Wednesday, 3 July 2013

Ketogenesis, & Calorie restriction increases fatty acid synthesis

Malonyl-CoA: the regulator of fatty acid synthesis and oxidation

This is a short paper on ketogenesis and is well wroth a read imo. Very accessible even to the layperson. Interestingly, the ketone acetoacetate is the preferred substrate for fuel, chosen above even glucose. The liver is the only place ketones are synthesized, and the liver itself cannot oxidize ketones, it can only release them.

I was one of the people who thought that the switch for ketogenesis was simply the depletion of oxaloacetate in the liver mitochondria, but this is not true. Apparently the signal for ketogenesis is glucagon, aswell as a decrease in Malonyl-CoA in the liver. Once the glucagon signal hits the liver, the rate-limiting step for ketogenesis is simply the amount of fats reaching the liver from the adipose tissue. The liver will burn fats and generate ketones as fast as it can.

Anyway, just read the paper. !

Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates

This is another fascinating paper, I havent seen it discussed elsewhere, if memory serves.....

The paper is another fantastic demonstration of the futility of calorie restriction in attempting to lose weight. ( although that was not the objective of the study ). Mice subjected to 30% calorie restriction achieved a lower bodyweight,

After an initial 1- to 2-wk period of weight loss, CR mice reestablish a state of energy balance in which fat mass is preserved or even increased.

The paper talks about the nutrient balancing hypothesis, and that to remain weight stable, the food quotient must match the respiratory quotient. I.E. if you eat 300g carbs and 100g fats per day, then you must also oxidize 300g of carbs and 100g of fats per day to remain weight stable. If you burnt 150g of fat per day in that example, then the theory says you would lose fat mass.

So what happened in this study was that, the 30% calorie restricted mice were only allowed to eat 92mg of fat per day, but the researchers found the mice were oxidizing 367mg of fat per day.  Thats a calorie deficit of 275mg of fat per day, so the question was, why werent the mice losing weight? Why where they weight stable? They were in calorie deficit!

Well, the researchers found that the adipose tissue ( not the liver ) of the calorie restricted mice were actually synthesizing the missing 275mg of fat per day!.

In addition, in the first 3 h postfeeding, endogenously synthesized palmitate accumulated in the subcutaneous depot five times faster in calorie restricted mice than in ad-libitum controls,
Glucose is likely the predominant substrate for FA synthesis in the adipose tissue. Consistent with adipose playing a role in FA synthesis, Wetter et al. (45) demonstrated that glucose uptake is increased in adipose tissue of calorie-restricted rats.

And this...

 immediately after food was provided, fatty-acid synthase enzyme expression increased 50-fold in calorie restricted mice, leading to values nearly threefold higher than ad-libitum controls

Anyway, as I spoke of before, calorie restriction increases AgRP, this in turn blocks MC4R signalling. Maybe whats happening is that a lack of MC4R signalling in adipose tissue leads to elevated FA synthesis in white adipocytes? Well, even if this is not the mechanism, the point remains, 30% calorie restriction increases FA synthesis in your adipocytes.

But what about 20% calorie restriction? Maybe I can lose weight there without the FA synthesis? Or 15%??



  1. Very interesting, especially the DNL part!

    Regarding glucagon, I guess it shouldn't be surprising. If you think about type 1 diabetics and blocking glucagon ( -->hyperlipid), no insulin (which inhibits the action of glucagon to some degree) + glucagon = unrestrained ketogenesis leading to ketoacidosis. insulin + glucoagon = happy balance, hopefully. no insulin + glucagon inhibition = also somewhat of a happy place

    Regarding calorie restriction.. maybe the answer is -75% one day, +25% the other?

  2. I find this interesting regarding longevity. This also happens in methionine restriction. There is an increase in DNL and fat burning.

    Calorie restricted humans have higher levels of FFA in the blood. No doubt the same thing is happening in them.

    If you're interested in longevity at all, you might want to take a look at this paper.

  3. I just went through some fat tissue-destroing procidure by kavitation equipment while slightly calorie-restricted. About 10 lb and 2 inches are gone.

  4. I`m extremely skeptical when it comes to the benefits of calorie restriction and especially of methionine restriction. Purified diet restriction isn`t the same as restricting real food, and we should never assume that it is. Benefit of diet restriction may depend on the nature of the diet going in.

    To restrict just methionine, researchers resorted to a diet where the protein requirements were satisfied by isolated amino acids, instead of full proteins. There`s no reason to assume that eating low-methionine protein will yield the same result as exchanging methionine for glutamic acid in a purified diet will.

    Funny with the fat synthesis and calorie restriction--you always see those carbohydrate overfeeding studies in humans where fat synthesis is negligible.

    I wonder what would have happened if the mice ate more fat, and less carbohydrate?

    1. You might be sceptical until you learn why these restrictions extend life. I wouldn't recommend calorie/methionine restriction per se but it does causes a shift to fat burning which itself causes less damage to cellular components such as DNA and telomeres. Humans who have a defect in mitochondrial complex I live longer despite eating like everyone around them. Inhibition of complex II shortens life. Glucose uses primarily complex I, which leaks more ROS, while lipids use mainly the least leaky complex II.

      Also, when you genetically modify animals or give them drugs to up regulate or down regulate the genes affected by CR, MR (and keto), such as insulin, IFG-1, AMPK, SIRT1, mTOR or FOXO, the animals live longer without the dietary restrictions. I find it compelling enough to keep on with LCHF.

  5. Also, figure 2 in the calorie restriction-fat synthesis study is interesting.

    `Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates`

    If you compare the one chart showing respiratory exchange ratio from initial feeding for the ad-lib group, to the restricted feeding group charts, I think there`s strong evidence that the restricted mice fed in an increasingly shortened window--so maybe in a way, this is sort of an overfeeding experiment, as during feeding, carbs fed per unit time goes up (until the mouse runs out of food, at least).

  6. I shoulda read the study before the graph. CR Mice ate most of their food in a one hour period, ad-libs ate all day.

    1. re: feeding window

      yeh im not sure how much of a different that would make though. Although it is kind of a bad control of variables. Eating fat should not increase fatty acid synthesis, thats a positive feedback mechanism, and these tend to be much rarer in biology.

      One study found that fatty acid synthase enzyme was 2.4fold higher in adipocytes of obese vs lean people.

      In conclusion, although it is not possible to establish a true causability chain, our data are compatible with the notion that increased FASN expression in adipose tissue links excess energy intake and accumulation of body fat. Thereby, adipose FASN mRNA expression is significantly related to obesity, predominantly visceral fat accumulation, impaired insulin sensitivity and circulating adipokines. Moreover, in addition to chronic hyperinsulinaemia, elevated leptin and RBP4 serum concentrations in obesity might contribute to increased FASN expression. Thus, inhibition of FASN specifically in adipose tissue may be a promising therapeutic approach in the prevention and treatment of obesity and its complications.

  7. I could imagine it making a big difference... pubmed gives me nothing particularly relevant when I search intermittent fasting + fat synthesis... In Jenkin's glucose bolus vs sipping experiments, postingestion respiratory quotient was higher with the bolus, suggesting the possibility of increased fat synthesis. Also that study that Flatt and Acheson(?) did in three subjects with massive overfeeding of carbs--fat synthesis didn't get into full gear until glycogen stores were saturated--it might not be a matter of saturating glycogen stores so much as carbohydrate coming into the system faster than it could be sequestered.

    I guess it's always possible the food window is even secondary to the fat synthesis--an increased ability to sequester carbohydrate as bodyfat promoting an increase in the rate of eating. In the overfeeding study, it's possible that glycogen storage didn't become saturated, so much as fatty acid synthesis ramped up to the point where glycogen stores stopped increasing, there being an alternative route to dispose of glucose.


    This will be my last post on this thread (just to make sure nobody starts thinking I'm on a psychotic lipogenesis-inspired binge or anything like that).
    Dynamics of Recovery of Body Composition After Overfeeding, Food Restriction or Starvation of Mature Female Rats1
    Punchline; with the food restriction, lipogenesis is upregulated, during starvation it isn't. The authors suggest starvation is an extended period of lipolysis, the push is in that direction, little need for lipogenesis, since there's little available substrate anyways.

    "Starved rats regained protein earlier than body
    fat. Restricted rats recovered body fat much earlier than body protein or weight."

    Despite the early differences, if I'm reading things right in figure four, the starved rats don't end up any leaner in the long term.

    1. im a psychotic lipogensis freak :D

      Simply because I think its real in humans, I dont trust all those studies attempting to show lipogenesis is insignificant in humans I think its bollocks.

      I rapidly gain weight on a 5% fat, 75% carbohyrate diet of mostly whole foods ex potato/banana. And it AINT water weight either, there is a rapid expansion of the mid section and inner thighs.

    2. BTW thanks for the study I need to read it in detail when I have time.