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Hypocretin Neurons: The Link Between Fasting, Stress, and Arousal, or, Why Fasting Breeds Insomniacs

There is a hell of a dichotomy occurring in the Paleo blogosphere this month.   99 percent of the time I am pleased as Pooh stuck up a honey tree, nestled in my esoteric corner of paleo-feminist rage, but every once in a while I wish more people could hear what I have to say.  Today is one of those days.

The split I am talking about is not all that nefarious.  In most cases, it’s benign and can be ignored.   But in general I would like to draw attention to it, because I think there’s a lot going on beneath the surface (and here, the depths are not just Nemo and Dory but are instead people’s lives), and that depth requires speaking to.  Immediately.

Mark’s Daily Apple has recently done a beautiful series on the benefits of fasting.   I loved it.  I learned plenty, as I always do on MDA.  The series was well-written and -organized, and in fact I ended up directing people who are unfamiliar with fasting to the site in hopes of swaying their opinions.   (So let it be clear: I am not against fasting per se.) Yet Chris Kresser has also done an April “Best your Stress” challenge.   Serendipitously enough, it concludes today.  And it is exactly what it sounds like: an endeavor to spend 30 days taking practical steps to counteract stress.  Chris’s idea was that people often spend 30 days trying to get their diets in line.  But what about their stress, and their lives?  I couldn’t agree more.   This man is a gale of fresh, important ideas.

The reason I say these two Big Themes are at odds is because they are.  Fasting is a stressor.  Period.  Mark Sisson would agree.  All people who advocate fasting would agree.  But all they ever do is put an asterisk at the end of their posts: *people who are stressed should probably not fast, they say.   But why?  Who is affected, and how?   What can fasting and other forms of restriction do to our brains, and to our lives?

What I want to draw attention to today are little loci that sit on the border of the hypothalamus called Hypocretin Neurons.    Hypocretin neurons (also called Orexins–and note that the word “orexin” means “appetite increasing”) were discovered just 14 years ago in 1998, but they have radically altered the landscape of eating neurobiology since then.   No, they are not the sole molecules responsible for sleep and waking.  Mice that have had these neurons removed still sleep and wake in roughly normal patterns.  But they never feel alert, and they never suffer insomnia.  And when the neurons are activated, the mice leap into action.  Hypocretin neurons wake animals up.  This much is certain.

The lack of Hypocretin Neuron signalling is the cause of narcolepsy, while elevated Hypocretin levels induce arousal, elevate food intake, and elevate adiposity.  Hypocretin Neurons  upregulate the production of molecules down several other pathways, too: these include noradrenergic, histaminergic, cholinergic, dopamine, and serotonergic.

The anatomy of Hypocretin Neurons is also coming into greater light.   When are the neurons active?  What signals do they receive, and what signals do they produce?     Research is beginning to show that Hypocretin Neurons are excited by excitatory synaptic currents and asymmetric synapses with minimum inhibitory input.   The fact of asymmetry is important.  It means that Hypocretin Neurons are instead always acted upon by mostly uniform – excitatory – signals they receive.    Hypocretin Neurons only ever up-regulate and relax.  They do not down-regulate.   Excitatory signals outnumber inhibitory signals 10:1.

One notable source of excitation is corticotrophin releasing hormone, which suggests that stress activates the activity of Hypocretin Neurons.    GABA neurons also create a bridge between Neuropeptite Y, which is the molecule that arguably has the strongest appetite-stimulating effect on the brain, and Hypocretin Neurons (more on Neuropeptide Y later this week).  From there, Hypocretin Neurons project to all regions of the brain, including the hypothalamus, cerebral cortex, brain stem, and spinal cord.   It seems as though Hypocretin Neurons may act as a nexus of signal input for the appropriate synchronization of various autonomic, endocrine, and metabolic processes.

Food restriction further augments recruitment of excitatory inputs onto Hypocretin cells.   This explains the relationship between insomnia and adiposity: because of the easy excitability of Hypocretin Neurons, any signal that triggers their activity, regardless of homeostatic needs, will elevate the need to feed in brain circuits such as the locus coeruleus and the melanocortin system while also promoting wakefulness through activation of noradrenaline-stimulating neurons.  Anything that promotes the release of corticotrophin releasing hormone (CRH) such as reduced sleep will further trigger Hyocretin Neuron firing and Appetite.   This is a vicious cycle.  Hypocretin Neurons play the role both of trigger and of accelerator, taking states of wakefulness, insomnia, stress, and obesity into continual positive feedback loops.

So how does leptin factor in?  Hypocretin Neurons express leptin receptors.   Moreover, some recent complicated neurobiological work done on mice has shown that injecting them with leptin decreases the activity of their Hypocretin Neurons.   What this means is that Hypocretin Neuron activity is stimulated in part by decreasing levels of leptin in the blood, and that increased leptin levels reduce the level of excitation running through Hypocretin Neurons.   This is coupled by ghrelin activity, which is also detected by Hypocretin Neurons.   Ghrelin, which originates in the gut and is known to stimulate appetite, also excites Hypocretin Neurons.   What does feeding do, then, for Hypocretin Neuron excitation?   Experiments on mice show that re-feeding restores normal Hypocretin activity, to an extent.  Repeated abuse takes longer to recover from, but the simple presence of leptin in the blood normalizes the brains of mice.

Hooray!  This is good for fasting, right?  So long as one re-feeds appropriately, everything should be fine?  Well, yes.  In a healthfully functioning individual.  But not in a) someone who is both stressed and leptin resistant, since increased leptin levels from the re-feed might not be powerful enough to offset other excitatory pathways b) someone who is currently emerging from yo-yo dieting or caloric restriction c) someone who is dealing with an over-stimulated appetite, d) someone experiencing stress, e) someone who has had a history of insomnia, f) someone who is underweight, since they have low leptin levels, g) anyone who has ever had an eating disorder, particularly bulimia or binge eating disorder or h) anyone with HPA axis or endocrine dysregulation, particularly women, including overt stress, hypogonadism, hypothalamic amenorrhea, hypercortisolism, or hypocortisolism (adrenal fatigue.)  I am sure the list is incomplete.

In animals, Hypocretin Neurons serve an important evolutionary function.  Arousal is a vital behavior in all species.    And normally, Hypocretin Neurons respond quickly to changes in input.  But in situations of chronic metabolic or endocrine stress, or of recovering from a stressor, they can lead to hyper-activity and hyper-feeding.

Researchers have long known about the link between leptin, sleep, and obesity.  The less someone sleeps, the lower her leptin levels, so the more she eats, and the heavier she gets.  Hypocretin Neurons may serve as one of the answers to the question of exactly how that phenomenon comes about.  Or at least it plays a role.  Because 1) Hypocretins simultaneously stimulate appetite and wakefulness, particularly through orexigenic output of the melanocortin system, and subsequent release of CRH, which activates the stress response, and 2) while Hypocretin Neurons wake us up, they also need to be quiet enough for people to go to sleep.

Finally, I raise the questions: how many disordered eaters have trouble sleeping?  How many anorexics, binge eaters, calorie restrictors, exercise-addicts, stressed-out individuals, and very low-carb dieters have trouble sleeping?   How many people try intermittent fasting and find that it disrupts their sleep or circadian rhythms?  How many people wake up in the middle of the night or early in the morning, even though they still need sleep, but for the life of them feel so awake?  Part of that answer lies in blood sugar metabolism, for sure.  And in other places.  Sleep is a hell of a complex phenomenon.  But here– Hypocretin Neurons can become overburdened by excitatory signals.  They get hyped up in the face of both decreasing leptin levels and leptin insensitivity.   They are upset by restriction, and they are upset by fasting.  Hypocretin Neurons demonstrate why so many people have difficulty with their appetite and their sleep.  If you find that fasting disturbs your sleep, or that you are suffering disordered circadian rhythms along with stress or appetite problems, do you best to relax your system.  Don’t fast.  Relax.  Exercise less.  Reduce stress.  Eat more.  Put on weight.  Eat more carbohydrates.  Don’t graze.  Increase your leptin sensitivity.  And listen to your body.

Coming up next: nighttime eating syndrome, and how it’s all related.




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Managing director of Paleo for Women and author of Sexy by Nature.


  1. I am neither a woman nor a paleowhatever; I am just some guy who happens to have had the misfortune of being a narcoleptic for the last 40-odd years. I read your HPA posts with great and bleary interest. Maybe someday if I am ever awake enough I’ll read them again.

    I have been trying to teach myself some neuroscience (in my sleep..ha!) for some years now in order to understand what the doctors will never tell narcoleptics about how we are ill. (Hooray for pubmedcentral.gov!) Your writings here are right on the money as far as I can tell. Why the docs don’t share more info I can’t say, but most narcoleptics are totally ignorant of the fact that the sleepiness of narcolepsy is only a symptom of the underlying endocrine disorder, and only one symptom at that. Narcolepsy continues to be classified as a sleep disorder, which it certainly is not, and that helps nobody.

    Anyway, thanks for writing this stuff. And BTW, I don’t frequent women’s issues web sites – I have Google news set to scour the net for anything relating to hypocretin / orexin or hypothalamus and it snagged your last post. I have also created a Google news topic called Narcolepsy with the same settings (check it out).

    • Hey, thank you Moshe. I appreciate you sharing, and hearing first hand a bit about what it’s like to be narcoleptic. Your resources are really helpful, too, and I’m super grateful for them. If you’d like to share any lifestyle or dietary habits you’ve adopted in order to mitigate your narcolepsy, I would love to hear about it.

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  3. Interesting info, at least as far as I could keep up with it. I was diagnosed with narcolepsy about 6 years ago. Found this while skipping around various posts/blogs initiated by a Google search for “narcolepsy paleo diet”. I’ve looked at the paleo diet off and on for over a year now. Between the bouts of sleep, fog, and trying to make my way through life, I just don’t have enough zest for life to make it worthwhile. Stanford University researchers found that narcoleptics lack the cells that create hypocretin, due to the body’s immune system killing them off (gee thanks). That was the big news at the Oct. 2010 “Annual Narcolepsy Patient Conference” I attended was. At least that’s how I remember it, but memory these days leaves much to be desired so I may be off a bit. Maybe they’ve found out more by now though – I haven’t kept up with it – too disappointing.
    I’ve found a definite relationship to how certain foods affect me negatively and avoid those anytime I need to stay awake (i.e. work and driving). When I do eat those foods, I follow them with large quantities of caffeine – usu. in the form of no-doz or similar caffeine pills and coffee or energy drinks. Certainly not healthy, but it does the job and doesn’t break the bank.

    I wanted to say thanks for sharing your data, much of it is ‘spot on’, and I know there are many narcoleptics out there who still have the desire for a better future. I hope they find this info and they are able to benefit from it.

  4. Thanks for this post. I have been dealing with 4am wakefulness since a bout of anorexia in 2005 and have not been able to solve it. I know it is somehow related to my food and weight, but not exactly sure how (in my own personal experiments, I haven’t found direct correlations between how I eat and how I sleep).

    • Absolutely. It could be related to blood sugar fluctuations as well, if you eat a very low carb diet, for example. But I feel do. Do you eat before you sleep? Even though that’s not optimal, eating a large meal before bed can at least help you get a full night’s sleep.

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  6. This is very interesting to me. I’m doing a low carb paleo diet for weight loss (45lbs down, 20 to go!) and also have adrenal fatigue/CFS. I’ve been doing IF for the past 6-7 months- it started just because I wasn’t hungry in the morning and then the more I read about fasting the more I pushed myself to hold off (I had a 6 hr window).
    You’ve given me more to consider especially on those mornings where I am feeling hungry and yet hold off to eat.

    • Well, sure, but if its working for you, it’s working! If you find that you begin having trouble on your current diet, you can always change it. No need to change what you’re doing unless your body is the one trying to call that shot. 🙂

  7. This post was super informative! I was practicing alternate day fasting last year with great weight loss results. I also felt really good – not deprived, much happier, sleeping well, plenty of energy – but noticed my cycle started getting a bit irregular. I took a break from ADF, which ended up not being the best decision because I became concerned about weight gain and started to restrict daily.
    This resulted in severe depression, irregular sleep, and essentially gaining back everything I had lost (and maybe a bit extra), although I have no idea how. My cycle also never really went back to normal.

    I decided to go back to ADF, only now this time it’s different. My cycle went even more irregular almost immediately, and although the depression is pretty much gone, I have trouble sleeping on fasting days. I’m also losing no weight at all. I thought it was because my eating days were calorically lower than they’d been the first time around, but after reading your post, I think my body is resisting. My progesterone is low and so is my T3, although I don’t have clinical hypothyroid.

    I know we’re not all meant to have 18% or even 20% BF, but I could definitely stand to loose some body fat. I’d be pretty happy at 22%-24%

    This post has given me more information to put into perspective.

  8. Really interesting article – thanks. I’ve slept badly for years, I wake early and even when I get 7-8 hours it’s rarely uninterrupted or restful. I’ve been paleo for around 9 months and feel there has been a small improvement (or it could just be that it affects me less because I generally feel more healthy) but it is still a fairly major issue that affects my quality of life.

    I tend to eat my main meal of the day in the evening and go to bed only 2 or so hours afterwards so I’m fairly sure my early waking isn’t a blood sugar issue. Stress? Perhaps. I don’t feel overly stressed and try to minimise stress in my life but my job can be quite stressful and I have gone through some very stressful events in the last 6 years or so.

    No point in speaking to the mdical profession – in the UK where I live early waking is almost always attributed to depression. Every time I have seen a GP they have suggested (sometimes forcefully) that I must be depressed. If I know one thing, it is that I’m absolutely not depressed – if I get a little emotional sometimes it’s because I’m shattered at not getting sufficient sleep, not the other way round.

    So, anyway, no fasting for me I think and I shall continue in my quest for a perfect night’s sleep. Ahh, one day I hope!

    • Haha, that’s interesting, Barbara, I had never heard of that about the UK before. Yes, I feel pretty strongly that dysregulated eating times as well as calorie restriction impairs sleep. I, too, eat my last meal late in the evening, and this is specifically because I need to eat in order to sleep, recovering from years of fasting and dieting.
      I would recommend trying to remove protein from that last meal. I have found that when I eat protein at night I sleep very poorly, if at all, but if I keep my protein in the morning I fall asleep like a log. I wake early, sometimes, and I find that this is associated with eating fewer calories the night before. what I am trying to do, and what I know others have done, is eat breakfast in order to tell my body to wake up and run it’s circadian rhythm properly in the morning, and to inch my evening meal back by little bits of time gradually. Just to speak from personal experience in case you find some resonance and want to try those ideas yourself.

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  12. One of the many problems that some narcoleptics experience is cataplexy, a sudden muscular weakness brought on by strong emotions (though many people experience cataplexy without having an emotional trigger).;”,:

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  13. Really interesting; thank you for raising this issue and for summarizing so much relevant info in such a short space! I also really appreciate your post on women and [intermittent] fasting.

    I am a woman (normal weight, very good health), and the one rock-solid consistent thing I’ve observed my whole life is that the fewer calories I take in, the more sleep I need. (And I never have trouble falling asleep or staying asleep.) This doesn’t seem to fit with much that I’ve read though.

    Maybe stress is the missing factor….

  14. I am a 37 year old woman with Narcolepsy.

    Narcolepsy is, I recently realized, a little like being a two year old in terms of sleep needs; every few hours, my brain needs to shut down and recover, or I become sleepy, grumpy, and can’t think clearly. I have some theories about delayed brain development and Narcolepsy…

    Anyway, if I eat anything with wheat for breakfast, I can expect to have a slow, low functioning morning. If I skip breakfast, or eat a high protein breakfast, I can think clearly, and accomplish much. Wheat in general makes me sleepy within 20 minutes, and I try to avoid it in the hours before I know I need to drive anywhere.

    If you have any more knowledge about how to optimize my brain wave functioning dietarily, I would be happy to hear it.


  15. Thank you so much for being a woman Stephanie 😉 and finding out these things!!!!

    I too had a phase of anorexia initiated by a very stressful life event. I hardly slept for 3 years! (it makes me wonder how these skinny celebrities manage to stay alive)

    Luckily for me, the love of a good man saved me from myself in the end and the miracle of a good meal and some carbs allowed me to sleep.

    That was nearly 20 years ago. Now I am 49 and going through the menopause.
    I have looked after my diet these last 20 years and have been eating a version of paleo with no meat but fish for many years. So I am not too unhealthy. But recently reading a book on leptin and then all the blogs on Paleo have been a revelation. Although my diet was good, my eating habits were not – I grazed, I never ate regular meals and as a result my energy and mood were up and down. I could start the day in a very good mood and end it in a very depressed mood. Adding some meat into my diet and eating 3 solid meals a day, with a big protein one at breakfast, another with salad for lunch and a bit more carbs for dinner has been a revelation. I have never felt better in my life. No snacking! Breakfast!

    I have skipped lunch a few times because I wasn’t hungry but after reading your blog I will certainly not skip meals if I am hungry. After eating this way I had a period again and I haven’t had one for ages despite taking bioidentical hormones.
    I had been playing around with intermittent fasting the last year (trying to lose the menopause tummy which I suddenly got) but I only did the IF in the morning so I would have 8pm-12pm as my fasting time and it did not affect my sleep. It felt good to fast in the morning but I have to say it feels better to have a protein breakfast! The 3 meals a day were hard at first, coming from an eating disorder background. Very scary to actually eat properly. But I did it!

    Also at first I went very low carb – my sleep went out the window IMMEDIATELY.
    I had a racing mind all night and the bright light in my eyes even with the lights out (does anyone else get that?) when that happens – when I can see a bright light in my head in the dark I know I am going to be awake all night. And also my body temperature stays elevated.

    So I added a sweet potato at night and lowered the protein and I can sleep again.

    I read ‘The Leptin Diet’ by Byron J Richards and I highly recommend it. No skipping meals, no super low carb. No gimmicks. 3 meals a day Primal Blueprint style.


    thank you so much. All the primal stuff is so male oriented

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  17. This interests me greatly because when I was pregnant with my (now 11-month-old) son, I found myself sometimes waking up at all hours of the night and feeling oddly alert and completely incapable of falling back asleep, but knowing that I needed to sleep more. I figured out that having a substantial snack cured the inability to feel sleepy; it was amazing how just having some food suddenly made 4 am feel like 4 am again! It feels exactly like the hypocretin neuron excitation you describe.

    Of course, I wasn’t fasting or anything like that while pregnant, and I wonder how I could avoid such excessive appetite in any future pregnancies. My appetite felt way too high and I gained 65 lbs., which I figure was much healthier than going hungry but is not as it should be.

  18. Very interesting article, although I will need to read it again more carefully. I did intermittent fasting based on the fast diet, and lost ~20 lbs, to get to a good weight of 190lbs (I am a 50 year old man, 6 foot, I exercise regularly). I lead a stressful life, very much so over the last year. I was using a cream for Testosterone replacement at the time. After the diet (or around that time if something else is the cause) my T level dropped very low (the creme stopped working), I became warm at night (can’t sleep in clothes any more) and (still) don’t sleep well. I was tested for LH and FSH hormones and they were both very low (still are), my pituitary gland MRI was fine. I wonder, with the high level of stress I am under, plus the fasting, did I change something in my hormone system that will not not switch back, even though I am eating normally (but still very stressed)? Please let me know your thoughts?

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  21. Thank you for this article! Very interesting – I have hypothalamic amenorrhea and have only recently started intermittent fasting again but after reading this I think I’ll be sure to have at least something to eat in the morning. I have read that it’s better for people with hypothalamic amenorrhea and also anxious tendencies to have smaller, more frequent meals to keep their blood sugar in line rather than peaking and crashing.
    Any suggestions for people who just don’t feel hungry in the morning?! I can only assume it’s something that will change with time…
    Definitely going to begin focusing on reducing stress levels with the hope that this could bring back a period!!
    Thank you for your articles – always interesting and backed up well with science 🙂

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