Thursday, 20 September 2012

Circadian entrainment of metabolism

Warning!, sloppy and controversial post incoming!

My interest in the 23/1 intermittent fasting regime was piqued again recently after reading this link. Its about Ori Hofmekler's Warrior Diet, I read this book in the day, and although I did agree with it, the science has since come along more to support his ideas over the years. However I believe I can take his theory further and really get to the "liver" of the matter. I propose that Ori's theory is correct only in as so much as your circadian rhythm is aligned with the light/dark cycle.

If you maintain a circadian rhythm such that you sleep during the day and are awake at night, you should still be able to reap all the benefits of this 23/1, because the key point about the whole thing is really to fast during the hours following waking up, while your liver AMPK activity is high, and your liver is burning fat like crazy. Then, 9 hours or so after waking, when diurnal cortisol flatlines, liver AMPK activity starts to fall off, liver fatty acid oxidation slows, and this flips the switch that turns on hunger. You now have an approximately 4 hour window to get in your big daily meal. I say 4 hours instead of 8 hours because I dont advise eating a massive meal just before going to sleep.

Now I want to get more into the "liver" of the matter why Intermittent Fasting in general is oh so important .

First some important things to recall, hepatic fatty acid oxidation controls appetite. When hepatic fatty acid oxidation falls, hunger increases. I firmly believe that is NOT just a coincidence, but is actually part of the circadian rhythmic tone of food intake.

If you've been reading Peter's "Proton" series recently, you should know that fatty acid oxidation induces insulin resistance. High levels of fatty acid oxidation in the liver likely contribute to making it IR, especially upon first waking in the morning.

Next, the degree of PPARα activation in the liver is positively correlated with liver fatty acid oxidation. ( The paper in that post also suggests that PPARα activation may have the power to reverse fatty liver btw. )

I also went back to read the full text of this paper Lets ignore all the bullshit about high-fat-diet VS chow. I only want to look at the Ad Lib feeding vs IF aspect. The important graph from this paper imo, is this one....

Red line = IF mice, pink line = Ad Lib mice.

PPARα is a surrogate for liver fatty acid oxidation, we can safely say then that liver fat oxidation was substantially higher in the IF group. From the graph above we see that, after feeding in the IF group , PPARα shoots up then gradually declines until a few hours before feeding again. This essentially means that, all that time PPARα was elevated, hepatic fatty acid oxidation was increased and hunger was most likely diminished.

The decline in liver fatty acid oxidation before feeding is also important, because this would naturally make the liver more insulin sensitive. Exactly what we need before we cram food down our throats.

Fatty acid synthesis inhibits mitochondrial beta-oxidation. This right here, is the breaking of the CICO theory.

Malonyl-CoA, a product of ACC activity in the first step of fatty acid synthesis, allosterically inhibits mitochondrial carnitine palmitoyltransferase (CPT). CPT is essential for the transit of longchain fatty acids and acylcarnitine esters into the mitochondria for b-oxidation. Increased hepatic malonylcarnitine levels in FA mice, but not in FT mice (Figure S4B), are indicative of the specific disruption of fatty acid oxidation caused by impaired entry of fatty acids into the mitochondria.
And this.....

increased levels of the transcriptional repressor Rev-erba (Figure 2E) led to reduced expression of its direct target and a key lipogenic gene, fatty acid synthase


Food intake and insulin stimulate fatty acid synthase. ( 1 ) , this blocks liver fat oxidation which in turn stimulates appetite. In order to overcome that increase in appetite, you need incretins from the food you just ate. The satiating affect from the incretins you get must be enough to offset the hunger stimulated by the drop in liver fat oxidation. This is a good reason why eating big and rarely wins, while eating small but often FAILS.

So what controls the diurnal pattern of Liver AMPK and fatty acid oxidation in liver? I think theres a chance its ghrelin. ( 2 ) . As meal time approach's, the circadian clock of the gastric system starts secreting ghrelin more.  This has the affect of reducing liver fat oxidation, stimulating hunger, and allowing the liver to become more insulin sensitive in preparation for the feeding. ( 3 ) 

It should be apparent by now that circadian entrainment of food intake is as vital as circadian entrainment of sleep. If I told you I didnt sleep straight 8 hours every night, but instead slept in 3 small bursts of 3 hours, would you think that was healthy? How good do you feel when you get a solid 9 hours of deep sleep. Compared to continuously waking up in the night and lying awake for 1-2 hours before returning to sleep.

The discontinuous sleep makes you feel like shit doesnt it?

So why is it then, when it comes to food, which is also dependent on circadian rhythmic  

 tone, that we insist on getting our calories in 3 small short bursts? i.e. breakfast, lunch,dinner? If getting our sleep in one large burst is healthy and makes us feel good, why wouldn't getting our daily calories all in one burst also be healthy? I.e. 23/1 Intermittent fasting. 

( BTW yes I know the mice in the intermittent fasting study weren't doing 23/1, they were doing 16/8 , but as far as im concerned, the fact remains, eating at the SAME TIME everyday is as important as sleeping at the same time everyday. And dont randomly nibble on food, youll fuck up your circadian clock of ghrelin secretion leading to random hunger pangs, like randomly napping during the day can affect your sleep at night. Random nibbles also risks inhibition of liver fat oxidation while failing to generate necessary incretin secretion to keep you un-hungry, )


  1. Kindke, I'm sold! Unfortunately, my body protests when I try to implement that kind of feeding schedule.

    1. Certainly 23/1 is not for everyone, but it becomes easier after 1 week of training the food bodyclock for it. Having said that the message im really trying to get across is that intermittent fasting is important for your health. Picking a consistent eating schedule is as important as picking a consistent sleeping schedule. Whether its 18/6 or even 16/8. I guess low-carb bypasses alot of these problems with disregulated eating times because it leaves you closer to ketosis all the time which is essentially the fasting state.

  2. Kindke, do you follow the Warrior Diet pattern with a low carb diet, or do you eat high carbs as Ori suggest ?

  3. I mix and match as I feel, I dont really follow Ori's nutritional recommendations at all. At moment im doing about 50/50 high-carb to low-carb days, the weight loss is definitely superior with the low-carb days.

    Even on the high-carb days I need to watch my intake because im still very sensitive to carb induced weight gain. On the high-carb days I keep carbs at 150g maximum. Low-carb days I keep it around 50-60g. Basically all im doing on the high-carb days is eating alot of potato's/fruit.

    Everyday should be high protein imo, Very hard to do the 24hour fast without sufficient protein. I stick to foods high in nutritional value, eggs,Dairy,meat,potato's,fruit etc. Vegetables are only used as flavorings/spices etc. The Only other dietary point I follow is to make sure I eat liver 1x week.

  4. Thanks for your answer.

    I usually eats a VLC diet, but did a 3 weeks experiment with high carbs (moderate protein, moderate/low fat). Regarding my postprandial glycemia, it seems i can handle up to 150-180g carbs per meal, but i'm better with 100g or less. Maybe i could get better at that by eating only one big carb meal ? Wondering...

    That leave me far from what some healthy (such as Tarahumaras) and/or long-living (trad. Okinawa, Sardinia...) eats ! I'm very interested to understand how these population thrives on such a high carb, low/moderate fat, mostly (but not exclusively) plant-based, diet... as it seems obvious they are (were) thriving.

    For VLC, things are prety clear for me. But high carbs raise a lot of questions. I can imagine that one can become very efficient with glucose disposal to glycogen/fat stores, and then accessing them at will. Insulin/glycemia would remain low most of the day... but do they have a massive insulin/glucose spike at each meal, or not ? And if they do, is it really as dangerous as most says it is ?

    More and more, i think (like you) that frequent eating is a major problem, and more so with carbs. Chronic elevation of glucose/insuline may be far worse than acute bursts, as it is for inflamation.

    I was intrigued to read about Chris "Hillfit" diet change, and recent blogblog's comments (and yours) on Peter's Hyperlipid blog... seems i'm not the only one to think a little bit outside the VLC frame.

    Now, i'm really asking myself what to do next!

  5. I wouldnt worry too much about what all these traditional cultures were eating, they have a different gene expression to you and live in a different environment. Instead, focus on yourself and what works for you. This is why Im so big on self-experimentation.

    You MAY do better with carbs in a single large meal at night. self-experiment! Measure your blood glucose after a large carby meal at night and see. I myself do not have an issue with postprandial glycemia because my fat tissue seems to be especially good at sucking up excess blood sugar. One thing that should be universal though is to avoid carbs all morning and early afternoon until your diurnal cortisol starts to come down.

    And yes I believe its the chronic elevation of blood sugar and insulin that is the problem. An acute spike following a meal ( in a insulin-sensitive individual ) should be fine. It is perfectly healthy to spend sometime, ( or probably MOST of your time ) in the fasting state. A chronic elevation of liver ChREBP by frequent carbohydrate consumption probably wasnt what nature intended for us.

  6. Thanks again for your reply. I agree, and i do a lot of self experiments (as well as trying to think criticaly). The problem is that there is an awful lot of parameters we can tweak, and an awful lot of opinions/studies to support each point of view and its oposite. The big thing is self experimentations, but we have to decide what to try, and there is limitations too : i can measure very few things, and have to rely on how i feel/weight/perform... wich says nothing for the long term.

    One of the other things i "worry" about is vegetables and fruits. Obviously fruit is limited if we limit carbs. But then, some says to eat lots of veggies and some to limit them... or even fear them. I know the pro-veggies arguments, but have read very few convincing anti-veg. I see anecdoticaly that one CAN go without for some time (V. Stefansson, Lex Rooker, etc.), but that's all... vegans can also go without meat for a while. I'm fine eating notable amount of veggies, but still wondering why some (You, Peter...) uses them only sparingly, and seems to have reasons other than taste.

    I could go on with questions about more (you, Phinney/Volek/Attia) or less (Peter, Gedgaudas) proteins, or favoring SFA or MUFA... that's just to show how wide the field of experimentation is, and in these cases it's probably not be easy to sort out the best.

  7. Quick question, do you exercise? If yes, how do you time this with this eating pattern? I think Hofmekler like DeVany would be proponents of fasted exercise so doing a morning workout would not be prohibitive. What is your experience of exercise timing?

    1. I agree exercise should be done in the fasted state, I personally prefer to exercise this way as I feel much more energetic while fasted.

      You would ideally need to exercise in the morning or afternoon to fit in with the warrior diet. IF your lifestyle or job only allows you to exercise at night youd have to change your intermittent fasting period to something like 18/6.

      Either way its much much better to exercise before getting in the bulk of your daily calories.