Why Sleep and Leptin are Yoked?

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Reader Summary

  1. How does sleep begin?
  2. Is there a disease that helps us understand how diet and sleep are linked?
  3. Neuroanatomical reasons to reject the “set point” theory of obesity.
  4. Why are addiction, metabolism and sleep all linked?
  5. Did you know that one cause of central leptin resistance maybe autoimmune damage similar to celiac?

To begin to understand how sleep interacts with metabolism, we need to understand a bit about neuroanatomy.  In sleep, the cerebral cortex is in a  state of cortical synchronization.  In wakefulness, several subcortical regions of the brain stimulate the cortex to remove this synchronization.  When DHA is lacking cortical synchronization is not able function optimally.  When we undergo slow wave non REM sleep (drowsiness) there are a small group of neurons in the hypothalamus called VLPO neurons that are GABAergic (inhibitory) and they fire on the subcortical areas that are stimulating the cortex.  In doing so, these VLPO neurons bring about cortical synchronization.  After sleep begins, NREM sleep gives way to REM sleep.  During REM sleep there is a coordination of cross talk between the grey matter brainstem nuclei while cortical synchronization is maintained.  This is quite complex coordination of events that occurs in the brain while we sleep.  A common disease of dis-coordination of sleep is narcolepsy.  In other words, the tracts that normally control the stages of sleep occur out of sequence and cause people to fall asleep and lose muscle control in wakefulness.  Narcolepsy occurs because we lose a specific set of neurons in the hypothalamus that effects this coordination of signals.  These neurons are called the hypocretin neurons (HC).  These neurons are found in the ventral lateral hypothalamus in a small area that also control appetite and feeding.  These neurons also effect loops that effect feeding.  There is no set point.  When we lose HC neurons we set up the neurochemistry that becomes resistant obesity.  The dopamine tracts are the direct targets of the HC neurons.  We don’t see obesity as a common phenotype when we see tumors of surgical ablation of these dopamine outflow tracts.  This is the main reason many do not believe there is a set point for obesity.  The hypocretin neurons sit scattered through many MSH cells (also involved in obesity).  The HC neurons make two peptides called (hypocretin 1 and 2)HCrT1 and HCrT2.  In the literature, these peptide hormones are also known as the orexins so you do not get confused.  These peptides are remarkably similar to gut incretin hormones that help tell the brain what type of foods (electrons) are present in the gut.  Another remarkable trait of the hypocretin neurons is that in the human brain there is only 50,000 total HC neurons in an organ with over one trillion cells.  And they appear to be very new in mammalian phylogeny.  It appears mammals handle sleep and energy metabolism very differently than the rest of the living.  The small amount of HC neurons, however, project widely all over the brain.  We now know that the hypocretin neurons control the stability of wakefulness or our arousal.  It appears they may also control energy metabolism via leptin function.

The HC neurons also stimulate appetite.  So they control two vital behaviors in humans simultaneously.  This is called pleiotrophic behavior of the neuropeptides.  This is where the story gets interesting between sleep, metabolism, and addiction.  The HC neurons are excited by Leptin, glucose, and gherlin hormones.  They are also stimulated by NPY, NYY, and cortisol releasing factor (a glucocorticoid).  Remember that high cortisol levels chronically are generally a bad thing for the brain.  We saw that in my Hormone 101 blog in relation to obesity and leptin resistance.  Leptin resistance long term ALWAYS leads to hyper-cortisolism.  This also increases the excitation of the HC neurons.  Drug addiction also begins with hyper-cortisolism and causes the nucleus accumbens to make higher amounts of dopamine while the rests of out brain has lower levels of serotonin.  Obesity begins with inflammation but once it is firmly established in  humans they become centrally leptin resistant.  Long term this causes high cortisol levels to be made chronically as well.  Those high levels of cortisol appear to knockout HC neurons where leptin signal transduction occurs in the brain.  This effect maybe mediated by a leaky gut due to molecular mimicry.  In effect, we become centrally leptin resistant.

The outflow of the HC neurons directly feeds to the dopamine tracts and receptors that were thrown about (Median forebrain bundle and ventral segmental area) in Stephen Guyenet’s series on food reward.  They also are excitatory to the Acetylcholine  tracts of the pre frontal cortex and to histaminergic system in the brain.  While I enjoyed Stephen’s series, I think it missed the obesity target because it did not focus in on the effect of leptin on the small numbers of HC neurons.  This is precisely where central leptin resistance effects are felt.  Leptin resistance knocks out hypocretin neuronal function.  There is also current research being done to see if the effects of chronically lowering hypocretin neuron numbers could cause a lack of coordination of tracts involving leptin function and food seeking behavior.  This has biologic plausibility because their exists another human disease with hypocretin neuron losses effect its targeted behavior.  That disease is narcolepsy-cataplexy.

It appears that leptin, and other metabolic cues,  stimulate the 50,000 HC cells to lead to a coordinated response in the arousal centers of the brain.  This has huge implications for sleep, eating and drug seeking behavior. George Koob is a very famous addiction researcher found that when he placed mice in an operant conditioning cage with an active button that delivered a cocaine dose and an inactive one that did not, the animals learned to push the cocaine button quickly.  The behavior of pressing the active button was then extinguished to cocaine but yolked to cues that could be described as drug seeking behavior in the mice.  This learning occurred quickly.  Then, Luis de Lecea from Stanford University, tested these animals with HCrT1 peptide instead of cocaine and he found that HCrT1 also caused continuation of drug seeking behaviors without any cocaine in the experiment.  Moreover, the infusion of HCrT1 peptide also caused the animals to have higher levels of cortisol present which also seemed to independently drive their drug seeking behaviors without any cocaine being present.  A second experiment was done to see if an HCrT1 receptor antagonists would diminish the drug seeking behavior and diminish the stress response.  This is precisely what occurred in the Stanford experiments

It is also well known in psychiatry and sleep literature that  patients with narcolepsy-cataplexy are extremely resistant to all forms of drug abuse but not to obesity!  It is clear that the HC neurons are extremely important in energy balance and sleep.  It appears this is the tract in the brain where dual control funnels down to.  It also helps explain why most people who are obese also tend to have central sleep apnea.  Central administration of orexin A/hypocretin-1 strongly promotes wakefulness, increases body temperature, locomotion, and elicits a strong increase in energy expenditure.  This is what one sees in extreme leptin sensitivity with UCP1 and UCP3 uncoupling.  Sleep deprivation also increases orexin A/hypocretin-1 transmission. The orexin/hypocretin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin/hypocretin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin/hypocretin were primarily an appetite stimulating peptide.   In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex. Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus. In conjunction, these genetic anomalies cause the autoimmune system to attack and kill the critical hypocretin neurons. Hence the absence of hypocretin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.  This could occur via a defect in molecular mimicry as seen in the leaky gut due to toll receptor proteins.  When DHA is deficient, so are electrons and toll receptor proteins do not not work well and the gut becomes more leaky.  Similar mechanisms are seen in Celiac disease, Hashimoto’s thyroiditis, Crohn’s disease, and psychiatric disorders such as GAPS.
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Additional Resources


  • http://en.wikipedia.org/wiki/Narcolepsy#cite_ref-url_eurekalert_12-0
  • http://med.stanford.edu/school/Psychiatry/narcolepsy/medications.html
  • The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. e Lecea, L.et al. Proc. Nat. Acad. Sci. 95: 322-327, 1998. (Stanford University), 13
  • http://www.sciencedaily.com/releases/2009/05/090503132613.htm


  1. Resurgent says:

    So if a person is obese and because of obesity loses HC producing neurons, he/she has no recourse as neurons do not re-generate..?

  2. You're bringin' it!!! Thanks for bumping sleep up in the order of things.

  3. Resurg that is one problem long term obesity could cause. This is why i think Stephen G believes in his set point theory. I don't see it that way. I think fat mass is controlled by a small number of neurons in the hypothalamus. In humans, there is only 50K of them and this is where leptin resistance is monitored by the brain. I also believe this is how MSG causes leptin resistance. The excitotoxic damage takes out the hypocretin neurons and this directly effects the outflow transmission to the reward tracts that Stephen has spoken about in his blog. There is some great research being done now in this area. There are many causes of leptin resistance and obesity. High omega six impacts SOCS3 signaling, fructose drives de novo lipogenesis and excess palmitic acid production, carbs drive NPY and leptin resistance.

  4. Hi

    I did read your post but I can't claim to understand it. LOL! Can I ask a simple question regarding my own experience? I was eating low carb, probably approx 50g a day for over a year, but then started to gain weight (after successful loss). I know it wasn't carb creep. Anyway, after some experimentation I added back in some carbs and was surprised to find that my sleep improved significantly, and that I started feeling warmer. In my mind I linked this to leptin, although I didn't really understand it. Anyway, as you say sleep is an important issue, so if I reduce my carbs how will leptin be affected if I don't sleep so well? I'm still talking less than 100g a day.

    @JJ the reason this occurred is because you recovered your thyroid function at the muscle and liver level and the warmness was from burning calories at your UCP…….which require LS and T3 to be working. You can read about that in my peripheral leptin note. Carb refeeds after your reset leptin also stimulate the AMPK pathways as well…….and this also helps the situation.

  5. @JJ I think this may also show that you have other undiagnosed hormone issues beside leptin. I 'd get them checked out. Pay attn to your energy. If its lower for sure you got something cooking.

  6. a potato before bed and i sleep like a rock, a VLC dinner and sleeping sucks for me, i dont sleep, my heart races and i sweat. im on the potatoes not prozac bandwagon

  7. @ Mal you do what works…..I bet your hormones are stacked to help you this way. Most people don't pay attention to their bodies to even know what moves them positively or negatively

  8. veggienft says:

    Potatoes contain the glycoprotein solanine. Depending on genetics, solanine can be a powerful narcotic. It mimics endorphin. Continued use of solanine elicits immune and metabolic responses.

  9. veggienft says:

    Okay, I should have said continued use of solanine *CAN* elicit immune and metabolic responses.

  10. Thanks Jack. Guess I better find myself a doctor.

  11. Diane S says:

    Jack I am in week 4 and have only had 25 carbs a day or less like you suggested, I stupidly had a 2 inch piece of corn bread the other night & the next morning I didnt feel good, felt abit bloaded just uncomfortable. I haven't had this feeling since starting this, someone asked me if I had celiac's is this possible? And does not having my gall bladder affect this? thanks

  12. Not having a GB is a critical key. It means your gastric emptying time is off. It also will mean loose stools or hard stools until you get your gut microbiota in order. Coconut oil and fermented carbs really help. You must avoid corn at all costs. You could have celiac but I doubt it. But you need to stay away from grains because of your shortened gut issues. That is a non negotiable point. You have a situation that is not ideal and that requires some tighter controls of your diet.

  13. @veggie……..for most people I am not a potato guy. Me personally I would never touch them. I think they have a place for perfomance paleo's however. The crossfit crew needs them for sure.

  14. Hi Jack, I wonder, do you think excess androgen hormones in women can be stimulated by high fat, low carb nutrition? Is this possible? I stopped this kind of eating because I became quite alarmed that I was growing excessive facial hair, and also I now have very bad acne! I understand this is a hormonal problem, and can be influenced by a number of factors (the problem could have been stimulated by something prior to the diet). I am concerned with regards to how I can correct this imbalance, and whether low carb, high fat nutrition is a help or a hindrance, in this regard. Any suggestions I would much appreciate, thanks.

  15. @Beth this is a great question……But its not likely. The reason why is a person who has PCOS has leptin and IR issues die to belly fat and body fat. This fat however is the source of the excess testosterone in PCOS women. So using a ketogenic low carb diet with loaded amounts of MCT will shred weight loss for about 20 weeks. This loss of fat will change the aromatization of the sex steroid hormones and this is change the PCOS issue. Your worries about about high fat diets providing substrate to make the sex steroid hormones is a decent one……but remember that in the conversion of cholesterol to testosterone requires ideal T3 levels and great Vitamin A levels. All women with PCOS have very poor T3 levels because of the IR and LR. This effectively blocks the formation to testosterone. So the summation of the biochemistry is you should eat a ketogenic VLC carb diet if you have PCOS for about 20 weeks…..then slowly up the carbs as you recover thyroid function. If you want to see my advice in action take a look at this thread that has a few ladies with your problem who completely reversed their problem in 8 weeks. http://www.marksdailyapple.com/forum/thread32345….

  16. Hi Jack,

    I have been reading your incredible website for days and have started the reset program, up to day 3. I have given up all processed sugar since june with no weightloss. I have the trifecta, PCOS, IR, and being overweight, so I am hopeful this will work for me. However, I wanted to thank you for the information on Narcalepsy-Cataplexy. It has answered so many questions, as my late father had this disorder, and it was living hell for him. It is so isolating and misunderstood, my father would often have a cateplectic fit from simply having a good laugh. I have been keeping an eye out for it in my kids, I wonder if u know whether it is inherited?

    Since serotonin is so important for sleep , how is the reset program going to affect sleep? I normally have no problems with sleep, though I have experienced insomnia and don't want to revisit that time again. Thanks again.

    • Sleep and metabolism are connected at the brain level specifically the hypocretin neurons. You need to read my latest series on central actions of leptin written at the end of August 2011

  17. Ta,

    The September posting with the faqs has been very helpful,as well. I feel really positive about change. Thank you

  18. http://reference.medscape.com/medline/abstract/21

    Sleep and obesity linked yet again.

  19. Hey Jack,

    I'm narcoleptic. Does this mean I'm basically screwed? I'm also (I'm guessing) insulin resistant, since I've been hypoglycemic for about 6 years now. I went on a low dose of Metformin about 9 months ago, and it helps some, but not much. Increasing it makes it worse, not better. I've been at about the same weight and body composition for a long time now (plus or minus 5 or 10lbs), despite diet/exercise. Although I'm not really overweight (5'5", 133lbs), I have more fat on my body than I would like, and I have a hard time maintaining muscle mass. I have symptoms of PCOS (but no cysts and normal periods), and thanks to a couple of years of stimulants, hypoglycemia, and stress, I have some pretty severe adrenal fatigue. I recently went on some vitamin/mineral supplements that have been helping with the adrenal fatigue, a less harsh stimulant (Nuvigil), and low carb paleo diet. I'm wondering if your leptin reset would do anything for me since I'm narcoleptic? Or should I just try to maintain a low carb paleo diet to help with the insulin resistance? Are narcoleptics basically doomed to become obese? Thank you so much for your help, and for everything you're doing!

    • @CT screwed? nope. It just means your time to reset will take longer and you might have to stay on it longer than most. I have no narcolepsy patients but if I did I would alter things as I followed them clinically.

  20. My narcolepsy is in remission when on a ketogenic diet – however the cataplexy is not (though feels a bit milder)

    Do you know what causes the seizures? Anything I can do, but keeping my o6/o3-ratio as good as possible and stay ketogenic paleo?

  21. @yurgh you need to see a neurologist to get an EEG to figure that out……if it is tied to the hypothalamus you may have destroyed some of those cells. You might consider contacting Dr. Luis DeLecea at Stanford. He discovered what cause narcolepsy and he may have some insight for you.

  22. Lisa Bento says:

    I do not understand many of the different overlapping conclusions you are making in you're article. I am a person with Narcolepsy. I am neither obese nor overweight. I am not an addict of any kind either, as far as I can tell. Nothing I am reading here makes me inclined to try the reset. Is there a more reader-friendly explanation of your theory, without casual mention of association between sleep issues and other diseases. Many forms of many illnesses have common threads, that does not mean that once one is sick they have then in turn acquired several other illnesses with common symptoms.

    Lisa Bento

    • @Lisa youre missing the point……narcolepsy is linked to the hypocretin neurons. This is a known fact. If you have narcolepsy it is impossible for you to become addicted to cocaine because of the mis- wiring to the hypocretin neurons. The hypocretin neurons also wire directly to the leptin receptor……..this links metabolism to sleep. You are confused because you are looking at my post reductively. I am weaving concepts together so you can see how they are all related. The physiologic function becomes much more understandable when you understand relationships between concepts.

  23. Dennis Walla says:

    Can’t stop reading your work JK!!!

    My sleep study indicated narcolepsy but I have no cataplexy. My Doc gave me Wellbutrin and after 5 days of taking it, that night I slept like a rockstar. Libido off the chart, return of strength and great energy for a 42 year old male. After reading this blog, I suspect that the Wellbutrin -dopamine- bridged the gap between the HC neurons and the dopamine tracts to regulate a proper sleep cycle and better functioning metabolism.

    Unfortunetly, after a late night out with friends a few days later, my successful sleep cycle ended and my return to disrupted sleep paterns returned. I’ve never been able to duplicate that success again…until I tried Clomid…which is another story I won’t go into here.

    Hoping that the CT therapy will fix my still chronic sleeping problems for a now 49 year old male.

    • @Dennis CT maybe it……talk to you doc about checking you alpha MSH and prolactin…..bet you find an issue.

  24. Dennis Walla says:

    Thanks JK…

    Checked prolactin years ago and it came back normal, but with modern reference ranges not sure what that means.

    Will check into alpha MSH and do prolactin again

    When I first started reading you I was doubtful about CT, but am trying your protocols anyway and am having slight improvements from something.

    After extensive testing, been working on a pregenolone steal which I read about here and will retest in 5 weeks for any needed modifications.

    Thanks again and Keep on Trucking!

  25. coldbren says:

    I am completely Mr. blue in the video…..definitely always want another beer after the first….best ways to increase seratonin? 5-htp?

  26. Dennis Walla says:

    Hey JK…

    Can a person be leptin resistant in the hypothalamus with normal cortisol levels? I’m trying to reconcile your adament stament of hyper-cortisolism relative to LR.

    Also, can a pregnenolone steal occur with normal diurnal cortisol levels combined with exteremly low steroidal homones? Could normal cortisol levels be a hyper-cortisol situation. After re-reading this and other blogs I think I am wasting my time on a preg steal.

    • @Dennis It is possible but I have never seen it clinically. the most common situation in those who are LR is to have, the clinical scenario of a high cortisol level that caves…….and cave badly. Most MD’s do not test in the LR high cortisol phase because people can compensate……..they come to us when their cortisol is low and alpha MSH trashed because they feel terrible. Yes a pregnenlone steal can occur that way…….if you have a situation where say the thyroid is irradiated from a child hood cancer……causing a low T3 and high LDL cholesterol…….but their sleep is maintained because of a good circadian light controls. Rare……..but I have seen this case myself.

  27. Dennis Walla says:

    Hey Doc…

    Still reading your latest blog for the second time. Huge verticle expanse of material.

    Relative to posts 26, 28, 29,32 and 33, I just had to say thanks for the tip on the pregnenolone steal! After a six week bio-hack I just got back my test results and I’m moving in the right direction.

    Six months ago, after taking 25 mg of DHEA, total testo was 344 and Free T at 4.8. OUCH!!! My doc said “it all shunted to cortisol.” Shortly thereafter I came upon your site and the preg steal. Hormones 101

    Most upsetting was my doc didn’t go that extra step and suggest a preg steal protocol. So, I started 100 mg preg, 50 mg DHEA. Also I slowly started CT therapy at that time, and after six weeks, (using labcorp) total testo came back at 449, free T at 9.7, DHEA-S at 516, and lipid profile was greatly improved. Estradiol came in at 33, hopefully I can knock that down with some chrysin. Not optimal for a 155lb 49 year old, but an improvement. I see my doc this Wednesday and will ask for some compounded testo cream to help elevate “things.”

    Anyway, still searching for an ID Doc relative to poor sleep, a-MSH, bio-toxins, prolactin, etc.

    Lastly, hope you and your family are doing well. I worry that you do so much that I picture you as Atlas holding up the world. Gotta be tough but also rewarding I hope. Thanks again and take care of yourself.

    • @Dennis glad the blog helped……..it is easy to do this when you fell like your 25 again because you treat yourself as you should. Evolution taught me that when I smartened up and listened to her. The moral…….when we look at our past we see our prologue.

  28. Rita Barandas says:

    Hey doc! You are doing such an amazing work! Im a portuguese psychiatrist and a great fan of yours! Im “devouring” your blog. Please keep up the good work and teatching us doctors!

    • @Rita B Soon We will have a continuing medical education course for physicians in Darwinian medicine completed. We are not sure if we will offer it on line or live as yet. We have a stable of MD’s who are asking for it and the more who push for it the sooner I will get off my lazy butt to do it. Thanks for the kind words. In your specialty Brain Gut 5 is critical information to employ!!!


  1. […] to generate energy.  Your hypothalamus integrates and yokes sleep and metabolism as I laid out here a year ago.   The hypothalamus only makes up 1% of the total volume of your  brain.  Moreover, the outflow […]

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