Central Leptin Dominance: Part 3 – King of The Hill

Central Leptin Dominance: Part 3 – King of The Hill

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Readers Summary

  1. What do the reward tracts do?
  2. Why Neurosurgery does not support reward theory
  3. Why leptin is King of the Hill with respect to obesity
  4. Why leptin is so critical for control of everything dependent of energy
  5. What type of diet is best for prevention of neolithic disease or aging

So now that we examined Dr. Lustig’s insulin theory of metabolic control we need to take a look at the reward tracts that are located in the human brain. These tracts have been well studied and their neurochemistry is well understood. What appears not to be as well known is how the hypocretin neurons and the leptin receptor control and modulate their activity. The key point here is that the dopaminegic tracts eloquently spoken of Dr. Guyenet’s reward series are the “efferent only” path that is part of the effector arm of the leptin receptor and the hypocretin neurons. This means, in English, they are playing second fiddle to the leptin receptors and are not the dominant cause of obesity. They clearly play a major role in the neuro-circutry but they do not control obesity. They carry out the action but the orders were given by someone else. One of the reasons I had a major problem with the reward series, is because of my “day job” as a neurosurgeon. I have had the opportunity to operate on many brain tumors in the reward tracts and never have I ever seen either preoperatively or postoperatively one patient develop severe morbid obesity. If these tracts were truly dominant causes this would lead neurosurgeon and neurologists to see many patients with this problem. Well, we do not. That was a big issue for me with the theory. The second issue I had with it was that when we neurosurgeon’s have patients with brain tumors involving the hypothalamus we see tremendous effects on feeding, obesity and on anorexia. This is well documented and I have personally seen this in many cases. Dr. Lustig pointed this out in his AHS 2011 talk when he showed some clinical cases of craniopharyngioma’s and of hypothalamic trauma’s that resulted in morbid obesity.

Reward Story: We now have to go back to the science.

The reward tracts are best understood if we read the work of Paul Kenny from the Scripp’s clinic in Florida. His recent paper from 2010 is a phenomenal work in neuroscience. His paper showed that the development of obesity was coupled (did not cause obesity) with the emergence of a progressively worsening brain reward deficit. He also referenced Dr. Lecea work on the hypocretin neurons and their affects on reward homeostasis on cocaine and on heroin addiction. The neurochemical change underlying obesity in the reward tracts showed striatal (part of the brain) dopamine (D2) receptors were down regulated. This has been found in rodents as well as humans. The lentivirus mediate knockout studies of the striatal D2R rapidly allowed the development of reward deficits and caused addictive behaviors to develop to drugs and to food. So the neuro-biology of these tracts clearly show that over-consumption of drugs or palatable food was able to trigger addiction like neuroadaptive behaviors. No one disputes this.

But here was the rub of the studies and where the dispute arises.

What controls the reward tracts neurochemistry to begin with?

Here we head back to Dr. Myers’ lab and the answer, not surprisingly, is the hypocretin neuron groups in the lateral hypothalamic area. These neurons project directly to the dopamine receptors in the ventral segmental areas of the brain. This is the seat of the reward tracts in Dr. Kenny’s studies and the ones referenced extensively in Dr. Guyenet’s reward series. Dr. Myers work showed using various adenoviral and transgenic systems that the hypocretin neurons directly control the firing and the behavior of the entire reward tract. This means in simple terms that the reward tracts are the outflow of the hypocretin neuron system and they are controlled totally by the leptin receptor. Given this work at the University of Michigan and at the Scripps Lab, I see no way one can say the reward tracts are dominant in causing obesity. The reward tracts clearly do allow for the action of the hypocretin neurons and the leptin receptor. Dr. Myers works shows that the totality of biologic function of leptin and it receptor have to be the summation of its action on the hypocretin neurons. He has tediously worked these pathways out in numerous publications. No where in his works did I find any evidence for insulin to play any control in modulating the biology of the leptin receptor or of the hypocretin neurons. In fact, there is a lot of evidence that leptin affects in the brain receptor modulate insulin effects directly. In simple terms, this means that the leptin receptor and leptin itself modulate control over insulin and the reward tracts at the hypothalamic level of the brain.

In fact, there is no neuro-biologic evidence that the reward tracts can feedback and modulate the hypocretin neurons outflow. This completely explains why I have never seen a brain tumor in the reward bundles cause obesity in a human. Moreover, there is no higher cerebral controls over the leptin receptor. This means that the cerebral cortex, the basal ganglia or thalamus play any role at all in modulating energy balance in the humans system. The sum of my writing here means that control of all energy balance, feeding, appetite, anorexia and obesity are all controlled by leptin function. This tight control is also then linked to the reward systems to drive behavior and it is also linked to the Parvo-cellular nucleus to control sex steroidogenesis and all endocrine function and fecundity to create a new generation of the species.

Another point I’d also like to make about these finding’s of Dr. Myers. In Dr. Lustigs, AHS 2011 lecture he mentioned the Melanocyte concentrating hormone binding receptors (MCH4 to be exact) and their linkage to leptin and insulin in the brain. What he told us about those tracts was certainly true in 2009, but in 2010 Dr. Myers new data showed that MCH4 role has now changed. The new data showed that the leptin receptor neurons in the lateral hypothalamic areas are quite distinct from the adjacent leptin-regulated neurons in the melanin concentrating hormone cluster. These neurons are biologically different and perform different functions and do not appear to be involved in obesity pathways at all. In 2009, this was not worked out. This was another reason why I was not accepting of the theory as it was presented to the AHS group at UCLA.

Dr. Lustig’s theory and Dr. Guyenet’s reward series have a lot in them that are correct and aid us all in understanding how obesity occurs. There is no doubt about this. But in science when we use the word always or never, or dominant, or non dominant, you can bet that some researcher or clinician somewhere will challenge that assertion with a new hypothesis and experiment. The work of Dr. Myers on leptin receptor biology and control put leptin as the “King of the Hill” with regards to obesity development. After studying this work for nearly 7 years as a neurosurgeon I became fully ready to accept its dominant position about three years ago. I did not write my Quilt document until I had read Dr. Myers work in its entirety. After doing so I put leptin at position two in my Quilt and I think I have laid out here in the last three blogs why I believe this to be true. I think obesity and anorexia are the sum quotient of the outflow of the neurochemical signals from the hypocretin neurons which are controlled directly by the leptin receptors’ biology.

Any theory on the dominant control of obesity must explain the neurobiology findings of these researchers work. What we learned here is the seat of control of energy metabolism is clearly delineated by these experiments. What the next step in researchers minds should be is how to clinically affect the leptin’s action to help people and disease whose biology is coupled to energy metabolism at its core. Examples of such conditions are anorexia, bulimia, osteoporosis, obesity, diabetes and aging. Dr. Ron Rosedale is one of those early pioneer’s and his work should be looked at closely and dissected. I think his theories are quite solid for healthy living, but I have two minor areas where I do not fully accept his thesis for optimal longevity. His book has some negative connotations for saturated fats and for protein intake. He is particularly concerned about the mTOR pathway being unregulated with moderate to high protein diets. This theory really separates himself from the work of his former partners, Dr’s. Eades of Protein Power fame.

This protein issue has been linked to shortened lifespans in many articles in the literature. The same is true of high carbohydrate diets that stimulate the IGF-1 pathways. Carbohydrates are broken down into two groups, high and low glycemic.  There are two other reasons why I think Rosedale’s thought might be superficial on mTOR and IGF 1 signaling.  The redox potential of the extracellular matrix is what opens the door to heaven or hell in this pathways, in my opinion.  Moreover, the 1930 studies Rosedale touts have never been reproduced in primates and they have not been reproducible in today’s modern world filled with non native energies that are fully capable of altering the redox potential of the extracellular matrix.  To my this is why I cannot get behind Rosedale’s idea’s 100{a7b724a0454d92c70890dedf5ec22a026af4df067c7b55aa6009b4d34d5da3c6}.   Both Dr. Rosedale and the “power couple Eades” are sour on both of these pathways.  Proteins are also broken into two groups. Those that are insulinogenic are called the branch chain amino acids proteins (BCCA) and the rest are made from unbranched amino acids (AA). Dr’s. Eades do not discriminate on proteins for his diet. Dr. Rosedale is not fan of protein at all in his diet. His diet is a high fat, low carb and low protein diet. The effect of neolithic diseases is directly proportional to aging. Neolithic disease increases as we age in all studies. So the diet we should advocate for humans is critical to us all. It also is clearly tied to this leptin story. An interesting aspect of the role of leptin in mTOR (levee 11) function is that within mature human adipocytes leptin synthesis itself is dependent on mTOR activation.  So that biologic fact alone tells me at the very least some protein is very helpful. How much is optimal is unknown. This supports Drs. Eades and the paleolithic diet for health and longevity. I believe the missing piece is DHA. This is why my template allows for natural development of ketosis while naturally restricting calories and increasing redox signaling.

Dr. Rosedale’s concerns are valid no doubt but not yet proven beyond a doubt. My mind on this issue remains very open. On this topic,  I won’t be dogmatic. I think telomere biologic studies and redox signaling of NAD+, along with calorie restriction studies will prove who’s theories are correct or not in the future.  One thing that we already do know from telomere biology that supports the use of protein in diets for longevity is that telomere lengths are increased when the diet is high in carnosine. The paleolithic diet has the highest level of carnosine in it. Carnosine is found in red meat that is grass fed. On the flip side of this issue is the calorie restriction data and the data found in lower animals to yeast. This strongly points to limiting protein and calories to extend lifespan.   This is why I believe the Epi-paleo Rx template matches our current environment much better for optimal performance and longevity.

Given these contradictions, I cannot in 2011, indict all proteins based upon what we know about leptin and mTor as it stands today. I personally believe that the best paleolithic diet for aging may eliminate the part of the macronutrients of carbs, proteins and fats that all decrease our telomere lengths. Right now this is completely unknown but the diet I eat uses this principle today. I think BCCA maybe the “bad side of protein” for neolithic disease development. But I don’t think the remaining AA that make the rest of proteins up are all bad. I think, like carbs, protein have the good and bad qualities. The same is true for fats. Sally Fallon and Dr. Mary Enig have shown this in their work. These are many years away from completion but they are being done now on humans and primates. These minor disagreements today may have huge implications for human aging and longevity recommendations for patients in the future, but I don’t believe any dogmatic statements can be made today based upon what we know now.

My quest is for a long healthy lifespan free of the neolithic diseases of aging. The reason should be obvious. I’m aging as I type, as we all are. If there are things we can do with dietary alterations as we age to extend lifespan and simultaneously limit disease we should consider these options. But one thing should be clear to you now. I believe leptin is king of the hill.

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  1. Cameron House August 29, 2011 at 8:04 pm - Reply

    Thanks Doc!

  2. Jonathan August 29, 2011 at 8:41 pm - Reply

    This is really great stuff, it is time to reread the quilt. I am curious how HCG interacts with leptin if it does at all. I think it binds the LH receptors or at least has most favord nation status with the LH receptors . You also mentioned on MDA that "HcG uncouples leptin", but we are not advanced enough to figure out exactly what that statement intended to convey. What do we know now about HCG that Dr Simeon could not have know in the '40's?

  3. Exceptionally Brash August 29, 2011 at 9:13 pm - Reply

    Do you have a reference with the viewpoints of Dr. Rosedale. I recall a couple of threads on Paleohacks. Thank you for this informative post.

  4. Jack August 29, 2011 at 9:19 pm - Reply

    Yes Dr. Rosedale diet book clearly lays our his beliefs. I own the book but I dont recommend it to my patients. I recommend Robb Wolf's book instead.

  5. v August 29, 2011 at 9:46 pm - Reply

    what damages the leptin receptors? do you have any theories on hot flashes? once professor de vany ventured a guess that they were caused by oxidative damage to the hypothalamus. his way is to take mega doses of antioxidants, which i remember you said interferes with signaling. he must have read what you wrote because he had a post up explaining why taking antioxidants did not in fact interfere with signaling.

  6. DrMommyN August 29, 2011 at 9:48 pm - Reply

    I understand that leptin sensitivity is very important to good health if leptin is "king" of our nutritional, metabolic, and endocrine status. What I'm trying to understand is how your Leptin RX accomplishes becoming leptin sensitive. Is it simply that we know the opposite (high carb, frequent snacking, insufficient protein or fat, chronic cardio) to cause leptin resistance? (I can see you cringing at the word simply.)

    How do you not get BCAA when eating meat? Or is it just pulling out the BCAA in supplement form that may be a detrimental form of protein?

  7. v August 29, 2011 at 10:00 pm - Reply

    for readers interested in how the mother's diet affects her baby's future metabolic health, this article was interesting:


  8. Cal August 30, 2011 at 12:42 am - Reply

    Concise and informative read, doc. Some of the most interesting health blog posts I've read anywhere. Gracias. Will be reading up on Dr Myer's work.

  9. Franco August 30, 2011 at 1:27 am - Reply


    But I wonder about the BCAA issue too! At least leucine seems a great driver of protein synthesis and as such does support muscle mass (which naturally declines with age). Declining muscle mass is responsible for making every day tasks harder for the elderly (e.g. move same weight – even if it's only a grocery bag – with less muscle fibers) and thus stressing the CV system more! How can retaining muscle then be bad?

  10. RJ August 30, 2011 at 9:55 am - Reply

    Didn't see the BCAA potentially being "bad" coming. I've taken them in the past to keep my body from catabolizing my muscles during a 24 hour fast. All I know is that, macronutrient-wise, my body loves protein and fat and only likes carbs in small amounts and NEVER unaccompanied.

    When I took the glucose tolerance test within 3 mins of drinking the glucose I felt weak and for 10 mins I sat in the waiting room feeling like I was going to pass out. (I assume from insulin flooding my veins and my blood sugar plummeting) When the 30 mins had elapsed and they took my blood again the feeling had passed and of course my curve ended up being normal. I'm a severely reactive hypoglycemic, I guess. Maybe I should have taken an insulin test instead?

    Your epigenetic posts make a lot of sense to me – both my mother and grandmother are diabetic and I was formula fed, so epigenetically I'm screwed. I control it with paleo diet and exercise and I feel great.

    • Jack August 30, 2011 at 5:48 pm - Reply

      RJ keep eating paleo. Until the data comes out that proves Dr Rosedale correct I can diss all protein. I think BCCA he is correct on. In his book he calls for a moderate protein approach but in several places in the book he also really downs red meat and almost sounds like a pescatarian. I really think his beef is with his former partners and their successes with the protein angle. I do think Dr. Rosedale was way before his time but what he believes is not totally proven as yet. He and I have gotten in to scraps over at Paleohacks but I dont think he realizes that I think he is 95% right. We are arguing over the 5% that science has not revealed as yet. He has a book to sell and I dont too……another factor.

  11. JRM August 30, 2011 at 5:45 pm - Reply

    Do you have an opinion on gelatin? BCAA comprise ~17% of the protein in muscle meat, but only ~7% of the protein in gelatin.

    • Jack August 30, 2011 at 5:40 pm - Reply

      @JRM Depends upon what you are using it for JRM. For healing a gut or osteoporosis I like it. If you have bad IR or T2D maybe not so much because it could spike your insulin. A blood glucometer would solve that issue with some post prandial testing

  12. Jack August 30, 2011 at 6:04 pm - Reply

    @Franco soon I will be writing about the BCCA issue. body builders will need to pay attn to it. This is why we don't see too many endurance athletes or body builders age well. Has a lot to do with AMPK pathway activation. When you live a life stimulating IGF-1 and mTOR you are not going to be around a long time. That defines endurance athletes and body builders.

  13. TMS71 August 30, 2011 at 8:25 pm - Reply

    Is it possible that highly rewarding food can decrease the sensitivity or number of leptin receptors?

    • Jack August 30, 2011 at 8:38 pm - Reply

      @TMS71 we already know what foods affect the leptin receptor and the neuropeptides associated with leptin signaling. NPY is the peptide is is heavily stimulated by foods that cause huge insulin spikes. Carbs are at the top of the list. So even Gary Taubes can be partially right here…….cause carbs can make you fat. But where he was off, was that its not the only way. The omega six pathway can too. Interestingly enough we can reset leptin sensitivity by avoiding carbs and PUFA's and limiting BCCA for about 6-8 weeks. This is laid out in my Leptin Rx for the reset. Then you can slowly reintroduce foods based upon how you tolerate them. Some need to avoid carbs a lot longer if they are sensitive to NPY because of how the gut incretin system is signaling the brain. Same thing with the obese with a large O6/O3 ratio prior to the reset. The BCCA issue can be found with a simple glucometer post prandial test done every 15 min for one hour.

  14. Dan H August 30, 2011 at 10:13 pm - Reply

    What protein foods do not contain BCAA's? Or should we just follow a Paleo diet and not worry about this…

    • Jack August 30, 2011 at 11:09 pm - Reply

      @DanH The foods that have high BCAA's are rye, meat, almonds, cashews, eggs, fish, chicken, chickpeas, lentils and liver. An example of this is chicken breast 113g (4oz) which has 2.5g of leucine, 1.7g of valine and 1.75g of isoleucine. I noticed the BCAA content when i took care of a body builder's spine who was eating lentils and was digging his muscle growth on them. Lentils are preferred by many bodybuilders for this reason. I'll pass on them

  15. Franco August 30, 2011 at 11:21 pm - Reply

    @Jack, you frighten me! Waiting for your further posts on this issue. How does IF (intermittend fasting) figure in?

    I checked Rosdale's www and have to say I don't like his diet. Among some good foods(fish, eggs, buffalo, bear(?)) there are: Seeds and nuts? Tofu? Veggie burgers? vegetable protein powder? Low fat cheese? Wasa fiber rye crackers?

    And allowance for beef and lamb (drip fat off???) sparingly but buffalo daily?

    Sounds like somebody got scared big time about SAFA halfway to paleo and decided to incorporate as much "conventional wisdom" items as possible. Not convincing!

  16. Franco August 30, 2011 at 11:29 pm - Reply

    Just read your last reply and thought "but Rosdale does endorse all that high BCAA-foods!" with the exception of lentils. Never hear before about the bodybuilder's lentil preference. Usually they eat chicken and rice.

  17. Dan H August 31, 2011 at 1:27 am - Reply

    So in other words, the optimal diet for reversing LR is low carb, high non-PUFA fat (like MCTs, saturated, omega-3's), and moderate protein while avoiding the highest BCAA containing foods?

    Its funny that chinese fast food actually turned out to be one of the worst foods in the world…its literally large portions of refined carbs (noodles, rice), heavy sauces/MSG, and tons of veggie oils. terrible stuff…

  18. TMS71 August 31, 2011 at 2:12 am - Reply

    Thanks doc. I was just wondering if there may be some evolutionary adaptation to take advantage of an environment that is rich in high calorie food sources. The idea being that an increased appetite in such an environment would lead to storing a great deal of body fat to protect against famine for the times when the environment is not so rich with high calorie food sources. I was wondering if the pleasure centers have any direct connection with the hypothalamic leptin receptors. I was thinking that the highly pleasurable consumption of high calorie density food may send messages directly to the hypothalamus that result in decreased leptin sensitivity so as to 'take advantage' of the availability of the high density energy sources in the environment by increasing appetite (via decreased leptin sensitivity). Its a reasonable hypothesis from an evolutionary perspective. I've no idea if its true though. You mentioned NPY via insulin spikes. But not all high density energy sources cause insulin spikes. Could it be that large game animals that were a bonanza of high energy density weren't clustered in the same way that fruit or tuber sources of energy were so we never evolved to decrease our leptin sensitivity (thereby increasing our short term appetite) in response to them?

    What I'm saying is that this decrease in leptin sensitivity is very likely an adaptation that conferred a survival advantage to our ancestors and if we understand its function it will give us insight into the details of how it works.

  19. Poisonguy August 31, 2011 at 3:48 am - Reply

    Leucine, a BCAA, is somewhat insulinergic (a 30 g dose raising insulin by 25 microU/mL). The most insulinergic amino acids are arginine (81 microU/mL), followed by lysine (52 microU/mL) and then followed by phenylalanine (28 microU/mL). Valine and isoleucine (the other two BCAA) are only slightly insulinergic (Floyd et al. Stimulation of insulin secretion by amino acids. 1966).

    Does anyone have a better reference?

    Jack, you didn't mention anything about BCAA in your Leptin Prescription post. So now I'm wondering how one can attain the 50 to 75 grams of protein you suggest for breakfast without meat or dairy or eggs (all high in BCAA)?

  20. Franco August 31, 2011 at 4:08 am - Reply


    interesting numbers. Now, who takes 30g Leucine at once? Most whey shakes have 2-2.5g/serving, BCAA powders usually 2.5g, 4 raw jumbo eggs according nutritiondata.com 2.7g.

    And what about glucagon which is concurrently elevated by proteins?

  21. Franco August 31, 2011 at 4:30 am - Reply

    Just found out that Floyd et al. used intravenous aminoacid administration, here's a better view on oral:


    They conclude:

    "In summary, an amount of arginine that should be present in a large beef protein meal, when ingested either alone or with glucose, does not increase the serum insulin concentration. However, it does stimulate an increase in glucagon. Arginine, when ingested with glucose, attenuates and prolongs the glucose and the insulin rise when compared with glucose ingestion alone. This attenuation is not caused by delayed gastric emptying. The mechanism remains to be determined. Overall, the present data indicate that the amount of arginine absorbed after ingestion of a mixed meal is not likely to contribute significantly to insulin secretion."

    Her is another study finding no change in plasma insuline levels after oral amino acids in infants:


  22. Jack August 31, 2011 at 6:28 am - Reply

    @Franco. If your read DR rosedales book his ideas are well thought out but then when you read the specifics of what he allows you to eat…..I have concerns. I think his diet is still very good for a diabetic but I'm not sure it's grea for a type 1.5 diabetic is is not heavy and has a hi HDL and lower triglyceride level than a straightforward type two diabetic. I think when you write a diet book it pigeon holes you to cover the 68 percent under the bell curve but it can not cover the tails of the curve.

  23. Jack August 31, 2011 at 6:32 am - Reply

    @ poison guy. Very few foods concentrate arginine. And arginine main affect is to increase igf 1 signaling over insulin alone. It is a potent muscle stimulator and has been used in medicine recently as a supplement for patients post op with muscle loss due to high cortisol levels that support muscle catabolism. It also plays a role on the ampk pathway but with regards to the leptin reset in the leptin Rx I don't think many foods have enough of this AA to male a huge difference. I use this AA in supplement form postoperatively in many catabolic or sarcopenic states just for this reason. Arginine also has a couple of other interesting effects. It increases nitric oxide formation so it improves blood flow so it's very helpful in recovery and diabetes and PAD. And specifically In diabetics it's an AA that is extremely sensitivity to glycation so if someone has high blood glucose or high hba1c it's acts as a glucose sump in the blood to decrease glycation. I use it in whopping doses because of this effect in neuropathy and cognitive decline

  24. Jack August 31, 2011 at 6:38 am - Reply

    @tms. I think it has more to do with evolutionary adaptations to seasonality. Carbs are more plentiful in spring and summer and this mechanism via gherkin, agouti, NPY and leptin allowed the animal to really capture this seasonal food source and store it as fat for the coming winter. Anotherinteresting hypothesis I have readmis that leptin resistance may have been biologically adaptive to the onset of the ice age because becoming leptin resistant first lead to insulin resistance and becoming insulin resistant allowed animals to survive better in colder temperatures because high blood glucose acted as an antifreeze substance in the blood. This has actually been seen in many current species like frogs and fish whomstill use this mechanism today to survive frozen lakes to live through winter.

  25. v August 31, 2011 at 7:21 am - Reply

    dr. k said: "This is why we don't see too many endurance athletes or body builders age well. "

    Prof. De Vany takes a lot of supplemental BCAAs and specifically arginine at night. he is aging very well. he also takes lots of antioxidant supplements, which you advocate against.

    from a study quoted by Franco above:

    "Overall, the present data indicate that the amount of arginine absorbed after ingestion of a mixed meal is not likely to contribute significantly to insulin secretion."

  26. Taylor August 31, 2011 at 1:49 pm - Reply

    Experimentally, the effect on leptin sensitivity could be compared of intravenous (flavorless) glucose to orally consumed glucose with a highly rewarding flavor. I don't think there is a direct human test of leptin sensitivity yet. But if there were I would guess that orally consumed, pleasing glucose would decrease leptin sensitivity more than IV glucose. I'm guessing that the activation of the pleasure centers via oral and olfactory taste/texture/aroma sensors play a role in the ratcheting up and down of leptin sensitivity with more stimulation decreasing it and less stimulation increasing it. I would love to see this tested.

  27. Taylor August 31, 2011 at 1:54 pm - Reply

    BTW I'm TMS71.

  28. moreporkplease August 31, 2011 at 2:02 pm - Reply

    On the BCCA/protein issue, I think we just have to say the science is mixed – muddy – not proven. We should just all be aware that it's a gray area, and watch for new developments, which could take several years or more to snap into focus. 🙂 I don't think we can even speculate about it very much, the data seems unclear. We just have to say "we don't know right now!"

  29. Jack August 31, 2011 at 2:08 pm - Reply

    @v. Think you misinterpreted what I said. Art and think very much alike about exercise and diet and aging. Art is no where close to a body builder. Some of the athletes I work with eat ridiculous amounts af bcca's and carbs. This will overstimulate both pathways and deplete their stem cells. Arginine is very stimulatory to igf1 but it does not cause a major insulin surge but glutamine used in many supplement regimes and in bone broths can be very insulinogenic. Depends upon how it affects your pancreas. Testing with a glucometer can sort it out.

  30. Jack August 31, 2011 at 2:12 pm - Reply

    Their are leptin receptors on our taste buds and on our olfactory groove and on our vagus nerve. So Taylor the brain is sensing what kind of food the senses are evaluating before we eat it. This why the taste of food changes dramatically once the reset occurs. The other reason this occurs is because with a high protein and fat diet we tend to increase or gut absorption of zinc which further sensitizes those sensory receptors further

  31. RJ August 31, 2011 at 4:09 pm - Reply

    re: "leptin receptors on our taste buds"

    Wow, that's interesting.

    I did a test once where I put a tablespoon of pepsi in my mouth for 15 secs and then spit. I had a mild but immediate (within mins) low blood sugar response. (see my earlier comment) Was never sure what it meant exactly and neither did my Dr. – if it was a cephalic reflex or learned (pavlovian) or what.

    • Jack August 31, 2011 at 4:40 pm - Reply

      2RJ That was leptin acting via the tenth cranial nerve. The vagus nerve. Leptin is king of the hill. When you understand how far it reaches you then have a 30,000 ft perspective of metabolism and you wont get lost in the forrest of calorie counting and macronutrient partitioning.

      And taste bud receptors is why we should not use artificial flavoring…….it fools the brain into expecting a different meal that arrives. The smell, sight or taste of a carbohydrate meal will stimulate the release of insulin before any food has entered the mouth……..not good. But that is how the body works. I did a test back in residency once……We showed pictures of gorgeous women to med students and measured their testosterone levels with a blood draw and they all went up. That is how fast the brain will respond. Leptin is exactly the same.

  32. livinlite August 31, 2011 at 4:52 pm - Reply

    RE: Endurance Activities – the Ironman/Marathon craze strikes me as one of those funny Western Civ things where folks think they are doing something good for their health, but are mostly running their bodies into the ground (literally). Even those who "appear healthy" are likely killing themselves from the inside out…adrenal fatigue, enlarged heart, etc…to say nothing of the effect of constantly relying on massive sugar-highs to pull you through the activity…aid stations every mile at most marathons loaded with sugar-water… Anyone ever wonder why prof. cyclists and runners don't live that long? It's probably even worse for amateurs who never develop the physiology to "handle" the stress/inflammation in the first place. Most 10min/mile guys running marathons are doing so with high-heartrates and constant sugar supply to avoid bonking. A recipe for disaster…down the road if not immediately.

    I'm glad I got off the endurance sports treadmill before I did even more damage to my adrenals/knees/heart.

    **all puns intended** lols

  33. Poisonguy September 1, 2011 at 2:47 am - Reply

    Hi Franco. I wasn't making any type of judgement call with my comment…just posting what I had. Thanks for the studies you provided.

    Hi Jack. Thanks for the feedback. I think the good provided by bone broths negate any potential insulinergic effect of the glutamine (I say potential because I've never seen a spike and I take bone broth daily).

    Still, you seem to recommend limiting BCAA in this post to help reset leptin, but made no mention of it back in your original post. Why is that? And how does that affect your recommendations concerning protein choice for breakfast (which are all high in BCAA)? Thanks.

  34. Franco September 1, 2011 at 11:36 pm - Reply


    I apologize if I sound to aggressive. It wasn't my intention. I really would like to know the answers to the questions I placed.

  35. Jack September 2, 2011 at 9:36 am - Reply

    @Franco no need to apologize. We are all here to learn and ask questions and optimize ourselves. There is no dogma in this. If there is then we become less than we might be!

  36. Jack October 10, 2011 at 12:23 am - Reply


    This article clearly lays out why leptin is in control and completely controls the reward tracts.

  37. Suzanne December 22, 2011 at 12:54 pm - Reply

    I'm a bit confused (as I tend to be)but in the above discussion of BCAAs yoou state "The foods that have high BCAA's are rye, meat, almonds, cashews, eggs, fish, chicken, chickpeas, lentils and liver. An example of this is chicken breast 113g (4oz) which has 2.5g of leucine, 1.7g of valine and 1.75g of isoleucine. I noticed the BCAA content when i took care of a body builder's spine who was eating lentils and was digging his muscle growth on them. Lentils are preferred by many bodybuilders for this reason. I'll pass on them."

    I know you and Robb Wolf both recommend meat, eggs, and fish and I believe organ meats (liver). Obviously not rye, checkpeas or lentils. At first glance, I would want to avaid all the food you list but that leave out many of the foods that you recommend.

    Sorry if this make no sense. I wish I could write it in German.

    • Jack December 22, 2011 at 12:59 pm - Reply

      @Suzanne of course I would not recommend these things……I just mention that these are the foods that have a lot of BCCA for completeness sake. My post script to the leptin Rx is clear……eat a primal template using the concepts I out line here.

  38. Mike david February 23, 2019 at 2:30 am - Reply

    Has any real progress been made regarding BCAA and AA from proteins? From what I can make out bcaa seems to be beneficial in a number of ways. They almost form a whole ring would that indicate your not far away from making a photon trap?

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