator of lipolysis.’ I was only confused about how ketones could suppress lipolysis, since I lose (and now maintain) my weight with a ketogenic diet. Bill answered that only a very high level of endogenous ketones would inhibit lipolysis, and that made sense to me.

        I realize that as a non-diabetic, insulin will regulate my level of ketones, so the inhibition Bill writes about is irrelevant for me, which is why I had suggested he title his post to be about ‘exogenous’ ketones.

        But your comments confuse me further. A type 1 diabetic who is undiagnosed will lose weight very rapidly because there is no insulin to control blood glucose. You say that their ketones go ‘up and up,’ which I’d agree with. So why isn’t lipolysis inhibited–which Bill claims happens with a very high level of endogenous ketones?

        • insulin is a much more potent inhibitor of lipolysis than ketones

          • Emmie

            Yes. that’s why I never test for ketones, but just focus on keeping my insulin low.

        • Amy B

          I don’t know, except for the absence/insufficiency of insulin. Maybe there’s an additional feedback mechanism that is also compromised in T1D, whereby the very high ketones don’t inhibit lipolysis. But I don’t know.

  • Great entry Bill.
    Seems evident we evolved for ketones to inhibit lipolysis specifically to regulate FFA metabolism during starvation, as you mention. FFA yeild ketones, ketones inhibit lipolysis and FFA in a neat little cycle.

    Ketone sups for weight loss are beyond useless. You might as well drink sugar, for the same effects. Quick energy, regulatory insulin to suppress lipolysis and prevent energy overload. Same/same. Ketone supps gave me “hypoglycemia” just as sugar might. Worthless. The only benefit i see for this are athletes who prefer to use ketones as fuel instead of sugar, but IMO sugar is cheap, ketone supps are not, I fail to see the point.

    • Sally Oh

      Weren’t useless for me and many many people I know. Appetite suppression is no small thing to me.

      You say exo ketones gave you hypoglycemia? Did you take your bs right after drinking it? Would like to know how you determined this so I can try it, too.

  • Imagine adipose tissue in a lipolytic milieu as a faucet with water coming out at a theoretical rate of 100%. Ketone supps might bring that down to 80 or 90%. Insulin to 30 or 40%. ANP to 110%. Sympathetic NS activation to 120%.

    Now, try combining them all and play around with the doses, concentrations, and duration of exposure… regulation of adipose mass can get complicated