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Leptin: It probably doesn't do what you think it does.

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  • #16
    I am not a big fan of looking for a smoking gun, there are probably multiple smoking guns wrt obesity. I like to look at the hypothalamus as a detective trying to solve a case. A good detective like the hypothalamus will look at all of the evidence and come to a conclusion, and leptin isn't the only evidence. For one, there are so many more hormones related to appetite such as ghrelin, PYY, CCK, and others that pinpointing a single culprit is unlikely. Second, the hypothalamus doesn't only use hormones as evidence, it senses substrate and we also have to consider food reward centers in the brains as other possible culprits. Case in point, Malonyl CoA. Hypothalamic malonyl CoA plays a key role in lipogenesis and high levels of Malonyl CoA signal to the brain that energy is sufficient. It also increases faty acid oxidation and mitochondrial biogenesis. An increased level of ketones tends to increase Malonyl CoA which would certainly provide support for what we see in decreased appetite with a paleo/ketogenic diet, so you can't really say that improved leptin signaling is solely responsible for the benefits of a paleo diet. If you are eating a ton of carbs circulating malonyl CoA would drop because it would be used to synthesize fatty acids as that is it's primary function. I don't think the point is leptin resistance causes this and low Malonyl CoA causes that and PYY does this, it's that we are sending mixed signals to our hypothalamus and whatever is given priority is leading the hypothalamus to decide the evidence is pointing to a low energy state. If the responsibility of leptin is to tell the hypothalamus energy levels are good and it ignores that signal, either something else is perceived as a better indicator of energy balance or the system is broken, but we don't know which it is. It could very well be that leptin sensitivity is the culprit, but it could just as well be that something else that is associated with leptin levels is the culprit. As is said in these circles time and time again, correlation doesn't show causality.
    Last edited by Dave Mayo; 03-21-2012, 08:36 AM.

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    • #17
      ^^ Agree 100%
      Primal since March 2011

      Female/29 years old/5' 1"/130ish lbs

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      • #18
        First off, I'll say I agree with you partially. It is hard to say that leptin is the culprit for all of our problems given the complexity of our biochemistry. But leptin resistance due to high blood sugar is a real phenomenon, and, phrased in your analogy, could mean that the fuel gauge on your car is broken. It would trick you into thinking you don't have any fuel and you may overflow your tank in response, leading to car obesity.

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        • #19
          Thanks so much PK. I read the leptin reset parameters and they just ran up the red flags in my mind as being a bit illogical. Love the fuel light analogy and you have made real sense to me.
          Odille
          F 58 / 170cms / SW 131.5 kgs / Current 112.4/ GW 65
          following Primal Lifestyle and swimming my way to health

          My Primal Blog / Photo Blog / RedBubble shop / My Calendars / My Facebook

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          • #20
            Originally posted by BestBetter View Post
            I don't think anyone really understands most of what happens in the body or why, and honestly I don't think we really need to. We just need to eat real food.
            I absolutely agree. The human organism is so complex it is likely we will never understand all the cascade effects of tweaking this or that macro to achieve some poorly understood "benefit." To believe otherwise is pure hubris, IMO. It is what has turned us into a nation of serial pill-poppers who constantly need the next pill to undo the damage the first pill did.

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            • #21
              Originally posted by Analog6 View Post
              Thanks so much PK. I read the leptin reset parameters and they just ran up the red flags in my mind as being a bit illogical. Love the fuel light analogy and you have made real sense to me.
              Yeah, that's what I thought too. Plus if I read Kruse's words myself, I simply cannot follow him. He speaks in word salad - a big bowl of words. Not that following his ideas don't help people, just that he's not very good at communicating in my opinion and some of his ideas come across, I'm not sure how to put this, but as having more exclamation points than evidence.

              As for leptin itself, I've heard that it has a long term function, that it offers the body a long term signal about energy rather than a short term one. So it's not that immediately when your fuel reserves hit the red zone the signal goes off but that after a while it goes off because the reduced energy state has been around for a while. Hence the reason it's hard to go from obese to not obese and stay that way without a struggle.
              Female, 5'3", 50, Max squat: 202.5lbs. Max deadlift: 225 x 3.

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              • #22
                Originally posted by Anonymouse View Post
                First off, I'll say I agree with you partially. It is hard to say that leptin is the culprit for all of our problems given the complexity of our biochemistry. But leptin resistance due to high blood sugar is a real phenomenon, and, phrased in your analogy, could mean that the fuel gauge on your car is broken. It would trick you into thinking you don't have any fuel and you may overflow your tank in response, leading to car obesity.
                Oh, I'm not saying it doesn't exist, and I agree it could mean the gauge is broken, but it certainly doesn't mean it is broken. The real question is how does it happen. If it's primarily a receptor downregulation dealio then yes, it's probably a broken gauge. If it's "Leptin's telling me there's enough energy and some other factor is telling me there isn't", the mere fact that the hypothalamus is ignoring the leptin signal is telling me that the information leptin is sending isn't as important as something else. Even if it is receptor downregulation this could still be the issue. The only thing we can say for sure is that our bodies do not do well on a surplus of energy, and this is probably the only point in our history that this has become an issue.

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                • #23
                  Originally posted by otzi View Post
                  Great Bro-Science, but I would suggest going to Google Scholar, type in some keywords like, Leptin, Obesity, Leptin-resistance, etc...
                  Luckily, I am well versed in the art of ad hominem argumentation, enough so that I can recognize it with ease. Calling my argument "Bro-Science" in no way invalidates it. It would be nice if you would specifically address anything that I said in my original post. Anything at all. Anything? Beuller?

                  Perhaps you skimmed my original post a bit quickly and missed the part where I indicated that I was about to make an argument from analogy? Or maybe your understanding of "analogy" differs fundamentally from mine? In any event, when I intend to make an argument from biochemistry, I will label it as such in order to help you and others identify it. That was my intent for part 2 of this, but if I need to accelerate my schedule and address some things now, then so be it. Thank you for your search tips, by the way. It may surprise you to learn that I'm actually quite proficient with Google Scholar. As proof of this, you may look at my posts on intermittent fasting, or check out my post on leptin on my blog. Be warned, however, that it is substantially longer than my original post.

                  I just pulled this from Google Scholar for instance.

                  The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS “feeding” circuitry—the brainstem, hypothalamus and distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy.
                  Keywords Leptin – Leptin receptors – Obesity
                  I don't know how this abstract that you pulled supports your argument, such as it is, so I've gone and highlighted some salient bits that actually support mine.

                  First, there are two types of leptin genetic mutations, one in the leptin that you produce, the other in the leptin receptor that is expressed in the hypothalamus ( I limit myself to the hypothalamic receptor, b/c that's the one responsible for affecting metabolism and appetite ).

                  Ob/Ob Mouse Model : Defective Leptin

                  The Ob/Ob mouse has a recessive mutation in the gene that encodes for the leptin peptide that results in a base pair substitution that truncates the leptin molecule. This renders it incapable of binding to and activating the leptin receptor in the hypothalamus. This type of leptin deficiency can be addressed by injecting recombinant leptin into the organism, much in the same way that insulin is injected to compensate for the malfunctioning pancreatic beta cells.

                  Db/Db Mouse Model : Defective Leptin Receptor

                  This recessive mutation results in a malformed receptor in the hypothalamus which means that effectively, despite producing copious amounts of leptin, the brain is blind to leptin. This condition cannot be addressed by administration of exogenous leptin, rather, you need to somehow reengineer the receptors in the brain, which is rather more difficult than producing recombinant leptin. This is what "the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date" means.

                  Once you get beyond the background information and the theorizing of the abstract, you are left with the facts as those researchers know them:
                  1. In a few unlucky humans with a genetic mutation, leptin driven morbid obesity starts from an early age. It doesn't sneak up on you in middle age.
                  2. If you happen to have the human version of the Db/Db mutation, there is nothing they can do for you, short of growing you a new hypothalamus
                  3. The only clinical successes that exist are in those cases where the subjects don't produce leptin, but were injected with exogenous leptin


                  Note that these facts say absolutely nothing about the development of "late onset leptin resistance", probably because there is no such thing. The researchers assume / theorize that the role of leptin is to decrease appetite and increase metabolic rate. This assumption does not jibe with the observation that you can have high circulating leptin levels and normal appetite and metabolic rate. This then forces them to start inventing explanations for the data, and that's the genesis of the leptin resistance hypothesis.

                  I question the base assumption that the role of leptin is to stimulate metabolism and curb appetite. I do not question the existence of leptin, nor the biochemical pathways of its action. I do not need to do so. I leave that intact. What I do say, is that if we reverse the direction of the base assumption, that the role of leptin signalling is not to make us thin ( which is pure wishful thinking, by the way ) but rather to make us fat. Fat enough to survive periods of uncertain food availability. With this assumption, all known data about leptin makes sense. I do not need to invent a new hypothesis to explain the data away. I can explain why Ob/Ob and Db/Db mice and humans exhibit the behaviour and phenotype that they do. Moreover, I can also easily explain normal mice and humans with high circulating leptin levels with the exact same framework. If you subscribe to Occam's Razor, that in itself is enough to select my assumed role for leptin in fat metabolism.

                  -PK
                  Last edited by pklopp; 03-21-2012, 01:22 PM.
                  My blog : cogitoergoedo.com

                  Interested in Intermittent Fasting? This might help: part 1, part 2, part 3.

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                  • #24
                    Google Scholar still needs to time to mature as an "academic" resource, IMO.
                    If you have a problem with what you read: 1. Get a dictionary 2. Don't read it 3. Grow up 4. After 3, go back to 1/ or 2. -- Dennis Blue. | "I don't care about your opinion, only your analysis"- Professor Calabrese. | "Life is more important than _______" - Drew | I eat animals that eat vegetables -- Matt Millen, former NFL Linebacker. | "This country is built on sugar & shit that comes in a box marinated in gluten - abc123

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                    • #25
                      Originally posted by Drea6681 View Post
                      thank you. Day two of my leptin reset and I am walking away. I'm sorry, I just don't think 6 slices of bacon, 4 eggs, and lots of butter is healthy unless you spend 5 hours at the gym.
                      When the leptin reset thing was the new craze, I decided to experiment with two components of it: big breakfast and no snacking. I have no reason to believe I have any sort of leptin resistence or anything, but I was curious to see what these things would do for managing appetite.

                      I found I couldn't do 50g of protein for breakfast without trimming fat. It was just too darned much food for me to eat. Eggs and some relatively lean meat could get me there. As it is, I seem happy with more like 30-35g of protein at breakfast and a bit of fat. It keeps me going for a good 5-7 hours until lunch.

                      The no-snacking idea seems pretty solid to me. It makes sense to let your insulin levels subside after eating. It also matches the way our ancestors ate, too. Does that mean it has anything to do with changing the way my leptin receptors work? I have no idea.

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                      • #26
                        Originally posted by DaisyEater View Post
                        When the leptin reset thing was the new craze, I decided to experiment with two components of it: big breakfast and no snacking. I have no reason to believe I have any sort of leptin resistence or anything, but I was curious to see what these things would do for managing appetite.

                        I found I couldn't do 50g of protein for breakfast without trimming fat. It was just too darned much food for me to eat. Eggs and some relatively lean meat could get me there. As it is, I seem happy with more like 30-35g of protein at breakfast and a bit of fat. It keeps me going for a good 5-7 hours until lunch.

                        The no-snacking idea seems pretty solid to me. It makes sense to let your insulin levels subside after eating. It also matches the way our ancestors ate, too. Does that mean it has anything to do with changing the way my leptin receptors work? I have no idea.
                        yeah my thoughts exactly. This morning was just way too much fat and I still didn't meet the protein requirement. However, it's now 7 hours later and Im not remotely hungry so take from that what you will. lol
                        SW175ish GW140 CW157

                        height 5'6"

                        Official for real start date 1/10/12

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                        • #27
                          Ok so here is my take on it- the leptin reset is similar in some ways to the Zone diet albeit with fewer carbs. My experience of the Zone over many years was that yes, eating the animal based protein based breakfast did shut off my hunger and did allow me to eat less, but as time this became a system of diminishing returns as I probably developed low leptin and at one pt may have veered in a little bit of anorexia- ie, chronic undereating.

                          From what I've read grains like wheat contain lectins that damage leptin signalling so that even if you eat less ??-- you may or may not be able to, it really becomes more a willpower thing- your brain will not read that you have been nourished/fed and will keep you fat. So it really isn't that wheat is any higher in calories.

                          I've wondered since wandering on to this forum if I need to go back to breakfast to "reset my leptin" but I already did that a decade and yes it helps but.............. just eating primally, no matter what time of day, seems to be what makes the difference for me. I've found eliminating carbs a few days a week (while it is still cold out- I agree with Dr. Kruse about that totally) has helped a lot. I woke up today refreshed at 6 without an alarm

                          Going back to the Zone, Barry Sears says that avoiding "carb hell" helps balance *eicosanoids*- this is the reason for being able to wake up refreshed.

                          Honestly just not so sure how worthwhile the leptin theory is apart from don't eat wheat and grains and don't eat carbs, eat primally, you will not be as hungry and automatically eat less, but also buy yourself some extra nutritious calories in case you want to eat more, which on occasion you might.

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                          • #28
                            Originally posted by DaisyEater View Post
                            When the leptin reset thing was the new craze, I decided to experiment with two components of it: big breakfast and no snacking. I have no reason to believe I have any sort of leptin resistence or anything, but I was curious to see what these things would do for managing appetite.

                            I found I couldn't do 50g of protein for breakfast without trimming fat. It was just too darned much food for me to eat. Eggs and some relatively lean meat could get me there. As it is, I seem happy with more like 30-35g of protein at breakfast and a bit of fat. It keeps me going for a good 5-7 hours until lunch.

                            The no-snacking idea seems pretty solid to me. It makes sense to let your insulin levels subside after eating. It also matches the way our ancestors ate, too. Does that mean it has anything to do with changing the way my leptin receptors work? I have no idea.
                            +1. It needn't get more complicated than that. Kruse is certainly onto something, however he over-engineers his solutions and needs to work harder on popularising his scientific arguments for the layman. Even for the initiated, his blog posts also come across as stream of consciousness and very chaotic.

                            He's totally right about the high protein breakfast, IMO, but 30g is enough for me.
                            F 5 ft 3. HW: 196 lbs. Primal SW (May 2011): 182 lbs (42% BF)... W June '12: 160 lbs (29% BF) (UK size 12, US size 8). GW: ~24% BF - have ditched the scales til I fit into a pair of UK size 10 bootcut jeans. Currently aligning towards 'The Perfect Health Diet' having swapped some fat for potatoes.

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                            • #29
                              Originally posted by paleo-bunny View Post
                              Even for the initiated, his blog posts also come across as stream of consciousness and very chaotic.
                              .
                              Wow that reminds me of someone.......
                              Primal since March 2011

                              Female/29 years old/5' 1"/130ish lbs

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                              • #30
                                After nearly a year of IF I've lost weight around my mid section and am actually smaller than I was on breakfast so no, breakfast isn't the key.

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